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Sample records for infection-mediated inflammation-induced tumorigenesis

  1. Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice.

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    Barashi, Neta; Weiss, Ido D; Wald, Ori; Wald, Hanna; Beider, Katia; Abraham, Michal; Klein, Shiri; Goldenberg, Daniel; Axelrod, Jonathan; Pikarsky, Eli; Abramovitch, Rinat; Zeira, Evelyne; Galun, Eithan; Peled, Amnon

    2013-09-01

    Human hepatocellular carcinoma (HCC) is an inflammation-induced cancer, which is the third-leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation-induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2-KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2-KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24(+) oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size. Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment. © 2013 by the American Association for the Study of Liver Diseases.

  2. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    NARCIS (Netherlands)

    Jurk, Diana; Wilson, Caroline; Passos, Joao F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia L. F.; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    2014-01-01

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-kappa B induces premature ageing in mice. We also show that these mice have reduced regenerati

  3. Nuclear receptors : mediators and modifiers of inflammation-induced cholestasis

    NARCIS (Netherlands)

    Mulder, Jaap; Karpen, Saul J.; Tietge, Uwe J. F.; Kuipers, Folkert

    2009-01-01

    Inflammation-induced cholestasis (IIC) is a frequently occurring phenomenon. A central role in its pathogenesis is played by nuclear receptors (NRs). These ligand-activated transcription factors not only regulate basal expression of hepatobiliary transport systems, but also mediate adaptive response

  4. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    NARCIS (Netherlands)

    Jurk, Diana; Wilson, Caroline; Passos, Joao F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia L. F.; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    2014-01-01

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-kappa B induces premature ageing in mice. We also show that these mice have reduced regenerati

  5. Inflammation-induced preterm lung maturation: lessons from animal experimentation.

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    Moss, Timothy J M; Westover, Alana J

    2016-10-20

    Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified that an increase in pulmonary surfactant production by the preterm lungs likely underlies this decreased risk of RDS in infants exposed to chorioamnionitis. Further animal experimentation has shown that infectious or inflammatory agents in amniotic fluid exert their effects on lung development by direct effects within the developing respiratory tract, and probably not by systemic pathways. Differences in the effects of intrauterine inflammation and glucocorticoids demonstrate that canonical glucocorticoid-mediated lung maturation is not responsible for inflammation-induced changes in lung development. Animal experimentation is identifying alternative lung maturational pathways, and transgenic animals and cell culture techniques will allow identification of novel mechanisms of lung maturation that may lead to new treatments for the prevention of RDS.

  6. Ambient oxygen promotes tumorigenesis.

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    Ho Joong Sung

    Full Text Available Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53-/- mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53-/- mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo.

  7. Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

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    Objective: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Treatments: Fo...

  8. Tart cherry anthocyanins suppress inflammation-induced pain behavior in rat.

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    Tall, Jill M; Seeram, Navindra P; Zhao, Chengshui; Nair, Muraleedharan G; Meyer, Richard A; Raja, Srinivasa N

    2004-08-12

    The use of complementary and alternative medicine (CAM) has increased in the United States and more patients are seeking CAM therapies for control of pain. The present investigation tested the efficacy of orally administered anthocyanins extracted from tart cherries on inflammation-induced pain behavior in rats. Paw withdrawal latency to radiant heat and paw withdrawal threshold to von Frey probes were measured. The first set of experiments examined the effects of tart cherry anthocyanins (400 mg/kg) on the nociceptive behaviors and edema associated with inflammation induced by intraplantar injection of 1% carrageenan. These studies also included tests of motor coordination. The second set of experiments determined if tart cherry anthocyanins (15, 85, and 400 mg/kg) dose-dependently affected the inflammation induced by intraplantar injection of 25% complete Freund's adjuvant. We found that tart cherry extracts reduce inflammation-induced thermal hyperalgesia, mechanical hyperalgesia and paw edema. The suppression of thermal hyperalgesia was dose-dependent and the efficacy of highest dose (400 mg/kg) was similar to indomethacin (5 mg/kg). The highest dose anthocyanin (400 mg/kg) had no effects on motor function. These data suggest that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain. The antihyperalgesic effects may be related to the anti-inflammatory and antioxidant properties of anthocyanins. A better understanding of the modulatory role of dietary constituents and phytonutrients on pain will offer further therapeutic options for treating patients with persistent and chronic pain conditions.

  9. Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

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    Kiraly, Orsolya; Gong, Guanyu; Olipitz, Werner; Muthupalani, Sureshkumar; Engelward, Bevin P.

    2015-01-01

    Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence. PMID:25647331

  10. MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination.

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    Yu, Zhongwang; Sun, Dingya; Feng, Jifeng; Tan, Weixing; Fang, Xue; Zhao, Ming; Zhao, Xiaolin; Pu, Yingyan; Huang, Aijun; Xiang, Zhenghua; Cao, Li; He, Cheng

    2015-04-22

    The major challenge for progressive multiple sclerosis therapy is the promotion of remyelination from inflammation-induced demyelination. A switch from an M1- to an M2-dominant polarization of microglia is critical in these repair processes. In this study, we identified the homeobox gene msh-like homeobox-3 (Msx3) as a new pivotal regulator for microglial polarization. MSX3 was induced during microglia M2 polarization and repressed in M1 cells. The expression of MSX3 in microglia was dynamically regulated during experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. The overexpression of MSX3 in microglia promoted M2 but impeded M1 polarization. Interrupting MSX3 expression in microglia accelerated inflammation-induced demyelination and neurodegeneration. The conditioned medium from MSX3-transduced microglia promoted oligodendrocyte progenitor survival, differentiation, and neurite outgrowth. The adoptive transfer of MSX3-transduced microglia suppressed EAE and facilitated remyelination within the murine CNS in EAE and the LPC model. Mechanically, chromatin immunoprecipitation assays also indicated that MSX3 directly regulated three key genes associated with microglia M2 polarization, including Pparg, Stat6, and Jak3. Importantly, we found that overexpression of MSX3 in human-derived microglia represents the M2 phenotype and ameliorated EAE after intraventricular injection. Our findings suggest a new homeobox protein-dependent mechanism for driving microglia M2 polarization and identify MSX3 as an attractive therapeutic approach for preventing inflammation-induced demyelination and promoting remyelination.

  11. Secreted Frizzled-Related Protein 2 and Inflammation-Induced Skeletal Muscle Atrophy.

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    Zhu, Xiaoxi; Kny, Melanie; Schmidt, Franziska; Hahn, Alexander; Wollersheim, Tobias; Kleber, Christian; Weber-Carstens, Steffen; Fielitz, Jens

    2017-02-01

    In sepsis, the disease course of critically ill patients is often complicated by muscle failure leading to ICU-acquired weakness. The myokine transforming growth factor-β1 increases during inflammation and mediates muscle atrophy in vivo. We observed that the transforming growth factor-β1 inhibitor, secreted frizzled-related protein 2, was down-regulated in skeletal muscle of ICU-acquired weakness patients. We hypothesized that secreted frizzled-related protein 2 reduction enhances transforming growth factor-β1-mediated effects and investigated the interrelationship between transforming growth factor-β1 and secreted frizzled-related protein 2 in inflammation-induced atrophy. Observational study and prospective animal trial. Two ICUs and research laboratory. Twenty-six critically ill patients with Sequential Organ Failure Assessment scores greater than or equal to 8 underwent a skeletal muscle biopsy from the vastus lateralis at median day 5 in ICU. Four patients undergoing elective orthopedic surgery served as controls. To search for signaling pathways enriched in muscle of ICU-acquired weakness patients, a gene set enrichment analysis of our recently published gene expression profiles was performed. Quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry were used to analyze secreted frizzled-related protein 2 expression and protein content. A mouse model of inflammation-induced skeletal muscle atrophy due to polymicrobial sepsis and cultured myocytes were used for mechanistic analyses. None. Gene set enrichment analysis uncovered transforming growth factor-β1 signaling activation in vastus lateralis from ICU-acquired weakness patients. Muscular secreted frizzled-related protein 2 expression was reduced after 5 days in ICU. Likewise, muscular secreted frizzled-related protein 2 expression was decreased early and continuously in mice with inflammation-induced atrophy. In muscle, secreted frizzled-related protein 2

  12. Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

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    Letitia Wong

    Full Text Available Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show-for the first time-that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process.

  13. Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

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    Wegner, Alexander; Elsenbruch, Sigrid; Rebernik, Laura; Roderigo, Till; Engelbrecht, Elisa; Jäger, Marcus; Engler, Harald; Schedlowski, Manfred; Benson, Sven

    2015-01-01

    Abstract A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P pain thresholds were significantly decreased in the LPS condition (all P visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes. PMID:26058036

  14. Hyperglycemia, tumorigenesis, and chronic inflammation.

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    Chang, Shu-Chun; Yang, Wei-Chung Vivian

    2016-12-01

    Hyperglycemia is the most prominent sign that characterizes diabetes. Hyperglycemia favors malignant cell growth by providing energy to cancer cells. Clinical studies also showed an increased risk of diabetes being associated with different types of cancers. In addition, poorly regulated glucose metabolism in diabetic patients is often found with increased levels of chronic inflammatory markers, e.g., interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, and emerging evidence has highlighted activation of the immune response in the progression and development of cancer cells. Therefore, uncontrolled proinflammatory responses could conceivably create a chronic inflammatory state, promoting a tumor-favorable microenvironment and potentially triggering immune overactivation and cancer growth. To further understand how hyperglycemia contributes to immune overactivation, the tumor microenvironment and the development of chronic inflammation-associated tumors may provide insights into tumor biology and immunology. This paper provides a brief introduction to hyperglycemia-associated diseases, followed by a comprehensive overview of the current findings of regulatory molecular mechanisms of glycosylation on proteoglycans in the extracellular matrix under hyperglycemic conditions. Then, the authors discuss the role of hyperglycemia in tumorigenesis (particularly in prostate, liver, colorectal, and pancreatic cancers), as well as the contribution of hyperglycemia to chronic inflammation. The authors end with a brief discussion on the future perspectives of hyperglycemia/tumorigenesis and potential applications of alternative/effective therapeutic strategies for hyperglycemia-associated cancers.

  15. The Carcinogenic Agent Azoxymethane (AOM) Enhances Early Inflammation-induced Colon Crypt Pathology

    DEFF Research Database (Denmark)

    Venning, Freja Albjerg; Claesson, Mogens Helweg; Kissow, Hannelouise

    2013-01-01

    mice and SCID mice with transfer colitis. AOM by itself did result in neither weight loss nor inflammation although treatment affected crypt widths and numbers. Although AOM together with T cell transfer did not increase the level of gut inflammation including COX-2 expression, AOM increased crypt......Severe combined immunodeficiency (SCID) mice transplanted with CD4+ T cells depleted of CD25+ regulatory T cells develop colitis within 2-3 weeks after the T cell transfer. In the present study we studied the effect of the carcinogen azoxymethane (AOM) on the colon crypt pathology of normal SCID...... changes associated with colon inflammation such as a decline in crypt numbers and an increase in crypts width throughout the large intestine. Thus it appears that AOM lower the threshold level for inflammation-induced changes which potentially may lead to neoplasia....

  16. Inflammation induced by infection potentiates tau pathological features in transgenic mice.

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    Sy, Michael; Kitazawa, Masashi; Medeiros, Rodrigo; Whitman, Lucia; Cheng, David; Lane, Thomas E; Laferla, Frank M

    2011-06-01

    Comorbidities that promote the progression of Alzheimer's disease (AD) remain to be uncovered and evaluated in animal models. Because elderly individuals are vulnerable to viral and bacterial infections, these microbial agents may be considered important comorbidities that could potentiate an already existing and tenuous inflammatory condition in the brain, accelerating cognitive decline, particularly if the cellular and molecular mechanisms can be defined. Researchers have recently demonstrated that triggering inflammation in the brain exacerbates tau pathological characteristics in animal models. Herein, we explore whether inflammation induced via viral infection, compared with inflammation induced via bacterial lipopolysaccharide, modulates AD-like pathological features in the 3xTg-AD mouse model and provide evidence to support the hypothesis that infectious agents may act as a comorbidity for AD. Our study shows that infection-induced acute or chronic inflammation significantly exacerbates tau pathological characteristics, with chronic inflammation leading to impairments in spatial memory. Tau phosphorylation was increased via a glycogen synthase kinase-3β-dependent mechanism, and there was a prominent shift of tau from the detergent-soluble to the detergent-insoluble fraction. During chronic inflammation, we found that inhibiting glycogen synthase kinase-3β activity with lithium reduced tau phosphorylation and the accumulation of insoluble tau and reversed memory impairments. Taken together, infectious agents that trigger central nervous system inflammation may serve as a comorbidity for AD, leading to cognitive impairments by a mechanism that involves exacerbation of tau pathological characteristics. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

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    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  18. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

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    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

  19. Analgesic effect of minocycline in rat model of inflammation-induced visceral pain.

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    Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N

    2014-03-15

    The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5min of administration, systemic injection of the drug produced a delayed effect (60min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. TLRs, Alcohol, HCV, and Tumorigenesis

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    Keigo Machida

    2010-01-01

    Full Text Available Chronic liver damage caused by viral infection, alcohol, or obesity can result in increased risk for hepatocellular carcinoma (HCC. Ample epidemiological evidence suggests that there is a strong synergism between hepatitis C virus (HCV and alcoholic liver diseases (ALD. The Toll-like receptor (TLR signaling pathway is upregulated in chronic liver diseases. Alcoholism is associated with endotoxemia that stimulates expression of proinflammatory cytokine expression and inflammation in the liver and fat tissues. Recent studies of HCC have centered on cancer-initiating stem cell (CSC, including detection of CSC in cancer, identification of CSC markers, and isolation of CSC from human HCC cell lines. Synergism between alcohol and HCV may lead to liver tumorigenesis through TLR signaling.

  1. Synergistic Effect of Green Tea Polyphenols and Vitamin D on Chronic Inflammation-Induced Bone Loss in Female Rats

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    Our recent study demonstrated a bone-protective role of green tea polyphenols (GTPs), extracted from green tea, in chronic inflammation-induced bone loss of female rats through reduction of inflammation and oxidative stress. This study further examines effects of GTPs in conjunction with vitamin D (...

  2. Inflammation-induced changes in BKCa currents in cutaneous dorsal root ganglion neurons from the adult rat

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    Zhang Xiu-Lin

    2012-07-01

    Full Text Available Abstract Background Inflammation-induced sensitization of primary afferents is associated with a decrease in K+ current. However, the type of K+ current and basis for the decrease varies as a function of target of innervation. Because glabrous skin of the rat hindpaw is used often to assess changes in nociception in models of persistent pain, the purpose of the present study was to determine the type and extent to which K+ currents contribute to the inflammation-induced sensitization of cutaneous afferents. Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion neurons from naïve and inflamed (3 days post complete Freund’s adjuvant injection rats were studied with whole cell and perforated patch techniques. Results Inflammation-induced sensitization of small diameter cutaneous neurons was associated with an increase in action potential duration and rate of decay of the afterhyperpolarization. However, no changes in voltage-gated K+ currents were detected. In contrast, Ca2+ modulated iberiotoxin sensitive and paxilline sensitive K+ (BKCa currents were significantly smaller in small diameter IB4+ neurons. This decrease in current was not associated with a detectable change in total protein levels of the BKCa channel α or β subunits. Single cell PCR analysis revealed a significant change in the pattern of expression of α subunit splice variants and β subunits that were consistent, at least in part, with inflammation-induced changes in the biophysical properties of BKCa currents in cutaneous neurons. Conclusions Results of this study provide additional support for the conclusion that it may be possible, if not necessary to selectively treat pain arising from specific body regions. Because a decrease in BKCa current appears to contribute to the inflammation-induced sensitization of cutaneous afferents, BKCa channel openers may be effective for the treatment of inflammatory pain.

  3. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

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    Mercado Ramon

    2011-01-01

    Full Text Available Abstract Background Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results Intraplantar Complete Freund's Adjuvant (CFA produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX, an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a is transient, (b driven by peripheral input resulting from the injury, (c dependent on TRPV1 positive

  4. Correlation of TLR4 and KLF7 in Inflammation Induced by Obesity.

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    Wang, Cuizhe; Ha, Xiaodan; Li, Wei; Xu, Peng; Gu, Yajuan; Wang, Tingting; Wang, Yan; Xie, Jianxin; Zhang, Jun

    2017-02-01

    Objective Recent studies have revealed a link between toll-like receptors (TLRs), Kruppel-like factors (KLFs), and the adipose tissue inflammation associated with obesity. TLR4 is associated with chronic inflammation in obesity. KLF7 is known to play an important role in the differentiation of adipocytes, but its role in visceral adipose tissue inflammation has not yet been investigated. Thus, the objective of this study was to determine the correlation of TLR4 and KLF7 in inflammation induced by obesity. Methods A total of 32 Wistar male rat subjects were fed in the center for experimental animals of Shihezi University. The rats were divided into normal control (NC) and high-fat diet (HFD) group. Surgical instruments were used to collect rats' visceral adipose tissue samples in the 10th week after HFD feeding. Ninety-five Uygur subjects between 20 and 90 years old were enrolled in the present study. The subjects were divided into two groups: the normal control group (NC, 18.0 kg/m(2) ≤ BMI ≤ 23.9 kg/m(2), n = 50) and the obesity group (OB, BMI ≥ 28 kg/m(2), n = 45), and visceral adipose tissue was collected from the subjects. Anthropometric and clinical parameters were measured using standard procedures; biochemical indices were detected using the glucose oxidase-peroxidase method and a standardized automatic biochemistry analyzer; the plasma levels of inflammatory factors and adipocytokines were measured by enzyme-linked immunosorbent assay (ELISA); the mRNA and protein expression levels of key genes involved in the inflammatory signaling pathway were measured by real-time PCR and Western blot. Results In rats, compared with the NC group, the weight, Lee's index, waist circumference, visceral fat mass, and the plasma level of Glu, TG, FFA, and TNF-α were higher in the HFD group, while the plasma levels of LPT and APN were significantly lower in the HFD group in the 10th week. Furthermore, compared with the NC group, visceral adipose

  5. Sex differences in severity of inflammation-induced anorexia and weight loss.

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    Lennie, Terry A

    2004-04-01

    Food intake and body weight changes in response to induction of acute inflammation were examined in intact cycling females, ovariectomized females, and sham-operated male rats. In intact females, body weight and feeding responses were compared between rats in which inflammation was induced on day of estrus with rats in which inflammation was induced on day of diestrus. Anorexia and weight loss were more severe in the female rats with inflammation induced on estrus day, which coincides with peak serum estrogen levels. In ovariectomized females, inflammation was induced the day after rats received injections of estrogen, progesterone, or sesame oil (vehicle). Males received vehicle injections. Among female rats, the group that received estradiol injections the previous day displayed the most severe anorexia. The least severe anorexia was observed in female rats that received progesterone the previous day. Food intake of female rats that received vehicle injections prior to induction of inflammation was greater than the rats receiving estrogen but less than the rats receiving progesterone. Male rats displayed the most severe anorexia and greatest weight loss. These data suggest that, although females exposed to estradiol prior to induction of acute inflammation display more severe anorexia than those exposed to progesterone, it may be that progesterone attenuates severity of anorexia rather than estrogen solely potentiating severity. Male rats, however, appear to experience the most severe anorexia in response to this form of inflammation.

  6. Cordycepin (3'-deoxyadenosine) down-regulates the proinflammatory cytokines in inflammation-induced osteoporosis model.

    Science.gov (United States)

    Zhang, Da-wei; Wang, Zhen-lin; Qi, Wei; Lei, Wei; Zhao, Guang-yue

    2014-08-01

    The effect of cordycepin (3'-deoxyadenosine) on inflammation-induced osteoporosis (IMO) was studied in this paper. After the rats were treated orally with cordycepin (20 mg/kg), serum osteocalcin (OC), homocysteine (HCY), C-terminal cross-linked telopeptides of collagen type I (CTX), maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), they were examined by ELISA or immunohistochemistry. The specimens from the liver were also processed for light microscopic examination. The IMO rats showed a significant increase in plasma CTX, MDA, PMN, IL-1β, TNF-α, and nitrate levels as well as a significant decrease in plasma OC. These changes were attenuated by cordycepin (20 mg/kg) supplementation in the IMO rats. Examination of the liver specimens revealed mononuclear cell infiltration in the portal areas in the IMO rats which was not detected in the cordycepin (20 mg/kg) rats. These results suggest that cordycepin may act as an anti-inflammatory agent in magnesium silicate-induced inflammation in osteoporosis.

  7. Type I interferons regulate susceptibility to inflammation-induced preterm birth

    Science.gov (United States)

    Cappelletti, Monica; Presicce, Pietro; Lawson, Matthew J.; Chaturvedi, Vandana; Stankiewicz, Traci E.; Vanoni, Simone; Harley, Isaac T.W.; McAlees, Jaclyn W.; Giles, Daniel A.; Moreno-Fernandez, Maria E.; Rueda, Cesar M.; Senthamaraikannan, Paranth; Karns, Rebekah; Hoebe, Kasper; Janssen, Edith M.; Karp, Christopher L.; Hildeman, David A.; Hogan, Simon P.; Kallapur, Suhas G.; Chougnet, Claire A.; Way, Sing Sing

    2017-01-01

    Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection–driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern–driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge–driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk. PMID:28289719

  8. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    Directory of Open Access Journals (Sweden)

    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  9. Euflammation attenuates peripheral inflammation-induced neuroinflammation and mitigates immune-to-brain signaling.

    Science.gov (United States)

    Liu, Xiaoyu; Nemeth, Daniel P; Tarr, Andrew J; Belevych, Natalya; Syed, Zunera W; Wang, Yufen; Ismail, Ahmad S; Reed, Nathaniel S; Sheridan, John F; Yajnik, Akul R; Disabato, Damon J; Zhu, Ling; Quan, Ning

    2016-05-01

    Peripheral inflammation can trigger a number of neuroinflammatory events in the CNS, such as activation of microglia and increases of proinflammatory cytokines. We have previously identified an interesting phenomenon, termed "euflammation", which can be induced by repeated subthreshold infectious challenges. Euflammation causes innate immune alterations without overt neuroimmune activation. In the current study, we examined the protective effect of euflammation against peripheral inflammation-induced neuroinflammation and the underlying mechanisms. When Escherichia coli or lipopolysaccharide (LPS) was injected inside or outside the euflammation induction locus (EIL), sickness behavior, global microglial activation, proinflammatory cytokine production in the brain, expression of endothelial cyclooxygenase II and induction of c-fos expression in the paraventricular nucleus of the hypothalamus were all attenuated in the euflammatory mice compared with those in the control unprimed mice. Euflammation also modulated innate immunity outside the EIL by upregulating receptors for pathogen-associated molecular patterns in spleen cells. In addition, euflammation attenuated CNS activation in response to an intra-airpouch (outside the EIL) injection of LPS without suppressing the cytokine expression in the airpouch. Collectively, our study demonstrates that signaling of peripheral inflammation to the CNS is modulated dynamically by peripheral inflammatory kinetics. Specifically, euflammation can offer effective protection against both bacterial infection and endotoxin induced neuroinflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Matrine protects neuro-axon from CNS inflammation-induced injury.

    Science.gov (United States)

    Kan, Quan-Cheng; Lv, Peng; Zhang, Xiao-Jian; Xu, Yu-Ming; Zhang, Guang-Xian; Zhu, Lin

    2015-02-01

    Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of β-amyloid (Aβ) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS.

  11. Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

    Science.gov (United States)

    Wegner, Alexander; Elsenbruch, Sigrid; Rebernik, Laura; Roderigo, Till; Engelbrecht, Elisa; Jäger, Marcus; Engler, Harald; Schedlowski, Manfred; Benson, Sven

    2015-10-01

    A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P pain thresholds were significantly decreased in the LPS condition (all P pain sensitization in both sexes.

  12. Anaplastic thyroid cancer, tumorigenesis and therapy.

    LENUS (Irish Health Repository)

    O'Neill, J P

    2010-03-01

    Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.

  13. The roles of PIKE in tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Qi QI; Keqiang YE

    2013-01-01

    Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints usually placed upon their growth and survival.To ensure the integrity of organs and tissues,the balance of cell proliferation and cell death is tightly maintained.The proteins controlling this balance are either considered oncogenes,which promote tumorigenesis,or tumor suppressors,which prevent tumorigenesis.Phosphoinositide 3-kinase enhancer (PIKE) is a family of GTP-binding proteins that possess anti-apoptotic functions and play an important role in the central nervous system.Notably,accumulating evidence suggests that PIKE is a proto-oncogene involved in tumor progression.The PIKE gene (CENTG1) is amplified in a variety of human cancers,leading to the resistance against apoptosis and the enhancement of invasion.In this review,we will summarize the functions of PIKE proteins in tumorigenesis and discuss their potential implications in cancer therapy.

  14. DNA Methylation in Thyroid Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Stephen, Josena K., E-mail: jstephe2@hfhs.org [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, Detroit, MI 48202 (United States); Chitale, Dhananjay [Department of Pathology, Henry Ford Hospital, Detroit, MI 48202 (United States); Narra, Vinod [Essex Surgical Associates, PC, Beverly, MA 01915 (United States); Chen, Kang Mei; Sawhney, Raja; Worsham, Maria J. [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, Detroit, MI 48202 (United States)

    2011-03-29

    Thyroid cancer is the most common endocrine cancer with 1,690 deaths each year. There are four main types of which the papillary and follicular types together account for >90% followed by medullary cancers with 3% to 5% and anaplastic carcinomas making up <3%. Epigenetic events of DNA hypermethylation are emerging as promising molecular targets for cancer detection. Our immediate and long term goal is to identify DNA methylation markers for early detection of thyroid cancer. This pilot study comprised of 21 patients to include 11 papillary thyroid cancers (PTC), 2 follicular thyroid cancers (FTC), 5 normal thyroid cases, and 3 hyperthyroid cases. Aberrant promoter methylation was examined in 24 tumor suppressor genes using the methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) assay and in the NIS gene using methylation-specific PCR (MSP). The frequently methylated genes were CASP8 (17/21), RASSF1 (16/21) and NIS (9/21). In the normal samples, CASP8, RASSF1 and NIS were methylated in 5/5, 4/5 and 1/5 respectively. In the hyperthyroid samples, CASP8, RASSF1 and NIS were methylated in 3/3, 2/3 and 1/3 respectively. In the thyroid cancers, CASP8, RASSF1, and NIS were methylated in 9/13, 10/13, and 7/13 respectively. CASP8, RASSF1 and NIS were also methylated in concurrently present normal thyroid tissue in 3/11, 4/11 and 3/11 matched thyroid cancer cases (matched for presence of both normal thyroid tissue and thyroid cancer), respectively. Our data suggests that aberrant methylation of CASP8, RASSF1, and NIS maybe an early change in thyroid tumorigenesis regardless of cell type.

  15. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

    Science.gov (United States)

    Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

    2010-12-01

    Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc

  16. Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells.

    Science.gov (United States)

    Manerba, Marcella; Di Ianni, Lorenza; Govoni, Marzia; Roberti, Marinella; Recanatini, Maurizio; Di Stefano, Giuseppina

    2017-01-01

    The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues. In cancer cells, lactate was recently found to directly increase migration ability; moreover, when released in the microenvironment, it can facilitate matrix remodeling. In this paper, we illustrate that treatment of human colon adenocarcinoma cells with TNF-α and IL-17, two pro-inflammatory cytokines, modifies LDH activity, causing a shift toward the A isoform which results in increased lactate production. At the same time, the two cytokines appeared to induce features of epithelial-mesenchymal transition in the treated cells, such as reduction of E-cadherin levels and increased secretion of metalloproteinases. Noteworthy, oxamate and galloflavin, two inhibitors of LDH activity which reduce lactate production in cells, were found to relieve the inflammation-induced effects. These results suggest LDH-A and/or lactate as common elements at the cross-road between cancer cell metabolism, tumor progression and inflammation. At present, LDH inhibitors suitable for clinical use are actively searched as possible anti-proliferative agents; our data lead to hypothesize for these compounds a wider potential in anticancer treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Inflammation induces multinucleation of Microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells.

    Science.gov (United States)

    Hornik, Tamara C; Neniskyte, Urte; Brown, Guy C

    2014-03-01

    Microglia are brain macrophages, which can undergo multinucleation to give rise to multinucleated giant cells that accumulate with ageing and some brain pathologies. However, the origin, regulation and function of multinucleate microglia remain unclear. We found that inflammatory stimuli, including lipopolysaccharide, amyloid β, α-synuclein, tumour necrosis factor-α and interferon γ, but not interleukin-4, induced multinucleation of cultured microglia: primary rat cortical microglia and the murine microglial cell line BV-2. Inflammation-induced multinucleation was prevented by a protein kinase C (PKC) inhibitor Gö6976 (100 nM) and replicated by a PKC activator phorbol myristate acetate (160 nM). Multinucleation was reversible and not because of cell fusion or phagocytosis, but rather failure of cytokinesis. Time-lapse imaging revealed that some dividing cells failed to abscise, even after formation of long cytoplasmic bridges, followed by retraction of bridge and reversal of cleavage furrow to form multinucleate cells. Multinucleate microglia were larger and 2-4 fold more likely to phagocytose large beads and both dead and live PC12 cells. We conclude that multinucleate microglia are reversibly generated by inflammation via PKC inhibition of cytokinesis, and may have specialized functions/dysfunctions including the phagocytosis of other cells. Inflammation resulted in the accumulation of multiple nuclei per cell in cultured microglia. This multinucleation was reversible and due to a PKC-dependent block of the last step of cell division. Multinucleate microglia were larger and had a greater capacity to phagocytose other cells, suggesting they might remove neurons in the brain. © 2013 International Society for Neurochemistry.

  18. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    Science.gov (United States)

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

  19. Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

    Science.gov (United States)

    Nakamura, Masuo; Wada, Hiroo; Honda, Kojiro; Nakamoto, Keitaro; Inui, Toshiya; Sada, Mitsuru; Watanabe, Masato; Takata, Saori; Yokoyama, Takuma; Saraya, Takeshi; Kurai, Daisuke; Ishii, Haruyuki; Goto, Hajime; Kamma, Hiroshi; Takizawa, Hajime

    2015-12-01

    Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. The role of carnitine on ovariectomy and inflammation-induced osteoporosis in rats.

    Science.gov (United States)

    Orsal, Ebru; Halici, Zekai; Bayir, Yasin; Cadirci, Elif; Bilen, Habib; Ferah, Irmak; Aydin, Ali; Ozkanlar, Seckin; Ayan, Arif Kursad; Seven, Bedri; Ozaltin, Seda

    2013-12-01

    This study was carried out to assess the protective bone-sparing effect of carnitine with anti-inflammatory properties on chronic inflammation-induced bone loss in ovariectomised (OVX) rats. A total of 64 rats were divided into eight groups. Sixteen rats were sham-operated (SH) while the others were ovariectomised (OVX). (1) SH, (2) sham + inflammation (SHinf), (3) OVX, (4) ovariectomy + inflammation (OVXinf), (5) OVX + CAR1, (6) OVX + CAR2, (7) OVXinf + CAR1, (8) OVXinf + CAR2. After the ovariectomy surgery, all the groups (3, 4, 5, 6, 7, and 8) were allowed to recover for two months. Sixty days after the OVX, inflammation was induced by subcutaneous injections of talc in groups 2, 4, 7, and 8. Group 5 and 7 were given 50 mg/kg CAR; Group 6 and 8 were given 100 mg/kg CAR from the 60th to the 80th day. Serum levels of TNF-α, IL-1, IL-6, OP, and OC were assessed to determine inflammation and to evaluate osteoblastic activity. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry in femur bones of rats. Carnitine administration was able to restore BMD up to values measured in both the OVX and the SH animals. The serum levels of TNF-α, IL-1β, and IL-6 were increased significantly in the OVXinf rats compared with the SH group. In OVX rats, inflammation which is evaluated by serum cytokine levels exacerbated this bone loss, as supported by values of BMD of the total femur. The two different doses of carnitine reduced bone loss and improved inflammatory biomarkers.

  1. Complexity, dynamic cellular network, and tumorigenesis.

    Science.gov (United States)

    Waliszewski, P

    1997-01-01

    A holistic approach to tumorigenesis is proposed. The main element of the model is the existence of dynamic cellular network. This network comprises a molecular and an energetistic structure of a cell connected through the multidirectional flow of information. The interactions within dynamic cellular network are complex, stochastic, nonlinear, and also involve quantum effects. From this non-reductionist perspective, neither tumorigenesis can be limited to the genetic aspect, nor the initial event must be of molecular nature, nor mutations and epigenetic factors are mutually exclusive, nor a link between cause and effect can be established. Due to complexity, an unstable stationary state of dynamic cellular network rather than a group of unrelated genes determines the phenotype of normal and transformed cells. This implies relativity of tumor suppressor genes and oncogenes. A bifurcation point is defined as an unstable state of dynamic cellular network leading to the other phenotype-stationary state. In particular, the bifurcation point may be determined by a change of expression of a single gene. Then, the gene is called bifurcation point gene. The unstable stationary state facilitates the chaotic dynamics. This may result in a fractal dimension of both normal and tumor tissues. The co-existence of chaotic dynamics and complexity is the essence of cellular processes and shapes differentiation, morphogenesis, and tumorigenesis. In consequence, tumorigenesis is a complex, unpredictable process driven by the interplay between self-organisation and selection.

  2. The gut microbiome modulates colon tumorigenesis.

    Science.gov (United States)

    Zackular, Joseph P; Baxter, Nielson T; Iverson, Kathryn D; Sadler, William D; Petrosino, Joseph F; Chen, Grace Y; Schloss, Patrick D

    2013-11-05

    Recent studies have shown that individuals with colorectal cancer have an altered gut microbiome compared to healthy controls. It remains unclear whether these differences are a response to tumorigenesis or actively drive tumorigenesis. To determine the role of the gut microbiome in the development of colorectal cancer, we characterized the gut microbiome in a murine model of inflammation-associated colorectal cancer that mirrors what is seen in humans. We followed the development of an abnormal microbial community structure associated with inflammation and tumorigenesis in the colon. Tumor-bearing mice showed enrichment in operational taxonomic units (OTUs) affiliated with members of the Bacteroides, Odoribacter, and Akkermansia genera and decreases in OTUs affiliated with members of the Prevotellaceae and Porphyromonadaceae families. Conventionalization of germfree mice with microbiota from tumor-bearing mice significantly increased tumorigenesis in the colon compared to that for animals colonized with a healthy gut microbiome from untreated mice. Furthermore, at the end of the model, germfree mice colonized with microbiota from tumor-bearing mice harbored a higher relative abundance of populations associated with tumor formation in conventional animals. Manipulation of the gut microbiome with antibiotics resulted in a dramatic decrease in both the number and size of tumors. Our results demonstrate that changes in the gut microbiome associated with inflammation and tumorigenesis directly contribute to tumorigenesis and suggest that interventions affecting the composition of the microbiome may be a strategy to prevent the development of colon cancer. The trillions of bacteria that live in the gut, known collectively as the gut microbiome, are important for normal functioning of the intestine. There is now growing evidence that disruptive changes in the gut microbiome are strongly associated with the development colorectal cancer. However, how the gut microbiome

  3. Inhibition of lung tumorigenesis by tea.

    Science.gov (United States)

    Yang, Chung S; Liao, Jie; Yang, Guang-yu; Lu, Gary

    2005-01-01

    Tea and tea constituents have been shown by different investigators to inhibit lung tumorigenesis in different animal model systems. This includes lung tumorigenesis in A/J mice induced by 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), N-nitrosodiethylamine, benzo[a]pyrene, N-nitrosomethylurea, or cisplatin. Inhibition of lung tumorigenesis has also been demonstrated in C3H mice treated with N-nitrosodiethylamine. In most of these experiments, reduction in tumor number and tumor size has been observed in the tea-treated group, and in some experiments, decreased tumor incidence has also been observed. The green tea constituent, epigallocatechin-3-gallate (EGCG), and the black tea constituent, theaflavins, have also been shown to be effective. Black tea preparations have been shown to reduce the incidence and number of spontaneously generated lung adenocarcinomas and rhabdomyosarcoma in A/J mice, as well as inhibit the progression of lung adenoma to adenocarcinoma. The mechanisms for the inhibitory action have not been well elucidated. It may be related to the antiproliferative, proapoptotic, and antiangiogenic activities of tea constituents that have been demonstrated in some experiments. These activities may be a result of the inhibition of key protein kinases involved in signal transduction and cell cycle regulation. Tea catechins, such as EGCG, have been suggested to be the effective components. However, a study suggests that caffeine is the key effective constituent for the inhibitory activity of lung tumorigenesis in Fisher 344 rats by black tea. In many of the experiments, tea consumption resulted in the reduction of body fat and body weight; these factors may also contribute to the inhibition of tumorigenesis.

  4. Herpes Virus Entry Mediator Signaling in the Brain Is Imperative in Acute Inflammation-Induced Anorexia and Body Weight Loss

    Directory of Open Access Journals (Sweden)

    Kwang Kon Kim

    2013-09-01

    Full Text Available BackgroundReduced appetite and body weight loss are typical symptoms of inflammatory diseases. A number of inflammatory stimuli are responsible for the imbalance in energy homeostasis, leading to metabolic disorders. The herpes virus entry mediator (HVEM protein plays an important role in the development of various inflammatory diseases, such as intestinal inflammation and diet-induced obesity. However, the role of HVEM in the brain is largely unknown. This study aims to investigate whether HVEM signaling in the brain is involved in inflammation-induced anorexia and body weight loss.MethodsFood intake and body weight were measured at 24 hours after intraperitoneal injection of lipopolysaccharide (LPS or intracerebroventricular injection of recombinant mouse LIGHT (also called tumor necrosis factor receptor superfamily 14, TNFSF14, an HVEM ligand, into 8- to 10-week-old male C57BL/6 mice and mice lacking HVEM expression (HVEM-/-. We also assessed LPS-induced change in hypothalamic expression of HVEM using immunohistochemistry.ResultsAdministration of LPS significantly reduced food intake and body weight, and moreover, increased expression of HVEM in the hypothalamic arcuate nucleus. However, LPS induced only minor decreases in food intake and body weight in HVEM-/- mice. Administration of LIGHT into the brain was very effective at decreasing food intake and body weight in wild-type mice, but was less effective in HVEM-/- mice.ConclusionActivation of brain HVEM signaling is responsible for inflammation-induced anorexia and body weight loss.

  5. Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.

    Science.gov (United States)

    Nilsson, Anna; Wilhelms, Daniel Björk; Mirrasekhian, Elahe; Jaarola, Maarit; Blomqvist, Anders; Engblom, David

    2017-03-01

    Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

  6. Menin represses tumorigenesis via repressing cell proliferation

    OpenAIRE

    Wu, Ting; Hua, Xianxin

    2011-01-01

    Multiple endocrine neoplasia type 1 (MEN1) results from mutations in the tumor suppressor gene, MEN1, which encodes nuclear protein menin. Menin is important for suppressing tumorigenesis in various endocrine and certain non-endocrine tissues. Although menin suppresses MEN1 through a variety of mechanisms including regulating apoptosis and DNA repair, the role of menin in regulating cell proliferation is one of the best-studied functions. Here, we focus on reviewing various mechanisms underly...

  7. Inactivating CUX1 mutations promote tumorigenesis

    OpenAIRE

    2013-01-01

    A major challenge for cancer genetics is to determine which low frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers to identify novel drivers and find inactivating mutations in the homeodomain transcription factor CUX1 (cut-like homeobox 1) in ~1-5% of tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical si...

  8. Role of Mesenchymal Stem Cells In Tumorigenesis

    Science.gov (United States)

    2009-08-01

    stem cells ( BMDC ), which then acts in a paracrine fashion on the cancer cells to enhance their invasion [7]. Interestingly the group of Karnoub showed...AD_________________ AWARD NUMBER: W81XWH-08-1-0523 TITLE: Role of Mesenchymal Stem Cells in...DATES COVERED 1 Aug 2008 – 31 Jul 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Role of Mesenchymal Stem Cells in Tumorigenesis 5b. GRANT

  9. An Anti-Inflammatory Sterol Decreases Obesity-Related Inflammation-Induced Insulin Resistance and Metabolic Dysregulation

    Directory of Open Access Journals (Sweden)

    Chris L. Reading

    2013-01-01

    Full Text Available Obesity-related inflammation-induced insulin resistance and metabolic dysregulation were investigated in retrospective analysis of placebo hematologic and metabolic laboratory data from trials associated with increasing chronic low-grade inflammation and body mass index. Studies included healthy subjects and those with progressive stages of metabolic dysregulation, including type 2 diabetes mellitus with uncontrolled hemoglobin A1c. Intrasubject variances in erythroid and metabolic values increased with metabolic dysregulation. Random effects were demonstrated in treatment-naïve diabetes for erythroid, glucose, and HbA1c fluctuations. The anti-inflammatory insulin sensitizer, HE3286, was tested for its ability to decrease obesity-related inflammation-induced insulin resistance and metabolic dysregulation in diabetes. HE3286 significantly decreased erythroid and metabolic variances and improved 1,5-anhydroglucitol (a surrogate of postprandial glucose compared to the placebo group. HE3286 HbA1c decrease correlated with weight loss and inversely with baseline monocyte chemoattractant protein-1 (MCP-1 in metformin-treated diabetics. Normalization of HbA1c to the 84-day average hemoglobin revealed that HE3286 HbA1c decrease correlated with high baseline MCP-1 and MCP-1 decrease in treatment-naïve diabetics. HE3286 decreased insulin resistance, increased the frequency of decreased day 84 HbA1c in metformin-treated subjects, and decreased day 112 HbA1c in treatment-naïve diabetics. HE3286 may be useful to restore metabolic homeostasis in type 2 diabetes.

  10. Innate lymphoid cells involve in tumorigenesis.

    Science.gov (United States)

    Tian, Zhiqiang; van Velkinburgh, Jennifer C; Wu, Yuzhang; Ni, Bing

    2016-01-01

    Innate lymphoid cells (ILCs) promptly initiate cytokine responses to pathogen exposure in the mucosa and mucosal-associated lymphoid tissues. ILCs were recently categorized as being of the lymphoid lineage and have been classified into three groups. ILCs play important roles in immunity against pathogens, and an anti-tumor immune-related function was recently demonstrated. In this review we discuss whether and how ILCs involve in the tumorigenesis, providing new insights into the mechanisms underlying the particular functions of ILCs as well as the potential targets for tumor intervention.

  11. Effects of Administration of Amlodipine and Lacidipine on Inflammation-Induced Bone Loss in the Ovariectomized Rat.

    Science.gov (United States)

    Karakus, Emre; Halici, Zekai; Albayrak, Abdulmecit; Bayir, Yasin; Demirci, Elif; Aydin, Ali; Ozturk-Karagoz, Berna; Cadirci, Elif; Ayan, Arif Kursat; Sahin, Ali; Unal, Deniz

    2016-02-01

    This study was performed to evaluate the possible protective effect of two calcium channel blocker's "lacidipine (LAC) and amlodipine (AML)" on bone metabolism in an experimental ovariectomized and inflammation-induced osteoporosis rat model (OVXinf). For the purpose of this study, the rats were divided into eight groups, each containing eight rats: sham-operated control (group 1, SH), sham + inflammation (group 2, SHinf), ovariectomy (group 3, OVX), ovariectomy + inflammation (group 4, OVXinf), ovariectomy + LAC 4 mg/kg (group 5, OVX + LAC), ovariectomy + inflammation + LAC 4 mg/kg (group 6, OVXinf + LAC), ovariectomy + AML 5 mg/kg (group 7, OVX + AML), ovariectomy + inflammation + AML 5 mg/kg (group 8, OVXinf + AML). The levels of osteocalcin and osteopontin decreased in OVXinf + LAC and OVXinf + AML groups. The serum levels of TNF-α, IL-1β, and IL-6 were increased significantly in the OVXinf rats compared with the SH group. Gene expression levels of the osteogenic factor runt-related transcription factor 2 (Runx2) and type I collagen 1A1 (Col1A1) significantly decreased in the OVXinf group, when compared with the control group. AML or LAC administrations increased the levels of Runx2 and Col1A1. These results suggest that amlodipine and lacidipine may be a novel therapeutic target for radical osteoporosis treatment in hypertensive patients.

  12. Interaction of ozone exposure with airway hyperresponsiveness and inflammation induced by trimellitic anhydride in sensitized guinea pigs

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Jian; Chung, K.Fan [National Heart & Lung Institute, London (United Kingdom)

    1997-09-01

    The effect of prior ozone (O{sub 3}) exposure on airway hyperresponsiveness and inflammation induced by trimellitic anhydride (TMA) has been investigated in TMA-sensitized guinea pigs. Airway responsiveness was measured as the concentration of acetylcholine needed to increase baseline lung resistance (RL) by 300% (PC300). Ozone (3 ppm, for 3 h) caused an increase in-log PC300 at 1 h after exposure, with return of -log PC300 to control levels at 8 h. Ozone also increased baseline RL at 8 h. TMA challenge increase -log PC300 in TMA-sensitized guinea pigs at 8 h after challenge from 3.85 {+-} 0.09 to 4.11 {+-} 0.09. Ozone exposure prior to TMA challenge prevented the induction of airway hyperresponsiveness with a mean -log PC300 of 3.51 {+-} 0.20, which was not different from that of control TMA-Sensitized group. Baseline RL was significantly higher in ozone-pretreated animals after TMA challenge when compared to those of either control or challenged with TMA alone. Ozone had no effect on TMA challenge-induced BAL eosinophilia and neutrophilia. We conclude that a single exposure to ozone inhibits the increase in airway responsiveness, but increases the bronchoconstrictor response induced by TMA in TMA-Sensitized guinea pigs; however, the inflammatory airway response to TMA is unchanged by preexposure to ozone. 29 refs., 2 figs., 1 tab.

  13. Roles of sphingosine 1-phosphate on tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Hsinyu; Lee

    2011-01-01

    Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with a variety of biological activities.It is generated from the conversion of ceramide to sphingosine by ceramidase and the subsequent conversion of sphingosine to S1P,which is catalyzed by sphingosine kinases.Through increasing its intracellular levels by sphingolipid metabolism and binding to its cell surface receptors,S1P regulates several physiological and pathological processes,including cell proliferation,migration,angiogenesis and autophagy.These processes are responsible for tumor growth,metastasis and invasion and promote tumor survival.Since ceramide and S1P have distinct functions in regulating in cell fate decision,the balance between the ceramide/sphingosine/S1P rheostat becomes a potent therapeutic target for cancer cells.Herein,we summarize our current understanding of S1P signaling on tumorigenesis and its potential as a target for cancer therapy.

  14. The role of menin in parathyroid tumorigenesis.

    LENUS (Irish Health Repository)

    Davenport, Colin

    2009-01-01

    Primary hyperparathyroidism is a common disorder that involves the pathological enlargement of one or more parathyroid glands resulting in excessive production of parathyroid hormone (PTH). The exact pathogenesis of this disease remains to be fully understood. In recent years interest has focussed on the interaction between menin protein and the transforming growth factor (TGF)-beta\\/Smad signalling pathway. In vitro experimentation has demonstrated that the presence of menin is required for TGF-beta to effectively inhibit parathyroid cell proliferation and PTH production. This observation correlates with the almost universal occurrence of parathyroid tumors accompanying the inactivation of menin in multiple endocrine neoplasia Type 1 (MEN1) syndrome and the high rate of somatic menin gene mutations seen in sporadic parathyroid adenomas. This chapter aims to review the role of menin in primary hyperparathyroidism and parathyroid hormone-regulation, including the influences of MEN1 gene mutations on parathyroid cell proliferation, differentiation and tumorigenesis.

  15. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Jianxin Lu; Lokendra Kumar Sharma; Yidong Bai

    2009-01-01

    Alterations in oxidative phosphorylation resulting from mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA (mtDNA) mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.

  16. Maternal Omega-3 Supplement Improves Dopaminergic System in Pre- and Postnatal Inflammation-Induced Neurotoxicity in Parkinson's Disease Model.

    Science.gov (United States)

    Delattre, Ana Marcia; Carabelli, Bruno; Mori, Marco Aurélio; Kempe, Paula G; Rizzo de Souza, Luiz E; Zanata, Silvio M; Machado, Ricardo B; Suchecki, Deborah; Andrade da Costa, Belmira L S; Lima, Marcelo M S; Ferraz, Anete C

    2017-04-01

    Evidence suggests that idiopathic Parkinson's disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.

  17. Involvement of spinal somatostatin receptor SST(2A) in inflammation-induced thermal hyperalgesia: ultrastructural and behavioral studies in rats.

    Science.gov (United States)

    Zhao, Jun; Hu, Jiang-Yuan; Zhang, Yu-Qiu; Zhao, Zhi-Qi

    2008-10-01

    Our previous results have shown that somatostatin receptor subtype SST(2A) is responsible for thermal, but not mechanical nociceptive transmission in the rat spinal cord. The present study was undertaken to further examine the ultrastructural localization of SST(2A) receptor in lamina II of the spinal dorsal horn and the role of SST(2A) receptor in thermal hyperalgesia following Complete Freund's Adjuvant (CFA)-induced inflammation. We found that SST(2A) receptors in lamina II are located primarily in postsynaptic dendrites and soma, but not in axons or synaptic terminals. CFA-induced inflammation markedly increased SST(2A) receptor-like immunoreactivity in lamina II. Paw withdrawal latency (PWL) evoked by noxious heating was obviously shortened 1 h after intraplantar injection of CFA, exhibiting thermal hyperalgesia. Pre-blocking SST(2A) activity by intrathecal pre-administration of CYN154806, a broad-spectrum antagonist of SST(2) receptor, or specific antiserum against SST(2A) receptor (anti-SST(2A)) significantly attenuated thermal hyperalgesia in a dose-dependent fashion in CFA-treated rats. But, administration of anti-SST(2A) or CYN154806 after CFA treatment had no effect upon thermal hyperalgesia. Intrathecal application of SST(2A) agonist SOM-14 at different doses prior to CFA treatment did not influence thermal hyperalgesia in inflamed rats, but at a low dose shortened PWL evoked by noxious heating in normal rats. These results suggest that spinal SST(2A) receptors play a key role in triggering the generation, but not maintenance, of thermal hyperalgesia evoked by CFA-induced inflammation. The up-regulation of SST(2A) receptors in the spinal cord may be one of the mechanisms underlying inflammation-induced thermal hyperalgesia.

  18. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Directory of Open Access Journals (Sweden)

    Argel Aguilar-Valles

    Full Text Available Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  19. Class I to III histone deacetylases differentially regulate inflammation-induced matrix metalloproteinase 9 expression in primary amnion cells.

    Science.gov (United States)

    Poljak, Marin; Lim, Ratana; Barker, Gillian; Lappas, Martha

    2014-06-01

    Matrix metalloproteinase (MMP) 9 plays an important role in the degradation of the extracellular matrix in fetal membranes, and pathological activation of MMP-9 can lead to preterm birth. In nongestational tissues, modulation of histone deacetylases (HDACs) regulates MMP-9 expression. The aim of this study was to determine whether class I to III HDACs regulate MMP-9 expression and activity in primary amnion cells. Class I and II HDAC regulation of MMP-9 was assessed using the general class I and II HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), the class I HDACi MS-275, and the class II HDACi MC1568. Class III HDAC regulation of MMP-9 was assessed using the SIRT1 activators resveratrol and SRT1720 as well as SIRT1 small interfering RNA (siRNA). Primary amnion epithelial cells were incubated with 1 ng/mL interleukin (IL) 1β in the absence or presence of 0.3 μmol/L TSA, 5 μmol/L SAHA, 2.5 μmol/L MS-275, 2.5 μmol/L MC1568, 50 μmol/L resveratrol, or 10 μmol/L SRT1720 for 20 hours. We found that the class I and II HDACi TSA and SAHA and the class II HDACi MC1568 significantly decreased IL-β-induced MMP-9 gene and pro-MMP-9 expression in primary amnion cells. There was, however, no effect of the class I HDACi MS-275 on IL-β-induced MMP-9 expression. On the other hand, inhibition of class III HDAC SIRT1 using siRNA significantly augmented IL-1β-induced MMP-9, and SIRT1 activation using resveratrol and SRT1720 inhibited IL-1β-induced MMP-9 expression. In summary, class I to III HDACs differentially regulate inflammation-induced MMP-9 expression in primary amnion cells.

  20. Protective role of µ opioid receptor activation in intestinal inflammation induced by mesenteric ischemia/reperfusion in mice

    Science.gov (United States)

    Francesca, Saccani; Laura, Anselmi; Jaramillo, Ingrid; Simona, Bertoni; Elisabetta, Barocelli; Sternini, Catia

    2012-01-01

    Intestinal ischemia is a clinical emergency with high morbidity and mortality. We investigated whether activation of µ opioid receptor (µOR) protects from the inflammation induced by intestinal ischemia and reperfusion (I/R) in mice. Ischemia was induced by occlusion of the superior mesenteric artery (45 min) and followed by reperfusion (5 hours). Sham Operated (SO) and normal (N) mice served as controls. Each group received subcutaneously: (1) saline solution; (2) the µOR selective agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (0.01 mg.kg−1); (3) DAMGO and the selective µOR antagonist [H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2] (CTAP) (0.1 mg.kg−1) or (4) CTAP alone. I/R induced intestinal inflammation as indicated by histological damage and the significant increase in myeloperoxidase (MPO) activity, index of tissue neutrophil accumulation. TNF-α and IL-10 mRNA levels were also increased in I/R mice compared to SO. DAMGO significantly reduced tissue damage, MPO activity and TNF-α mRNA levels in I/R and these effects were reversed by CTAP. By contrast, DAMGO did not modify IL-10 mRNA levels and gastrointestinal transit. DAMGO effects are receptor-mediated and are likely due to activation of peripheral µORs since it does not readily cross the blood brain barrier. These findings suggest that activation of peripheral µOR protects from the inflammatory response induced by I/R through a pathway involving the pro-inflammatory cytokine, TNF-α. Reduction of acute inflammation might prevent I/R complications, including motility impairment, which develop at a later stage of reperfusion and are likely due to inflammatory cell infiltrates. PMID:22806643

  1. Mesenteric hypoperfusion and inflammation induced by brain death are not affected by inhibition of the autonomic storm in rats

    Directory of Open Access Journals (Sweden)

    Rafael Simas

    2015-06-01

    Full Text Available OBJECTIVES: Brain death is typically followed by autonomic changes that lead to hemodynamic instability, which is likely associated with microcirculatory dysfunction and inflammation. We evaluated the role of the microcirculation in the hemodynamic and inflammatory events that occur after brain death and the effects of autonomic storm inhibition via thoracic epidural blockade on mesenteric microcirculatory changes and inflammatory responses. METHODS: Male Wistar rats were anesthetized and mechanically ventilated. Brain death was induced via intracranial balloon inflation. Bupivacaine (brain death-thoracic epidural blockade group or saline (brain death group infusion via an epidural catheter was initiated immediately before brain death induction. Sham-operated animals were used as controls (SH group. The mesenteric microcirculation was analyzed via intravital microscopy, and the expression of adhesion molecules was evaluated via immunohistochemistry 180 min after brain death induction. RESULTS: A significant difference in mean arterial pressure behavior was observed between the brain death-thoracic epidural blockade group and the other groups, indicating that the former group experienced autonomic storm inhibition. However, the proportion of perfused small vessels in the brain death-thoracic epidural blockade group was similar to or lower than that in the brain death and SH groups, respectively. The expression of intercellular adhesion molecule 1 was similar between the brain death-thoracic epidural blockade and brain death groups but was significantly lower in the SH group than in the other two groups. The number of migrating leukocytes in the perivascular tissue followed the same trend for all groups. CONCLUSIONS: Although thoracic epidural blockade effectively inhibited the autonomic storm, it did not affect mesenteric hypoperfusion or inflammation induced by brain death.

  2. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Science.gov (United States)

    Aguilar-Valles, Argel; Flores, Cecilia; Luheshi, Giamal N

    2010-06-04

    Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  3. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs during inflammation induced visceral hypersensitivity

    Directory of Open Access Journals (Sweden)

    Caudle Robert M

    2009-09-01

    Full Text Available Abstract Background Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs, co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG neurons expressing the transient receptor potential vanilloid-1 (TRPV1 receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX prior to inflammation and behavioural testing. Results CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Conclusion Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned

  4. Cited1 deficiency suppresses intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Valérie Méniel

    Full Text Available Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with Apc(Min/+ and AhCre(+Apc(fl/fl mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in Apc(Min/+ mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in Apc(Min/+ mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1.

  5. Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

    Science.gov (United States)

    Lee, W T Y; Cain, J E; Cuddihy, A; Johnson, J; Dickinson, A; Yeung, K-Y; Kumar, B; Johns, T G; Watkins, D N; Spencer, A; St John, J C

    2016-01-01

    Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.

  6. Controversies about the genetic model of colorectal tumorigenesis.

    Science.gov (United States)

    Waliszewski, P

    1995-01-01

    According to the genetic model, intestinal tumorigenesis is a result of the ordered in time inactivation of tumor suppressor genes and the activation of oncogenes. A tacit assumption is that both genes involved in the regulation of proliferation and growth factor-inducible genes, although inactivated, would not be changed during that process. The model requires that cancer cell population is homogenous, exists in a deterministic environment, and develops in a teleological manner. Meanwhile, tumorigenesis is rather a combination of both deterministic and stochastic molecular phenomena. Therefore, a novel notion of bifurcating point genes is defined as a generalization of the idea of tumor suppressor genes and oncogenes. Alternative stochastic mechanisms of tumorigenesis are discussed such as a decreased expression of intestinal-specific genes in cancer cells, most likely reflecting adaptation to survival within a heterogeneous, and non-equilibrated cellular population.

  7. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing.

    Science.gov (United States)

    Svensson, Camilla I; Marsala, Martin; Westerlund, Anna; Calcutt, Nigel A; Campana, Wendy M; Freshwater, Jason D; Catalano, Rosanne; Feng, Ying; Protter, Andrew A; Scott, Brian; Yaksh, Tony L

    2003-09-01

    We examined the effect of p38 mitogen-activated protein kinase (MAPK) inhibitors in models of nociception and correlated this effect with localization and expression levels of p38 MAPK in spinal cord. There was a rapid increase in phosphorylated p38 MAPK in spinal cord following intrathecal administration of substance P or intradermal injection of formalin. Immunocytochemistry revealed that phosphorylated p38 MAPK-immunoreactive cells were predominantly present in laminae I-IV of the dorsal horn. Double-staining with markers for neurons, microglia, astrocytes and oligodendrocytes unexpectedly revealed co-localization with microglia but not with neurons or other glia. Pretreatment with p38 MAPK inhibitors (SB20358 or SD-282) had no effect on acute thermal thresholds. However, they attenuated hyperalgesia in several nociceptive models associated with spinal sensitization including direct spinal activation (intrathecal substance P) and peripheral tissue inflammation (intraplantar formalin or carrageenan). Spinal sensitization, manifested by enhanced expression of cyclo-oxygenase-2 and inflammation-induced appearance of Fos-positive neurons, was blocked by pretreatment, but not post-treatment, with p38 MAPK inhibitors. Taken together, these results indicate that spinal p38 MAPK is involved in inflammation-induced pain and that activated spinal microglia play a direct role in spinal nociceptive processing.

  8. A critical reassessment of the role of mitochondria in tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Antonio Salas

    2005-11-01

    Full Text Available BACKGROUND: Mitochondrial DNA (mtDNA is being analyzed by an increasing number of laboratories in order to investigate its potential role as an active marker of tumorigenesis in various types of cancer. Here we question the conclusions drawn in most of these investigations, especially those published in high-rank cancer research journals, under the evidence that a significant number of these medical mtDNA studies are based on obviously flawed sequencing results. METHODS AND FINDINGS: In our analyses, we take a phylogenetic approach and employ thorough database searches, which together have proven successful for detecting erroneous sequences in the fields of human population genetics and forensics. Apart from conceptual problems concerning the interpretation of mtDNA variation in tumorigenesis, in most cases, blocks of seemingly somatic mutations clearly point to contamination or sample mix-up and, therefore, have nothing to do with tumorigenesis. CONCLUSION: The role of mitochondria in tumorigenesis remains unclarified. Our findings of laboratory errors in many contributions would represent only the tip of the iceberg since most published studies do not provide the raw sequence data for inspection, thus hindering a posteriori evaluation of the results. There is no precedent for such a concatenation of errors and misconceptions affecting a whole subfield of medical research.

  9. Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis

    Science.gov (United States)

    Zackular, Joseph P.; Baxter, Nielson T.

    2015-01-01

    ABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likely that the loss of key bacterial populations may result in the loss of protective functions that are normally provided by the microbiota. We explored the role of the gut microbiota in colon tumorigenesis by using an inflammation-based murine model. We observed that perturbing the microbiota with different combinations of antibiotics reduced the number of tumors at the end of the model. Using the random forest machine learning algorithm, we successfully modeled the number of tumors that developed over the course of the model on the basis of the initial composition of the microbiota. The timing of antibiotic treatment was an important determinant of tumor outcome, as colon tumorigenesis was arrested by the use of antibiotics during the early inflammation period of the murine model. Together, these results indicate that it is possible to predict colon tumorigenesis on the basis of the composition of the microbiota and that altering the gut microbiota can alter the course of tumorigenesis. IMPORTANCE Mounting evidence indicates that alterations to the gut microbiota, the complex community of bacteria that inhabits the gastrointestinal tract, are strongly associated with the development of colorectal cancer. We used antibiotic perturbations to a murine model of inflammation-driven colon cancer to generate eight starting communities that resulted in various severities of tumorigenesis. Furthermore, we were able to quantitatively predict the final number of tumors on the basis of the initial composition of the gut microbiota. These results further bolster the evidence that the gut microbiota is involved in mediating the development of colorectal cancer. As a final proof of

  10. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

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    Karantza-Wadsworth, Vassiliki; Patel, Shyam; Kravchuk, Olga; Chen, Guanghua; Mathew, Robin; Jin, Shengkan; White, Eileen

    2007-01-01

    Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression. PMID:17606641

  11. CUEDC2: an emerging key player in inflammation and tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Jianghong Man; Xuemin Zhang

    2011-01-01

    CUE domain-containing 2 (CUEDC2) is a protein involved in the regulation of the cell cycle,inflammation,and tumorigenesis and is highly expressed in many types of tumors.CUEDC2 is phosphorylated by Cdk1 during mitosis and promotes the release of anaphase-promoting complex or cyclosome (APC/C) from checkpoint inhibition.CUEDC2 is also known to interact with IkB kinase α (IKKα) and IKKβ and has an inhibitory role in the activation of transcription factor nuclear factor-κB.Moreover,CUEDC2 plays an important role in downregulating the expression of hormone receptors estrogen receptorα and progesterone receptor,thereby impairing the responsiveness of breast cancer to endocrine therapies.In this review,current knowledge on the multi-functions of CUEDC2 in normal processes and tumorigenesis are discussed and summarized.

  12. Non-metabolic functions of glycolytic enzymes in tumorigenesis.

    Science.gov (United States)

    Yu, X; Li, S

    2017-05-11

    Cancer cells reprogram their metabolism to meet the requirement for survival and rapid growth. One hallmark of cancer metabolism is elevated aerobic glycolysis and reduced oxidative phosphorylation. Emerging evidence showed that most glycolytic enzymes are deregulated in cancer cells and play important roles in tumorigenesis. Recent studies revealed that all essential glycolytic enzymes can be translocated into nucleus where they participate in tumor progression independent of their canonical metabolic roles. These noncanonical functions include anti-apoptosis, regulation of epigenetic modifications, modulation of transcription factors and co-factors, extracellular cytokine, protein kinase activity and mTORC1 signaling pathway, suggesting that these multifaceted glycolytic enzymes not only function in canonical metabolism but also directly link metabolism to epigenetic and transcription programs implicated in tumorigenesis. These findings underscore our understanding about how tumor cells adapt to nutrient and fuel availability in the environment and most importantly, provide insights into development of cancer therapy.

  13. The role of antimicrobial peptides in skin tumorigenesis

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    Małgorzata Marcinkiewicz

    2016-05-01

    Full Text Available Antimicrobial peptides (AMPs, known as “natural antibiotics”, are the first line of defense in humans as effector molecules of the innate immune system of the skin. They present activity against a broad spectrum of bacteria, fungi, parasites and enveloped viruses. An increasing number of studies report altered expression of AMPs in human cancers. Antimicrobial peptides such as human β defensins, human cathelicidin, ribonuclease 7 and psoriasin, a member of S100 proteins, are suggested to play a role in tumor progression and tumor suppression in pre-malignant skin lesions and malignancies. Noticeable changes in AMPs expression in skin tumorigenesis suggest a correlation between peptides and cutaneous cancers, though it is still a matter of discussion. In this article we review recent studies on the relationship between antimicrobial peptides and skin tumorigenesis.

  14. Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model.

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    Lokender Kumar

    Full Text Available Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP and inflammatory cytokines (MIP-2, IL-6 and TNF-α were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2 indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti

  15. BAG-1 haplo-insufficiency impairs lung tumorigenesis

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    Camarero Guadalupe

    2004-11-01

    Full Text Available Abstract Background BAG-1 is a multifunctional co-chaperone of heat shock proteins (Hsc70/Hsp70 that is expressed in most cells. It interacts with Bcl-2 and Raf indicating that it might connect protein folding with other signaling pathways. Evidence that BAG-1 expression is frequently altered in human cancers, in particular in breast cancer, relative to normal cells has been put forward but the notion that overexpression of BAG-1 contributes to poor prognosis in tumorigenesis remains controversial. Methods We have evaluated the effect of BAG-1 heterozygosity in mice in a model of non-small-cell lung tumorigenesis with histological and molecular methods. We have generated mice heterozygous for BAG-1, carrying a BAG-1 null allele, that in addition express oncogenic, constitutively active C-Raf kinase (SP-C C-Raf BxB in type II pneumocytes. SP-C C-Raf BxB mice develop multifocal adenomas early in adulthood. Results We show that BAG-1 heterozygosity in mice impairs C-Raf oncogene-induced lung adenoma growth. Lung tumor initiation was reduced by half in BAG-1 heterozygous SP-C C-Raf BxB mice compared to their littermates. Tumor area was reduced by 75% in 4 month lungs of BAG-1 haploinsufficient mice compared to mice with two BAG-1 copies. Whereas BAG-1 heterozygosity did not affect the rate of cell proliferation or signaling through the mitogenic cascade in adenoma cells, it increased the rate of apoptosis. Conclusion Reduced BAG-1 expression specifically targets tumor cells to apoptosis and impairs tumorigenesis. Our data implicate BAG-1 as a key player in oncogenic transformation by Raf and identify it as a potential molecular target for cancer treatment.

  16. Cytoplasmic phospholipase A2 deletion enhances colon tumorigenesis.

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    Ilsley, Jillian N M; Nakanishi, Masako; Flynn, Christopher; Belinsky, Glenn S; De Guise, Sylvain; Adib, John N; Dobrowsky, Rick T; Bonventre, Joseph V; Rosenberg, Daniel W

    2005-04-01

    Cellular pools of free arachidonic acid are tightly controlled through enzymatic release of the fatty acid and subsequent utilization by downstream enzymes including the cyclooxygenases. Arachidonic acid cleavage from membrane phospholipids is accomplished by the actions of phospholipase A(2) (PLA(2)). Upon release, free arachidonic acid provides substrate for the synthesis of eicosanoids. However, under certain conditions, arachidonic acid may participate in ceramide-mediated apoptosis. Disruption of arachidonic acid homeostasis can shift the balance of cell turnover in favor of tumorigenesis, via overproduction of tumor-promoting eicosanoids or alternatively by limiting proapoptotic signals. In the following study, we evaluated the influence of genetic deletion of a key intracellular phospholipase, cytoplasmic PLA(2) (cPLA(2)), on azoxymethane-induced colon tumorigenesis. Heterozygous and null mice, upon treatment with the organotropic colon carcinogen, azoxymethane, developed a significant (P < 0.05) increase in colon tumor multiplicity (7.2-fold and 5.5-fold, respectively) relative to their wild-type littermates. This enhanced tumor sensitivity may be explained, in part, by the attenuated levels of apoptosis observed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining within the colonic epithelium of heterozygous and null mice ( approximately 50% of wild type). The lower frequency of apoptotic cells corresponded with reduced ceramide levels (69% and 46% of wild-type littermates, respectively). Remarkably, increased tumorigenesis resulting from cPLA(2) deletion occurred despite a significant reduction in prostaglandin E(2) production, even in cyclooxygenase-2-overexpressing tumors. These data contribute new information that supports a fundamental role of cPLA(2) in the control of arachidonic acid homeostasis and cell turnover. Our findings indicate that the proapoptotic role of cPLA(2) in the colon may supercede its contribution to

  17. MerTK Does Not Mediate Phagocytosis of Staphylococcus aureus but Attenuates Inflammation Induced by Staphylococcal Lipoteichoic Acid Through Blocking NF-κB Activation.

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    Zhang, Bing; Wu, Huimei; Fang, Lei; Ding, Peishan; Xu, Ke; Yang, Qingbin; Liu, Rongyu

    2017-05-20

    Mer receptor tyrosine kinase (MerTK) expressed in macrophages is essential for phagocytosis of apoptotic cells. Here, we investigate whether MerTK is involved in the phagocytosis of Staphylococcus aureus (S. aureus) and regulation of staphylococcal lipoteichoic acid (LTA)-induced inflammatory response in macrophages. We found that stimulating RAW264.7 macrophages with S. aureus activated multiple signaling pathways including toll-like receptor 2 (TLR2), scavenger receptor A (SR-A), and MerTK. Meanwhile, S. aureus stimulation also induced activation of proteins focal adhesion kinase (FAK) and Rac1, which are related to phagocytosis. Pretreatment with a specific Mer-blocking antibody significantly inhibited S. aureus-induced phosphorylation of MerTK, while it had no effect on S. aureus-induced activation of FAK and Rac1. Moreover, by confocal laser microscope, we observed that the antibody blockade of MerTK had little impact on the phagocytosis of S. aureus by RAW264.7 macrophages. Additionally, pretreatment with this antibody further promoted LTA-induced phosphorylation of nuclear factor κB (NF-κB) p65 subunit and production of pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1β, and macrophage inflammatory protein-2 (MIP-2). Collectively, these results suggest that MerTK does not play an essential role in the phagocytosis of S. aureus but attenuates inflammation induced by staphylococcal LTA through blocking NF-κB activation.

  18. Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression

    Science.gov (United States)

    Obora, Kayoko; Onodera, Yuta; Takehara, Toshiyuki; Frampton, John; Hasei, Joe; Ozaki, Toshifumi; Teramura, Takeshi; Fukuda, Kanji

    2017-01-01

    Intracerebral inflammation resulting from injury or disease is implicated in disruption of neural regeneration and may lead to irreversible neuronal dysfunction. Analysis of inflammation-related microRNA profiles in various tissues, including the brain, has identified miR-155 among the most prominent miRNAs linked to inflammation. Here, we hypothesize that miR-155 mediates inflammation-induced suppression of neural stem cell (NSC) self-renewal. Using primary mouse NSCs and human NSCs derived from induced pluripotent stem (iPS) cells, we demonstrate that three important genes involved in NSC self-renewal (Msi1, Hes1 and Bmi1) are suppressed by miR-155. We also demonstrate that suppression of self-renewal genes is mediated by the common transcription factor C/EBPβ, which is a direct target of miR-155. Our study describes an axis linking inflammation and miR-155 to expression of genes related to NSC self-renewal, suggesting that regulation of miR-155 may hold potential as a novel therapeutic strategy for treating neuroinflammatory diseases. PMID:28240738

  19. Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus

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    Chul-Kyu Park

    2015-01-01

    Full Text Available In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ. Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1 in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye, I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Gαi-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region.

  20. The Role of MUC1 Cytoplasmic Domain in Tumorigenesis

    Science.gov (United States)

    2005-05-01

    5 AD Award Number: DAMD17-02-1-0476 TITLE: The Role of MUCI Cytoplasmic Domain in Tumorigenesis PRINCIPAL INVESTIGATOR: Assah Al-Masri CONTRACTING ...The overall aim of the research is to develop a better understanding of the role of MUCI in breast cancer. Loss of Mucl (mouse homologue of MUC1...significant delay in tumor progression that is observed in the absence of Mucl . We suggest that the interaction of Mucl with c-Src, a key player in PyV MT

  1. Drosophila as a model for context-dependent tumorigenesis.

    Science.gov (United States)

    Tipping, Marla; Perrimon, Norbert

    2014-01-01

    Drosophila can exhibit classic hallmarks of cancer, such as evasion of apoptosis, sustained proliferation, metastasis, prolonged survival, genome instability, and metabolic reprogramming, when cancer-related genes are perturbed. In the last two decades, studies in flies have identified several tumor suppressor and oncogenes. However, the greatest strength of the fly lies in its ability to model cancer hallmarks in a variety of tissue types, which enables the study of context-dependent tumorigenesis. We review the organs and tissues that have been used to model tumor formation, and propose new strategies to maximize the potential of Drosophila in cancer research.

  2. New and emerging factors in tumorigenesis: an overview.

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    Kim, Suwon

    2015-01-01

    This article provides an overview of the genes and cellular processes that have emerged recently as new key factors in tumorigenesis. We review these in the context of three broad categories. First, genome-scale sequencing studies have revealed a set of frequently mutated genes in cancer. Genes that are mutated in >5% of all cancers across tissue types are discussed, with a highlighted focus on the two most frequently mutated genes, TP53 and PIK3CA. Second, the mechanisms of resistance to targeted therapy are reviewed. These include acquired resistance under targeted therapy selection owing to mutations and amplification of genes in the same or parallel signaling pathways. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance. Third, "metastasis-specific genes", or rather lack thereof, are discussed. While many genes have been shown to be capable of promoting metastasis in experimental systems, no common genetic alterations have been identified specific to metastatic lesions. Rather, the same gene mutations frequently found in primary tumors are also found prevalent in metastases, suggesting that the genes that drive tumorigenesis may also drive metastasis. In this light, an emerging view of metastatic progression is discussed. Collectively, these recent advances in cancer research have refined our knowledge on cancer etiology and progression but also present challenges that will require innovative new approaches to treat and manage cancer.

  3. Patched2 modulates tumorigenesis in patched1 heterozygous mice.

    Science.gov (United States)

    Lee, Youngsoo; Miller, Heather L; Russell, Helen R; Boyd, Kelli; Curran, Tom; McKinnon, Peter J

    2006-07-15

    The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis. Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man. In many cases, medulloblastoma arising from perturbations of Ptch1 function leads to a concomitant up-regulation of a highly similar gene, Patched2 (Ptch2). As increased expression of Ptch2 is associated with medulloblastoma and other tumors, we investigated the role of Ptch2 in tumor suppression by generating Ptch2-deficient mice. In striking contrast to Ptch1-/- mice, Ptch2-/- animals were born alive and showed no obvious defects and were not cancer prone. However, loss of Ptch2 markedly affected tumor formation in combination with Ptch1 haploinsufficiency. Ptch1+/-Ptch2-/- and Ptch1+/-Ptch2+/- animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with Ptch1+/- animals. Therefore, Ptch2 modulates tumorigenesis associated with Ptch1 haploinsufficiency.

  4. Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.

    Science.gov (United States)

    Cheng, Ka Wing; Wong, Chi C; Alston, Ninche; Mackenzie, Gerardo G; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Wiedmann, Timothy; Rigas, Basil

    2013-08-01

    Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation.

  5. IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression.

    Science.gov (United States)

    Liu, Mo; Lee, Dung-Fang; Chen, Chun-Te; Yen, Chia-Jui; Li, Long-Yuan; Lee, Hong-Jen; Chang, Chun-Ju; Chang, Wei-Chao; Hsu, Jung-Mao; Kuo, Hsu-Ping; Xia, Weiya; Wei, Yongkun; Chiu, Pei-Chun; Chou, Chao-Kai; Du, Yi; Dhar, Debanjan; Karin, Michael; Chen, Chung-Hsuan; Hung, Mien-Chie

    2012-01-27

    Proinflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/S111, thereby suppressing FOXA2 transactivation activity and leading to decreased NUMB expression, and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report a TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.

  6. The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis

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    Yuhang Zhou

    2016-01-01

    Full Text Available The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers.

  7. The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis.

    Science.gov (United States)

    Zhou, Yuhang; Huang, Tingting; Cheng, Alfred S L; Yu, Jun; Kang, Wei; To, Ka Fai

    2016-01-21

    The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers.

  8. Anti-inflammatory activity of four solvent fractions of ethanol extract of Mentha spicata L. investigated on acute and chronic inflammation induced rats.

    Science.gov (United States)

    Arumugam, P; Priya, N Gayatri; Subathra, M; Ramesh, A

    2008-07-01

    Anti-inflammatory effects of four solvent fractions of ethanol extract of Mentha spicata were evaluated in acute and chronic inflammation induced in Wistar albino rats. Lipid peroxidation (LPO) and some antioxidants produced during chronic inflammation were quantitated. Hexane (320mg/kg of body weight in 25% DMSO), chloroform (320mg/kg body weight in 25% DMSO), ethyl acetate (160mg/kg body weight in 25% DMSO), aqueous (320mg/kg of body weight in ddH(2)O) fractions, two negative control groups (25% DMSO and ddH(2)O) and two anti-inflammatory drugs (Diclofenac: 25mg/kg of body weight; Indomethacin: 10mg/kg of body weight both in ddH(2)O) were administered by oral intubations to the eight groups of rats consisting six animals, each. In acute study, 1% carrageenan was injected subcutaneously in the sub-plantar region of the right hind paw after 1h of administration of test doses. The increased paw edema was measured at 0.5, 1, 2, 4, 8, 16 and 24h intervals. In the chronic study, the oral administration was carried out for seven consecutive days. On eighth day, four sterile cotton pellets (50mg each) were implanted subcutaneously in the dorsal region of the rats. On the sixteenth day, the rats were sacrificed and the cotton pellets with granulomatous tissue were dissected out and weighed (fresh and dry). Both in chronic and acute inflammation, ethyl acetate (EAF) and aqueous fraction (AF) were effective. EAF is comparable with the positive standards in chronic inflammation. The results indicate that EAF's anti-inflammatory activity is largely due to its ability to modulate in vivo antioxidants.

  9. Development and validation of an animal model of prostate inflammation-induced chronic pelvic pain: evaluating from inflammation of the prostate to pain behavioral modifications.

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    Feng Zeng

    Full Text Available BACKGROUND: Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS is the most common type of prostatitis. Due to the lack of a suitable animal model partly, the pathogenesis for this condition is obscure. In the current study we developed and validated an animal model for nonbacterial prostatitis and prostate inflammation-induced chronic pelvic pain in rats with the use of intraprostatic injection of λ-carrageenan. METHODS: Male Sprague-Dawley rats weighing 250-350 g were used for the experiments. After intraprostatic injection of 3% λ-carrageenan, at different time points(after 24 h, 7 d, 14 d and 30 d of injection, radiant heat and von Frey filaments were applied to the scrotum of rats to measure the heat and mechanical thresholds respectively. Then the prostate was removed for histology, and cyclooxygenase (COX 2 protein expression was determined by Western-blot. Evans blue(50 mg/kg was also injected intravenously to assess for plasma protein extravasation at different time points after injection of λ-carrageenan. RESULTS: Compared to control group, inflamed animals showed a significant reduction in mechanical threshold (mechanical allodynia at 24 h and 7d(p = 0.022,0.046, respectively, and a significant reduction in heat threshold (thermal hyperalgesia at 24 h, 7d and 14 d(p = 0.014, 0.018, 0.002, respectively in the scrotal skin. Significant increase of inflammatory cell accumulation, COX2 expression and Evans blue extravasation were observed at 24 h, 7d and 14 d after injection. CONCLUSIONS: Intraprostatic λ-carrageenan injection induced neurogenic prostatitis and prostate inflammation pain, which lasted at least 2 weeks. The current model is expected to be a valuable preclinical tool to study the neurobiological mechanisms of male chronic pelvic pain.

  10. Phlebotomine salivas inhibit immune inflammation-induced neutrophil migration via an autocrine DC-derived PGE2/IL-10 sequential pathway.

    Science.gov (United States)

    Carregaro, Vanessa; Valenzuela, Jesus G; Cunha, Thiago M; Verri, Waldiceu A; Grespan, Renata; Matsumura, Graziela; Ribeiro, José M C; Elnaiem, Dia-Eldin; Silva, João S; Cunha, Fernando Q

    2008-07-01

    In the present study, we investigated whether saliva from Phlebotomus papatasi and Phlebotomus duboscqi inhibited antigen-induced neutrophil migration and the mechanisms involved in these effects. The pretreatment of immunized mice with salivary gland extracts (SGE) of both phlebotomines inhibited OVA challenge-induced neutrophil migration and release of the neutrophil chemotactic mediators, MIP-1alpha, TNF-alpha, and leukotriene B4 (LTB4). Furthermore, SGE treatment enhanced the production of anti-inflammatory mediators, IL-10 and PGE2. SGE treatments failed to inhibit neutrophil migration and MIP-1alpha and LTB4 production in IL-10-/- mice, also failing in mice treated with nonselective (indomethacin) or selective (rofecoxibe) cyclooxygenase (COX) inhibitors. COX inhibition resulted in diminished SGE-induced IL-10 production, and PGE2 release triggered by SGE remained increased in IL-10-/- mice, suggesting that prostanoids are acting through an IL-10-dependent mechanism. SGE treatments in vivo reduced the OVA-induced lymphoproliferation of spleen-derived cells. Further, the in vitro incubation of bone marrow-derived dendritic cells (DC) with SGE inhibited the proliferation of CD4+T cells from OVA-immunized mice, which was reversed by indomethacin and anti-IL-10 antibody treatments. Supporting these results, SGE induced the production of PGE2 and IL-10 by DC, which were blocked by COX inhibition. These effects were associated with the reduction of DC-membrane expression of MHC-II and CD86 by SGE treatment. Altogether, the results showed that Phlebotomine saliva inhibits immune inflammation-induced neutrophil migration by an autocrine DC sequential production of PGE2/IL-10, suggesting that the saliva constituents might be promising therapeutic molecules to target immune inflammatory diseases.

  11. Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.

    Science.gov (United States)

    Pinzaru, Alexandra M; Hom, Robert A; Beal, Angela; Phillips, Aaron F; Ni, Eric; Cardozo, Timothy; Nair, Nidhi; Choi, Jaehyuk; Wuttke, Deborah S; Sfeir, Agnel; Denchi, Eros Lazzerini

    2016-06-01

    Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

  12. Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Alexandra M. Pinzaru

    2016-06-01

    Full Text Available Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1 function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

  13. Wnt signaling and colon tumorigenesis - A view from the periphery

    Energy Technology Data Exchange (ETDEWEB)

    Burgess, Antony W., E-mail: burgess@ludwig.edu.au [Parkville Branch, Ludwig Institute for Cancer Research, Melbourne, 3050 (Australia); Faux, Maree C. [Parkville Branch, Ludwig Institute for Cancer Research, Melbourne, 3050 (Australia); Layton, Meredith J. [Department of Biochemistry and Molecular Biology, Monash University, Melbourne, 3800 (Australia); Ramsay, Robert G. [Peter MacCallum Cancer Centre, Melbourne, 3002 (Australia); Pathology Department, the University of Melbourne, Parkville, 3050 (Australia)

    2011-11-15

    In this brief overview we discuss the association between Wnt signaling and colon cell biology and tumorigenesis. Our current understanding of the role of Apc in the {beta}-catenin destruction complex is compared with potential roles for Apc in cell adhesion and migration. The requirement for phosphorylation in the proteasomal-mediated degradation of {beta}-catenin is contrasted with roles for phospho-{beta}-catenin in the activation of transcription, cell adhesion and migration. The synergy between Myb and {beta}-catenin regulation of transcription in crypt stem cells during Wnt signaling is discussed. Finally, potential effects of growth factor regulatory systems, Apc or truncated-Apc on crypt morphogenesis, stem cell localization and crypt fission are considered.

  14. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

    Science.gov (United States)

    Pusapati, Raju V.; Rounbehler, Robert J.; Hong, Sungki; Powers, John T.; Yan, Mingshan; Kiguchi, Kaoru; McArthur, Mark J.; Wong, Paul K.; Johnson, David G.

    2006-01-01

    Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of H2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development. p53 | DNA damage

  15. Role of Dicer on tumorigenesis in glioma cells

    Institute of Scientific and Technical Information of China (English)

    Anling Zhang; Lei Han; Guangxiu Wang; Zhifan Jia; Peiyu Pu; Chunsheng Kang

    2010-01-01

    Micro RNAs(miRNAs)are non-coding,single-stranded RNAs that regulate target gene expression by repressing translation or promoting RNA cleavage.Recent studies show that miRNA expression is globally decreased in some human tumors.Dicer is an essential component of the miRNA processing machinery.To determine whether global reduction of miRNA effects tumorigenesis,small interfering RNA were designed to target Dicer to restrain whole miRNA expression in the glioblastoma cell line-TJ905.With effective knock-down of Dicer,tumor cells were invasive and proliferative,and globally impaired miRNA processing enhanced proliferation and invasiveness of glioma cells in vitro.Suppression of Dicer expression resulted in a more aggressive glioma phenotype,which suggests that global reduction of miRNA expression could have an oncogenic role in glioblastoma cells.

  16. Expression and methylation pattern of p16 in neuroblastoma tumorigenesis.

    Science.gov (United States)

    Aktas, Safiye; Celebiler, Aydan Cavusoglu; Zadeoğlulari, Zeynep; Diniz, Gulden; Kargi, Aydanur; Olgun, Nur

    2010-03-01

    Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.

  17. Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

    Science.gov (United States)

    Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

    2012-05-01

    3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

  18. New and emerging factors in tumorigenesis: an overview

    Directory of Open Access Journals (Sweden)

    Kim S

    2015-07-01

    Full Text Available Suwon Kim1,2 1Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, 2Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: This article provides an overview of the genes and cellular processes that have emerged recently as new key factors in tumorigenesis. We review these in the context of three broad categories. First, genome-scale sequencing studies have revealed a set of frequently mutated genes in cancer. Genes that are mutated in >5% of all cancers across tissue types are discussed, with a highlighted focus on the two most frequently mutated genes, TP53 and PIK3CA. Second, the mechanisms of resistance to targeted therapy are reviewed. These include acquired resistance under targeted therapy selection owing to mutations and amplification of genes in the same or parallel signaling pathways. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance. Third, “metastasis-specific genes”, or rather lack thereof, are discussed. While many genes have been shown to be capable of promoting metastasis in experimental systems, no common genetic alterations have been identified specific to metastatic lesions. Rather, the same gene mutations frequently found in primary tumors are also found prevalent in metastases, suggesting that the genes that drive tumorigenesis may also drive metastasis. In this light, an emerging view of metastatic progression is discussed. Collectively, these recent advances in cancer research have refined our knowledge on cancer etiology and progression but also present challenges that will require innovative new approaches to treat and manage cancer. Keywords: cancer, genomics, gene mutations, targeted therapy resistance, tumor heterogeneity, metastasis

  19. Transcription factor myocyte enhancer factor 2D regulates interleukin-10 production in microglia to protect neuronal cells from inflammation-induced death.

    Science.gov (United States)

    Yang, Shaosong; Gao, Li; Lu, Fangfang; Wang, Bao; Gao, Fei; Zhu, Gang; Cai, Zhibiao; Lai, Juan; Yang, Qian

    2015-02-20

    -10, increased the TNF-α mRNA, and promoted inflammation-induced cytotoxicity, consistent with the result of inhibiting IL-10 activity with an anti-IL-10 neutralizing antibody. Our study identifies MEF2D as a critical regulator of IL-10 gene expression that negatively controls microglia inflammation response and prevents inflammation-mediated cytotoxicity.

  20. Harderian Gland Tumorigenesis: Low-Dose and LET Response

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Polly Y. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cucinotta, Francis A. [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Bjornstad, Kathleen A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Bakke, James [SRI International, Menlo Park, CA (United States). Biosciences Div.; Rosen, Chris J. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Du, Nicholas [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Fairchild, David G. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cacao, Eliedonna [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Blakely, Eleanor A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.

    2016-04-19

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  1. Harderian Gland Tumorigenesis: Low-Dose and LET Response.

    Science.gov (United States)

    Chang, Polly Y; Cucinotta, Francis A; Bjornstad, Kathleen A; Bakke, James; Rosen, Chris J; Du, Nicholas; Fairchild, David G; Cacao, Eliedonna; Blakely, Eleanor A

    2016-05-01

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  2. Luminal Iron Levels Govern Intestinal Tumorigenesis after Apc Loss In Vivo

    Directory of Open Access Journals (Sweden)

    Sorina Radulescu

    2012-08-01

    Full Text Available It is clear from epidemiological studies that excess iron is associated with increased risk of colorectal cancer; however, questions regarding the mechanism of how iron increases cancer risk, the source of the excess iron (circulating or luminal, and whether iron reduction represents a potential therapeutic option remain unanswered. In this study, we show that after Apc deletion, the cellular iron acquisition proteins TfR1 and DMT1 are rapidly induced. Conversely, restoration of APC reduces cellular iron due to repression of these proteins. To test the functional importance of these findings, we performed in vivo investigations of the impact of iron levels on intestinal tumorigenesis. Strikingly, depletion of luminal (but not systemic iron strongly suppressed murine intestinal tumorigenesis, whereas increased luminal iron strongly promoted tumorigenesis. Taken together, our data definitively delineate iron as a potent modifier of intestinal tumorigenesis and have important implications for dietary iron supplementation in patients at high risk of colorectal cancer.

  3. Stem-Like Cells in Bone Sarcomas: Implications for Tumorigenesis

    Directory of Open Access Journals (Sweden)

    C. Parker Gibbs

    2005-11-01

    Full Text Available Bone sarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. Despite advances in medical and surgical management, survival rates for high-grade tumors have remained static at 50% to 70%. Tumor stem cells have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors. We demonstrate here the existence of a small subpopulation of self-renewing bone sarcoma cells that are capable of forming suspended spherical, clonal colonies, also called “sarcospheres,” in anchorage-independent, serum-starved conditions. These bone sarcoma cells as well as tissue specimens express activated STAT3 and the marker genes of pluripotent embryonic stem (ES cells, Oct 3/4 and Nanog. Expression levels of Oct 3/4 and Nanog are greater in sarcospheres than in adherent cultures. A subset of bone sarcoma cells displays several surface markers of mesenchymal stem cells (Stro-1, CD105, and CD44 as well as attributes of mesodermal, ectodermal, and endodermal differentiation. Although previously documented in brain and breast tumors, our results support the extension of the cancer stem cell hypothesis to include tumors of mesenchymal lineage. Furthermore, they suggest the participation of ES cell homeobox proteins in non-germ cell tumorigenesis.

  4. MicroRNA-429 Modulates Hepatocellular Carcinoma Prognosis and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Xiao-Ying Huang

    2013-01-01

    Full Text Available MicroRNA-429 (miR-429 may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR, 2.70; 95% confidence interval (CI, 1.28–5.56 and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47–6.67. Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target.

  5. Luteinizing hormone promotes gonadal tumorigenesis in inhibin-deficient mice

    Science.gov (United States)

    Nagaraja, Ankur K.; Agno, Julio E.; Kumar, T. Rajendra; Matzuk, Martin M.

    2009-01-01

    Summary The inhibins are secreted α:β heterodimers of the TGF-β superfamily that are mainly synthesized in Sertoli cells and granulosa cells, and are critical regulators of testicular and ovarian development and function. Mice homozygous for a targeted deletion of the inhibin α subunit gene (Inha-/-) develop sex cord-stromal tumors in a gonadotropin-dependent manner. Here, we determine the contribution of LH to gonadal tumorigenesis by generating mice deficient in both inhibins and LH. Inha-/-Lhb-/- mice have increased survival and delayed tumor progression, and these observations correlate with lower serum FSH and estradiol levels compared to Inha-/- controls. Double mutant testicular tumors demonstrate decreased expression of cyclin D2, while double mutant ovarian tumors have elevated expression of p15INK4b and trend toward higher levels of p27Kip1. We conclude that LH is not required for tumor formation in the absence of inhibins but promotes tumor progression, likely through alterations in serum hormone levels and cell cycle regulators. PMID:18657590

  6. Molecular genetics of cancer and tumorigenesis: Drosophila models

    Institute of Scientific and Technical Information of China (English)

    Wu-Min Deng

    2011-01-01

    Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.

  7. The Functional Analysis of Histone Acetyltransferase MOF in Tumorigenesis.

    Science.gov (United States)

    Su, Jiaming; Wang, Fei; Cai, Yong; Jin, Jingji

    2016-01-14

    Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in most cellular biological processes. Thus, abnormal regulation of epigenetics is implicated in the occurrence of various diseases, including cancer. Human MOF (males absent on the first) is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60) family of histone acetyltransferases (HATs). As a catalytic subunit, MOF can form at least two distinct multiprotein complexes (MSL and NSL) in human cells. Both complexes can acetylate histone H4 at lysine 16 (H4K16); however, the NSL complex possesses broader substrate specificity and can also acetylate histone H4 at lysines 5 and 8 (H4K5 and H4K8), suggesting the complexity of the intracellular functions of MOF. Silencing of MOF in cells leads to genomic instability, inactivation of gene transcription, defective DNA damage repair and early embryonic lethality. Unbalanced MOF expression and its corresponding acetylation of H4K16 have been found in certain primary cancer tissues, including breast cancer, medulloblastoma, ovarian cancer, renal cell carcinoma, colorectal carcinoma, gastric cancer, as well as non-small cell lung cancer. In this review, we provide a brief overview of MOF and its corresponding histone acetylation, introduce recent research findings that link MOF functions to tumorigenesis and speculate on the potential role that may be relevant to tumorigenic pathways.

  8. The Functional Analysis of Histone Acetyltransferase MOF in Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jiaming Su

    2016-01-01

    Full Text Available Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in most cellular biological processes. Thus, abnormal regulation of epigenetics is implicated in the occurrence of various diseases, including cancer. Human MOF (males absent on the first is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60 family of histone acetyltransferases (HATs. As a catalytic subunit, MOF can form at least two distinct multiprotein complexes (MSL and NSL in human cells. Both complexes can acetylate histone H4 at lysine 16 (H4K16; however, the NSL complex possesses broader substrate specificity and can also acetylate histone H4 at lysines 5 and 8 (H4K5 and H4K8, suggesting the complexity of the intracellular functions of MOF. Silencing of MOF in cells leads to genomic instability, inactivation of gene transcription, defective DNA damage repair and early embryonic lethality. Unbalanced MOF expression and its corresponding acetylation of H4K16 have been found in certain primary cancer tissues, including breast cancer, medulloblastoma, ovarian cancer, renal cell carcinoma, colorectal carcinoma, gastric cancer, as well as non-small cell lung cancer. In this review, we provide a brief overview of MOF and its corresponding histone acetylation, introduce recent research findings that link MOF functions to tumorigenesis and speculate on the potential role that may be relevant to tumorigenic pathways.

  9. Alternative RNA Structure-Coupled Gene Regulations in Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Feng-Chi Chen

    2014-12-01

    Full Text Available Alternative RNA structures (ARSs, or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions.

  10. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India); Patra, Samir Kumar, E-mail: samirp@nitrkl.ac.in [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India)

    2012-10-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  11. Dynamics of notch expression during murine prostate development and tumorigenesis.

    Science.gov (United States)

    Shou, J; Ross, S; Koeppen, H; de Sauvage, F J; Gao, W Q

    2001-10-01

    Notch signaling has been widely demonstrated to be responsible for cell fate determination during normal development and implicated in human T-cell leukemia and mouse mammary carcinomas. Here we show that Notch signaling may be involved in prostatic development and cancer cell growth. In situ hybridization and reverse transcription-PCR analyses revealed that Notch1 was expressed in prostate epithelial cells during normal development and in prostate cancer cells. Characterization of Notch1-green fluorescent protein transgenic mice, in which the expression of reporter green fluorescent protein is under the control of the Notch1 promoter, indicated that Notch1-expressing cells were associated with the basal epithelial cell population in the prostate. Examination of the transgenic adenocarcinoma of the mouse prostate showed that expression of Notch1 was elevated in malignant prostatic epithelial cells of primary and metastatic tumors. Expression of Notch ligands, however, was low or undetectable in cultured prostate cancer cells or in malignant prostatic epithelial cells in transgenic adenocarcinoma of the mouse prostate. Furthermore, overexpression of a constitutively active form of Notch1 inhibited the proliferation of various prostate cancer cells, including DU145, LNCaP, and PC3 cells. Taken together, our data indicate for the first time that Notch signaling may play a role in murine prostatic development and tumorigenesis.

  12. Survival and tumorigenesis in O6-methylguanine DNA methyltransferase-deficient mice following cyclophosphamide exposure

    OpenAIRE

    Nagasubramanian, Ramamoorthy; Hansen, Ryan J.; Delaney, Shannon M.; Cherian, Mathew M.; Samson, Leona D.; Kogan, Scott C.; Dolan, M Eileen

    2008-01-01

    O6-methylguanine DNA methyltransferase (MGMT) deficiency is associated with an increased susceptibility to alkylating agent toxicity. To understand the contribution of MGMT in protecting against cyclophosphamide (CP)-induced toxicity, mutagenesis and tumorigenesis, we compared the biological effects of this agent in transgenic Mgmt knockout and wild-type mice. In addition, neurofibromin (Nf1)+/− background was used to increase the likelihood of CP-induced tumorigenesis. Cohorts of Mgmt-profic...

  13. Overexpression of Id1 in transgenic mice promotes mammary basal stem cell activity and breast tumorigenesis

    OpenAIRE

    Shin, Dong-Hui; Park, Ji-Hye; Lee, Jeong-Yeon; Won, Hee-Young; Jang, Ki-Seok; MIN, KYUENG-WHAN; Jang, Si-Hyong; Woo, Jong-Kyu; Oh, Seung Hyun; Kong, Gu

    2015-01-01

    Inhibitor of differentiation/DNA binding (Id)1 is a crucial regulator of mammary development and breast cancer progression. However, its effect on stemness and tumorigenesis in mammary epithelial cells remains undefined. Herein, we demonstrate that Id1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities in transgenic mice. MaSC-enriched basal cell expansion and increased self-renewal and in vivo regenerative capacity of MaSCs are observed in th...

  14. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  15. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  16. Conserved mechanisms of tumorigenesis in the Drosophila adult midgut.

    Directory of Open Access Journals (Sweden)

    Òscar Martorell

    Full Text Available Whereas the series of genetic events leading to colorectal cancer (CRC have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.

  17. Molecular mechanisms of thyroid tumorigenesis; Molekulare Mechanismen der Schilddruesentumorgenese

    Energy Technology Data Exchange (ETDEWEB)

    Krause, K.; Fuehrer, D. [Universitaetsklinikum Leipzig (Germany). Abt. fuer Endokrinolgoie, Diabetologie und Nephrologie

    2008-09-15

    Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30% of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70% of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8/ PPAR{gamma} rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K/AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations. (orig.)

  18. Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

    Science.gov (United States)

    Mattoscio, Domenico; Casadio, Chiara; Miccolo, Claudia; Maffini, Fausto; Raimondi, Andrea; Tacchetti, Carlo; Gheit, Tarik; Tagliabue, Marta; Galimberti, Viviana E.; De Lorenzi, Francesca; Chiesa, Fausto; Ansarin, Mohssen; Tommasino, Massimo

    2017-01-01

    UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells’ resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies. PMID:28253371

  19. Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis.

    Science.gov (United States)

    Mossine, Valeri V; Chopra, Pankaj; Mawhinney, Thomas P

    2008-06-01

    Prior investigations on the beneficial effect of dietary processed tomato products and lycopene on prostate cancer risk suggested that lycopene may require the presence of other constituents to exert its chemopreventive potential. We investigated whether ketosamines, a group of carbohydrate derivatives present in dehydrated tomato products, may interact with lycopene against prostate tumorigenesis. One ketosamine, FruHis, strongly synergized with lycopene against proliferation of the highly metastatic rat prostate adenocarcinoma MAT-LyLu cell line in vitro. The FruHis/lycopene combination significantly inhibited in vivo tumor formation by MAT-LyLu cells in syngeneic Copenhagen rats. Energy-balanced diets, supplemented with tomato paste, tomato powder, or tomato paste plus FruHis, were fed to Wistar-Unilever rats (n = 20 per group) treated with N-nitroso-N-methylurea and testosterone to induce prostate carcinogenesis. Survival from carcinogenesis was lowest in the control group (median survival time, 40 weeks) and highest in the group fed the tomato paste/FruHis diet (51 weeks; P = 0.004, versus control). The proportions of dying rats with macroscopic prostate tumors in the control, tomato paste, tomato powder, and tomato paste/FruHis groups were 63% (12 of 19), 39% (5 of 13), 43% (6 of 14), and 18% (2 of 11), respectively. FruHis completely blocked DNA oxidative degradation at >250 micromol/L in vitro, whereas neither ascorbate nor phenolic antioxidants from tomato were effective protectors in this assay. FruHis, therefore, may exert tumor-preventive effect through its antioxidant activity and interaction with lycopene.

  20. Cyr61 promotes breast tumorigenesis and cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Miaw-Sheue; Bogart, Daphne F.; Castaneda, Jessica M.; Li, Patricia; Lupu, Ruth

    2002-01-16

    Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ''normal'' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.

  1. Biomarkers in Tumorigenesis Using Cancer Cell Lines: A Systematic Review

    Science.gov (United States)

    Raju K, Lizbeth; Augustine, Dominic; Rao, Roopa S; S V, Sowmya; Haragannavar, Vanishri C; Nambiar, Shwetha; Prasad, Kavitha; Awan, Kamran Habib; Patil, Shankargouda

    2017-09-27

    Cancer is a leading cause of death worldwide. Despite many research advancements in the field, the genetic changes regulating the transformation of normal oral cells into malignant cells have not been fully elucidated. Several studies have evaluated carcinogenesis at the molecular level. Cancer cell lines are commonly used in biomedical research because they provide an unlimited source of cells and represent various stages of initiation and progression of carcinogenesis in vitro. Aims: The objective of the study was to review original research articles using cancer cell lines as a tool to understand carcinogenesis and to identify the genes involved in tumor development. Additionally, we also examined the application of the genes as predictive biomarkers. Methods and Materials: Several databases, including PubMed, Google Scholar, Ebsco, and Science Direct, were searched from 1985 to December 2016 using various combinations of the following key words: “mouth neoplasm”, “cell lines”, and “tumorigenesis”. Original experimental studies published in English were included. We excluded letters to the editor, historic reviews, and unpublished data from the analysis. Results: There were 17 studies (in vitro) included in the analysis. There were 14 genes and 4 miRNAs involved in malignant transformation of oral keratinocytes into cancer cells. The most commonly studied genes were p53, cyclin D1, and hTERT. Conclusion: Additional reviews and studies are needed to identify a panel of genes specific to various potentially malignant disorders and to aid in the early detection of oral squamous cell carcinoma (OSCC) because tumorigenesis involves the mutation of multiple genes. Furthermore, improving advanced cost-effective diagnostic methods may benefit the public health sector. Creative Commons Attribution License

  2. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    Energy Technology Data Exchange (ETDEWEB)

    Thonel, Aurelie de [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); Mezger, Valerie, E-mail: valerie.mezger@univ-paris-diderot.fr [CNRS, UMR7216 Epigenetics and Cell Fate, Paris (France); University Paris Diderot, 75013 Paris (France); Garrido, Carmen, E-mail: valerie.mezger@univ-paris-diderot.fr [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); CHU, Dijon BP1542, Dijon (France)

    2011-03-07

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

  3. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.

    Science.gov (United States)

    Cicchini, Michelle; Chakrabarti, Rumela; Kongara, Sameera; Price, Sandy; Nahar, Ritu; Lozy, Fred; Zhong, Hua; Vazquez, Alexei; Kang, Yibin; Karantza, Vassiliki

    2014-01-01

    Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1(+/-);MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

  4. The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence

    Directory of Open Access Journals (Sweden)

    Sang Soo Kim

    2013-01-01

    Full Text Available Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.

  5. Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde?

    Science.gov (United States)

    Zhou, Shengtao; Zhao, Linjie; Kuang, Manchao; Zhang, Bingjie; Liang, Zhu; Yi, Tao; Wei, Yuquan; Zhao, Xia

    2012-10-28

    Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment. Copyright © 2012. Published by Elsevier Ireland Ltd.

  6. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats

    Science.gov (United States)

    Vinogradova, Irina A.; Anisimov, Vladimir N.; Bukalev, Andrey V.; Semenchenko, Anna V.; Zabezhinski, Mark A.

    2009-01-01

    We evaluated the effect of various light/dark regimens on the survival, life span and tumorigenesis in rats. Two hundred eight male and 203 females LIO rats were subdivided into 4 groups and kept at various light/dark regimens: standard 12:12 light/dark (LD); natural lighting of the North-West of Russia (NL); constant light (LL), and constant darkness (DD) since the age of 25 days until natural death. We found that exposure to NL and LL regimens accelerated development of metabolic syndrome and spontaneous tumorigenesis, shortened life span both in male and females rats as compared to the standard LD regimen. We conclude that circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans. PMID:20157558

  7. Fecal excretion pattern of bile acids in rats fed high fat diets and neomycin in induced colon tumorigenesis.

    Science.gov (United States)

    Panda, S K; Broitman, S A

    1999-09-06

    Neomycin augments colon tumorigenesis in 1,2 - dimethylhydrazine treated rats fed polyunsaturated fat diet and decreases fecal cholic acid excretion, while it inhibits tumorigenesis with increased cholic acid and decreased deoxycholic acid excretions in rats fed high cholesterol diet. Participation of other fecal bile acids seems to be insignificant in relation to colon carcinogenesis.

  8. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma

    NARCIS (Netherlands)

    Campos, M; Kool, M M J; Daminet, S; Ducatelle, R; Rutteman, G; Kooistra, H S; Galac, S; Mol, J A

    2014-01-01

    BACKGROUND: Information on the genetic events leading to thyroid cancer in dogs is lacking. HYPOTHESIS/OBJECTIVES: Upregulation of the PI3K/Akt pathway has an important role in the tumorigenesis of thyroid carcinoma in dogs. ANIMALS: Fifty-nine dogs with thyroid carcinoma and 10 healthy controls. ME

  9. For better or for worse : the role of Pim oncogenes in tumorigenesis

    NARCIS (Netherlands)

    Nawijn, Martijn C.; Alendar, Andrej; Berns, Anton

    2011-01-01

    Pim oncogenes are overexpressed in a wide range of tumours from a haematological and epithelial origin. Pim genes encode serine/threonine kinases that have been shown to counteract the increased sensitivity to apoptosis induction that is associated with MYC-driven tumorigenesis. Recently, considerab

  10. Chemoprevention of intestinal tumorigenesis by nabumetone: induction of apoptosis and Bcl-2 downregulation.

    Science.gov (United States)

    Roy, H K; Karoski, W J; Ratashak, A; Smyrk, T C

    2001-05-18

    Treatment of MIN mice with the nonsteroidal anti-inflammatory drug, nabumetone, resulted in a dose-dependent suppression of intestinal tumorigenesis. In both the uninvolved MIN mouse colonic epithelium and HT-29 colon cancer cells, nabumetone downregulated the anti-apoptotic protein, Bcl-2, with concomitant induction of apoptosis, suggesting a potential mechanism for colon cancer chemoprevention.

  11. MORINGA TEA BLOCKS ACUTE LUNG INFLAMMATION INDUCED BY SWINE CONFINEMENT DUST THROUGH A MECHANISM INVOLVING TNF-α EXPRESSION, C-JUN N-TERMINAL KINASE ACTIVATION AND NEUTROPHIL REGULATION

    Directory of Open Access Journals (Sweden)

    Mykea Mcknight

    2014-01-01

    Full Text Available Plant based products represent a promising alternative to conventional treatments for inflammation. Moringa oleifera Lam is a tree rich in proteins, vitamins, minerals and a variety of phytochemcals with health benefits. Among the reported health benefits are antioxidant and anti-inflammatory properties. The purpose of this study was to investigate whether tea brewed from dried Moringa leaves would abrogate inflammation in a mouse model of acute lung inflammation induced by LPS or extracts prepared from dust collected from a swine confinement facility (DE. Mice were offered water or Moringa tea for seven days. Tea consumption was significantly greater than that of water consumption on days 1 and 6, but there were no significant differences in weight gain or food consumption. On day seven, mice from both groups were forced to inhale, via intranasal challenge, either Phosphate Buffered Saline (PBS, Lipopolysaccharide (LPS [10 µg mL-1] or DE [10%]. Compared to mice that drank water, mice that drank Moringa tea had significantly less protein (p<0.05 and cellular influx (p<0.0001 into the lung after inhalation of 10% DE. No difference in neutrophil migration into the lungs of water and M. tea groups after LPS or DE challenge was detected. But mice that drank tea had significantly (p<0.05 more neutrophils with apoptotic morphology after DE challenge. TNF-α expression 24 h after inhalation of 10% DE, was significantly higher (p<0.05 in lungs of M. tea mouse group as compared to water group. This increase in TNF-α was accompanied by higher levels of pro and anti-inflammatory cytokines. Finally, activation of c-Jun N-terminal Kinase (JNK in lungs of M. tea+DE group 24 h post inhalation was decreased. Taken together these results suggest that Moringa oleifera leaf tea exerts anti-inflammatory properties on acute lung inflammation induced by swine confinement dust through a mechanism involving neutrophil regulation and JNK

  12. MiR-218 Mediates tumorigenesis and metastasis: Perspectives and implications

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ying-fei [Institute Guangzhou of Advanced Technology, Chinese Academy of Sciences, Guangzhou (China); Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Zhang, Li [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong (China); Waye, Mary Miu Yee [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Fu, Wei-ming, E-mail: wm.fu@giat.ac.cn [Institute Guangzhou of Advanced Technology, Chinese Academy of Sciences, Guangzhou (China); School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Jin-fang, E-mail: zhangjf06@cuhk.edu.hk [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen (China)

    2015-05-15

    MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. As a highly conserved miRNA across a variety of species, microRNA-218 (miR-218) was found to play pivotal roles in tumorigenesis and progression. A group of evidence has demonstrated that miR-218 acts as a tumor suppressor by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-218, including its regulatory mechanisms, known functions in cancer and future challenges as a potential therapeutic target in human cancers. - Highlights: • miR-218 is frequently down regulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

  13. Alveolar rhabdomyosarcoma – The molecular drivers of PAX3/7-FOXO1-induced tumorigenesis

    Directory of Open Access Journals (Sweden)

    Marshall Amy D

    2012-12-01

    Full Text Available Abstract Rhabdomyosarcoma is a soft tissue sarcoma arising from cells of a mesenchymal or skeletal muscle lineage. Alveolar rhabdomyosarcoma (ARMS is more aggressive than the more common embryonal (ERMS subtype. ARMS is more prone to metastasis and carries a poorer prognosis. In contrast to ERMS, the majority of ARMS tumors carry one of several characteristic chromosomal translocations, such as t(2;13(q35;q14, which results in the expression of a PAX3-FOXO1 fusion transcription factor. In this review we discuss the genes that cooperate with PAX3-FOXO1, as well as the target genes of the fusion transcription factor that contribute to various aspects of ARMS tumorigenesis. The characterization of these pathways will lead to a better understanding of ARMS tumorigenesis and will allow the design of novel targeted therapies that will lead to better treatment for this aggressive pediatric tumor.

  14. Modulation of K-ras-dependent lung tumorigenesis by microRNA-21

    Science.gov (United States)

    Hatley, Mark E.; Patrick, David M.; Garcia, Matthew R.; Richardson, James A.; Bassel-Duby, Rhonda; Van Rooij, Eva; Olson, Eric N.

    2010-01-01

    SUMMARY Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) accounts for 80% of cases. MicroRNA-21 (miR-21) expression is increased and predicts poor survival in NSCLC. Although miR-21 function has been studied in vitro using cancer cell lines, the role of miR-21 in tumor development in vivo is unknown. We utilize transgenic mice with loss-of-function and gain-of-function miR-21 alleles combined with a model of NSCLC to determine the role of miR-21 in lung cancer. We show that over-expression of miR-21 enhances tumorigenesis and genetic deletion of miR-21 partially protects against tumor formation. MiR-21 drives tumorigenesis through inhibition of negative regulators of the Ras/MEK/ERK pathway and inhibition of apoptosis. PMID:20832755

  15. Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells.

    Science.gov (United States)

    Saito, Taku; Yano, Fumiko; Mori, Daisuke; Kawata, Manabu; Hoshi, Kazuto; Takato, Tsuyoshi; Masaki, Hideki; Otsu, Makoto; Eto, Koji; Nakauchi, Hiromitsu; Chung, Ung-il; Tanaka, Sakae

    2015-01-01

    Induced pluripotent stem cells (iPSCs) are a promising cell source for cartilage regenerative medicine. Meanwhile, the risk of tumorigenesis should be considered in the clinical application of human iPSCs (hiPSCs). Here, we report in vitro chondrogenic differentiation of hiPSCs and maturation of the differentiated hiPSCs through transplantation into mouse knee joints. Three hiPSC clones showed efficient chondrogenic differentiation using an established protocol for human embryonic stem cells. The differentiated hiPSCs formed hyaline cartilage tissues at 8 weeks after transplantation into the articular cartilage of NOD/SCID mouse knee joints. Although tumors were not observed during the 8 weeks after transplantation, an immature teratoma had developed in one mouse at 16 weeks. In conclusion, hiPSCs are a potent cell source for regeneration of hyaline articular cartilage. However, the risk of tumorigenesis should be managed for clinical application in the future.

  16. STAT1 and STAT3 in tumorigenesis: A matter of balance.

    Science.gov (United States)

    Avalle, Lidia; Pensa, Sara; Regis, Gabriella; Novelli, Francesco; Poli, Valeria

    2012-04-01

    The transcription factors STAT1 and STAT3 appear to play opposite roles in tumorigenesis. While STAT3 promotes cell survival/proliferation, motility and immune tolerance and is considered as an oncogene, STAT1 mostly triggers anti-proliferative and pro-apoptotic responses while enhancing anti-tumor immunity. Despite being activated downstream of common cytokine and growth factor receptors, their activation is reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may re-direct cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non-canonical effects of STAT1 and STAT3 activation in tumorigenesis and their potential cross-regulation mechanisms.

  17. Bmi1 promotes prostate tumorigenesis via inhibiting p16 and p14 expression

    OpenAIRE

    Fan, Catherine; He, Lizhi; Kapoor, Anil; Gillis, Aubrey; Rybak, Adrian P.; Cutz, Jean-Claude; Tang, Damu

    2008-01-01

    Bmi1 promotes prostate tumorigenesis via inhibiting p16INK4A and p14ARF expression correspondence: Corresponding authors. Anil Kapoor is to be contacted at Tel.: +1 (905) 522 1155, ext. 33218; fax: +1 (905) 521 6195. Damu Tang, T3310, St. Joseph?s Hospital, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6. Tel.: +1 (905) 522 1155, ext. 35168; fax: +1 (905) 521 6181. (Kapoor, Anil) correspondence: Corresponding authors. Anil Ka...

  18. Overexpression of Sprouty 2 in Mouse Lung Epithelium Inhibits Urethane-Induced Tumorigenesis

    OpenAIRE

    Minowada, George; Miller, York E.

    2008-01-01

    Members of the Sprouty family encode novel proteins that are thought to function primarily as intracellular antagonists of the Ras-signaling pathway. Increased Ras signaling is a critical characteristic of human lung adenocarcinoma, the most common type of non–small cell lung cancer. Sprouty 2 is expressed in the lung epithelium, the tissue layer from which lung cancers arise. We hypothesized that overexpression of Sprouty 2 in the distal lung epithelium would inhibit lung tumorigenesis. To t...

  19. Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis, and viral infection

    OpenAIRE

    2014-01-01

    The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in all aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. In addition, DDX3 is also implicated in cell cycle regulation, apoptosis, Wnt-β-catenin signaling, tumorigenesis, and viral infection. Notably, recent studies suggest that DDX3 is a component of anti-viral innate immune signaling pathways. Indeed, DDX3 contributes to enhance the induction ...

  20. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Hiroto Kinoshita

    Full Text Available Interleukin-6 (IL-6 is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/- mice with wild-type (WT mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/- mice, compared with WT mice. Impaired tumor development in IL-6(-/- mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1 receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.

  1. Hypomethylation of Long Interspersed Nuclear Element-1 is Involved in the Early Tumorigenesis of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Wenhua Piao

    2014-08-01

    high FAL group. No associations between the level of hypomethylation of LINE-1 and HBV infection, age, sex, and cirrhosis were found. Conclusions: These results are strongly suggested that the hypomethylation of LINE-1 plays a role in the hepatocarcinogenesis; moreover, the hypomethylation of LINE-1 occurs not only in the progression of HCC, but also in the early stage of HCC tumorigenesis. [J Interdiscipl Histopathol 2014; 2(4.000: 191-196

  2. Role of the Rb and p53 Tumor Suppressor Pathways in Mammary Tumorigenesis

    Science.gov (United States)

    2012-09-01

    kinase screen and off-patent drug screen) REPORTABLE OUTCOMES Jones, Robert., Jiang, Zhe ., Deng, Tao., Schimmer, AD., Moffat, J and...Robert., Jiang, Zhe ., Deng, Tao., Schimmer, AD., Moffat, J and Zacksenhaus, E. Role of the RB and p53 tumor suppressor pathways in mammary tumorigenesis...CDMRP 2011 Era of Hope Conference Jiang Z, Jones R, Liu JC, Deng T, Robinson T, Chung PE, Wang S, Herschkowitz Jl, Egan SE, Perou CM

  3. Chemoprevention of intestinal tumorigenesis by nabumetone: induction of apoptosis and Bcl-2 downregulation

    OpenAIRE

    Roy, H K; Karoski, W J; Ratashak, A; Smyrk, T. C.

    2001-01-01

    Treatment of MIN mice with the nonsteroidal anti-inflammatory drug, nabumetone, resulted in a dose-dependent suppression of intestinal tumorigenesis. In both the uninvolved MIN mouse colonic epithelium and HT-29 colon cancer cells, nabumetone downregulated the anti-apoptotic protein, Bcl-2, with concomitant induction of apoptosis, suggesting a potential mechanism for colon cancer chemoprevention. © 2001 Cancer Research Campaign www.bjcancer.com

  4. Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis.

    Science.gov (United States)

    Han, Bing; Shin, Hye-Jun; Bak, In Seon; Bak, Yesol; Jeong, Ye-Lin; Kwon, Taeho; Park, Young-Ho; Sun, Hu-Nan; Kim, Cheol-Hee; Yu, Dae-Yeul

    2016-10-18

    Peroxiredoxin I (Prx I), an antioxidant enzyme, has multiple functions in human cancer. However, the role of Prx I in hepatic tumorigenesis has not been characterized. Here we investigated the relevance and underlying mechanism of Prx I in hepatic tumorigenesis. Prx I increased in tumors of hepatocellular carcinoma (HCC) patients that aligned with overexpression of oncogenic H-ras. Prx I also increased in H-rasG12V transfected HCC cells and liver tumors of H-rasG12V transgenic (Tg) mice, indicating that Prx I may be involved in Ras-induced hepatic tumorigenesis. When Prx I was knocked down or deleted in HCC-H-rasG12V cells or H-rasG12V Tg mice, cell colony or tumor formation was significantly reduced that was associated with downregulation of pERK pathway as well as increased intracellular reactive oxygen species (ROS) induced DNA damage and cell death. Overexpressing Prx I markedly increased Ras downstream pERK/FoxM1/Nrf2 signaling pathway and inhibited oxidative damage in HCC cells and H-rasG12V Tg mice. In this study, we found Nrf2 was transcriptionally activated by FoxM1, and Prx I was activated by the H-rasG12V/pERK/FoxM1/Nrf2 pathway and suppressed ROS-induced hepatic cancer-cell death along with formation of a positive feedback loop with Ras/ERK/FoxM1/Nrf2 to promote hepatic tumorigenesis.

  5. CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Bisweswar Nandi

    Full Text Available Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC gene (APCMIN/+ mice to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice. CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.

  6. Miz1 is a critical repressor of cdkn1a during skin tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Jan Hönnemann

    Full Text Available The transcription factor Miz1 forms repressive DNA-binding complexes with the Myc, Gfi-1 and Bcl-6 oncoproteins. Known target genes of these complexes encode the cyclin-dependent kinase inhibitors (CKIs cdkn2b (p15(Ink4, cdkn1a (p21(Cip1, and cdkn1c (p57(Kip2. Whether Miz1-mediated repression is important for control of cell proliferation in vivo and for tumor formation is unknown. Here we show that deletion of the Miz1 POZ domain, which is critical for Miz1 function, restrains the development of skin tumors in a model of chemically-induced, Ras-dependent tumorigenesis. While the stem cell compartment appears unaffected, interfollicular keratinocytes lacking functional Miz1 exhibit a reduced proliferation and an accelerated differentiation of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA. Tumorigenesis, proliferation and normal differentiation are restored in animals lacking cdkn1a, but not in those lacking cdkn2b. Our data demonstrate that Miz1-mediated attenuation of cell cycle arrest pathways via repression of cdkn1a has a critical role during tumorigenesis in the skin.

  7. Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.

    Science.gov (United States)

    Housseau, Franck; Wu, Shaoguang; Wick, Elizabeth C; Fan, Hongni; Wu, Xinqun; Llosa, Nicolas J; Smith, Kellie N; Tam, Ada; Ganguly, Sudipto; Wanyiri, Jane W; Iyadorai, Thevambiga; Malik, Ausama A; Roslani, April C; Vadivelu, Jamunarani S; Van Meerbeke, Sara; Huso, David L; Pardoll, Drew M; Sears, Cynthia L

    2016-04-15

    IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.

  8. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.

    Science.gov (United States)

    Inokuchi-Shimizu, Sayaka; Park, Eek Joong; Roh, Yoon Seok; Yang, Ling; Zhang, Bi; Song, Jingyi; Liang, Shuang; Pimienta, Michael; Taniguchi, Koji; Wu, Xuefeng; Asahina, Kinji; Lagakos, William; Mackey, Mason R; Akira, Shizuo; Ellisman, Mark H; Sears, Dorothy D; Olefsky, Jerrold M; Karin, Michael; Brenner, David A; Seki, Ekihiro

    2014-08-01

    The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.

  9. Extra sex combs, chromatin, and cancer: Exploring epigenetic regulation and tumorigenesis in Drosophila

    Institute of Scientific and Technical Information of China (English)

    Can Zhang; Bo Liu; Guangyao Li; Lei Zhou

    2011-01-01

    Developmental genetic studies in Drosophila unraveled the importance of Polycomb group (PcG) and Trithorax group (TrxG) genes in controlling cellular identity.PcG and TrxG proteins form histone modifying complexes that catalyze repressive or activating histone modifications,respectively,and thus maintaining the expression status of homeotic genes.Human orthologs of PcG and TrxG genes are implicated in tumorigenesis as well as in determining the prognosis of individual cancers.Recent whole genome analyses of cancers also highlighted the importance of histone modifying proteins in controlling tumorigenesis.Comprehensive understanding of the mechanistic relationship between histone regulation and tumorigenesis holds the promise of significantly advancing our understanding and management of cancer.It is anticipated that Drosophila melanogaster,the model organism that contributed significantly to our understanding of the functional role of histone regulation in development,could also provide unique insight for our understanding of how histone dysregulation can lead to cancer.In this review,we will discuss several recent advances in this regard.

  10. MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer.

    Science.gov (United States)

    Edmonds, Mick D; Boyd, Kelli L; Moyo, Tamara; Mitra, Ramkrishna; Duszynski, Robert; Arrate, Maria Pia; Chen, Xi; Zhao, Zhongming; Blackwell, Timothy S; Andl, Thomas; Eischen, Christine M

    2016-01-01

    MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.

  11. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    Directory of Open Access Journals (Sweden)

    Wang Jufang

    2011-08-01

    Full Text Available Abstract Background Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Methods Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Results Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. Conclusions The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

  12. Effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on viral hemorrhagic septicemia virus (VHSV) infection-mediated apoptosis and viral replication.

    Science.gov (United States)

    Kim, Min Sun; Lee, Ji Ae; Kim, Ki Hong

    2016-04-01

    In the development of inactivated or attenuated viral vaccines for cultured fish, viral titers harvested from the cultured cells would be the most important factor for the determination of vaccine's cost effectiveness. In this study, we hypothesized that the lengthening of cell survival time by the inhibition of apoptosis can lead to an increase of the final titer of viral hemorrhagic septicemia virus (VHSV). To test the hypothesis, we investigated the effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on VHSV infection-mediated apoptosis in Epithelioma papulosum cyprini (EPC) cells and on the VHSV titers. VHSV infection induced the DNA laddering in EPC cells, and the progression of DNA fragmentation was in proportion to the CPE extension. The progression of DNA fragmentation in EPC cells infected with VHSV was clearly inhibited by exposure to Z-VAD(OMe)-FMK, and the inhibition was intensified according to the increase of the inhibitor concentration. These results confirmed the previous reports that the death of host cells by VHSV infection is through apoptosis. Cells infected with a recombinant VHSV, rVHSV-ΔNV-eGFP, that was generated from our previous study by replacement of the NV gene ORF with the enhanced green fluorescent protein (eGFP) gene ORF, showed earlier and more distinct DNA fragmentations compared to the cells infected with wild-type VHSV, suggesting the inhibitory role of the NV protein in VHSV-mediated apoptosis that was previously reported. The final viral titers in the supernatant isolated from Z-VAD(OMe)-FMK treated cells after showing an extensive CPE were significantly higher than the viral titers from cells infected with virus alone, indicating that the delay of apoptosis by Z-VAD(OMe)-FMK extended the survival time of EPC cells, which lengthen the time for VHSV replication in the cells. In conclusion, Z-VAD(OMe)-FMK-mediated inhibition of apoptosis significantly increased the final titers of both wild-type VHSV and r

  13. Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits.

    Science.gov (United States)

    Tao, Wenjuan; Chen, Quan; Zhou, Wenjie; Wang, Yunping; Wang, Lu; Zhang, Zhi

    2014-08-08

    The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.

  14. Inflammation Induces TDP-43 Mislocalization and Aggregation.

    Directory of Open Access Journals (Sweden)

    Ana Sofia Correia

    Full Text Available TAR DNA-binding protein 43 (TDP-43 is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Here we report that lipopolysaccharide (LPS-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

  15. Inflammation induced loss of skeletal muscle.

    Science.gov (United States)

    Londhe, Priya; Guttridge, Denis C

    2015-11-01

    Inflammation is an important contributor to the pathology of diseases implicated in skeletal muscle dysfunction. A number of diseases and disorders including inflammatory myopathies and Chronic Obstructive Pulmonary Disorder (COPD) are characterized by chronic inflammation or elevation of the inflammatory mediators. While these disease states exhibit different pathologies, all have in common the loss of skeletal muscle mass and a deregulated skeletal muscle physiology. Pro-inflammatory cytokines are key contributors to chronic inflammation found in many of these diseases. This section of the review focuses on some of the known inflammatory disorders like COPD, Rheumatoid Arthritis (RA) and inflammatory myopathies that display skeletal muscle atrophy and also provides the reader an overview of the mediators of inflammation, their signaling pathways, and mechanisms of action. This article is part of a Special Issue entitled "Muscle Bone Interactions".

  16. SIGNIFICANCE AND CORRELATION OF MAPK/ERK2 AND PI3-K IN HUMAN BREAST TUMORIGENESIS

    Institute of Scientific and Technical Information of China (English)

    MA Ping; LI Bai-lin; ZHANG Ying; SONG Min; SONG Ji-ye

    2006-01-01

    Objective: MAPK ((Mitogen-actived Protein Kinase) and PI3-K (Phosphatidylinositol 3-kinase) pathways have been implicated in the mitogenic pathways regulating cell growth, proliferation, differentiation and transformation and thus involved in tumorigenesis. This study was designed to examined the protein expression, activity and mRNA levels of both ERK and PI3-K in a series of breast tumors and adjacent mammary glands, and to figure out the changes of ERK2 and PI3-K during the dynamic process of breast tumorigenesis. Methods: A series of breast tumors and adjacent mammary glands were collected at surgery, including 37 cases of breast cancer, 6 cases of atypical hyperplasia-breast carcinoma in situ and 15 cases of benign conditions. Western blot, kinase activity assay and RT-PCR were used to detect the protein expression, kinase activity and mRNA level, respectively. Results: The revels of protein, activity and mRNA of ERK2 were elevated during the stages of both initiation and progression. The increasing tendency in breast cancer was equal to atypical hyperplasia -in situ carcinoma, but higher than in benign lesion and adjacent normal mammary gland. PI3-K was activated during the stage of progression of breast cancer. An inverse correlation between the activity of PI3-K and ERK2 in breast cancer was found. Conclusion: Our findings indicate that ERK2 may perform its function during both the stages of breast cancer initiation and breast cancer progression, while PI3-K may exert its effect during the stage of breast cancer progression. Both PI3-k and ERK2 are involved in the tumorigenesis of breast cancer.

  17. Evaluation of Rint1 as a modifier of intestinal tumorigenesis and cancer risk

    Science.gov (United States)

    Otterpohl, Karla L.; Gould, Karen A.

    2017-01-01

    The Rad50 Interacting Protein 1 (Rint1) influences cellular homeostasis through maintenance of endoplasmic reticulum, Golgi and centrosome integrity and regulation of vesicle transport, autophagy and the G2/M checkpoint. Rint1 has been postulated to function as a tumor suppressor as well as an oncogene, with its role depending perhaps upon the precise cellular and/or experimental context. In humans, heterozygosity for germline missense variants in RINT1 have, in some studies, been associated with increased risk of both breast and Lynch syndrome type cancers. However, it is not known if these germline variants represent loss of function alleles or gain of function alleles. Based upon these findings, as well as our initial consideration of Rint1 as a potential candidate for Mom5, a genetic modifier of intestinal tumorigenesis in ApcMin/+ mice, we sought to explicitly examine the impact of Rint1 on tumorigenesis in ApcMin/+ mice. However, heterozygosity for a knockout of Rint1 had no impact on tumorigenesis in Rint1+/-; ApcMin/+ mice. Likewise, we found no evidence to suggest that the remaining Rint1 allele was lost somatically in intestinal tumors in ApcMin/+ mice. Interestingly, in contrast to what has been observed in Rint1+/- mice on a mixed genetic background, Rint1+/- mice on a pure C57BL/6J background did not show spontaneous tumor development. We also evaluated colorectal cancer data available in the COSMIC and ONCOMINE databases and found that RINT1 overexpression, as well as the presence of somatic missense mutations in RINT1 were associated with colorectal cancer development. In vitro evaluation of two missense variants in RINT1 suggested that such variants do have the potential to impact RINT1 function. PMID:28264000

  18. Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.

    Science.gov (United States)

    Liu, Chunping; Shen, Haitao; Yi, Li; Shao, Peilu; Soulika, Athena M; Meng, Xinxing; Xing, Lingxiao; Yan, Xia; Zhang, Xianghong

    2015-02-03

    Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis.

  19. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

    Science.gov (United States)

    Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P.; Taylor, Renea A.; Watt, Matthew J.

    2016-01-01

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis. PMID:27351281

  20. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts.

    Science.gov (United States)

    Lo, Jennifer C Y; Clark, Ashlee K; Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P; Taylor, Renea A; Watt, Matthew J

    2016-07-26

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.

  1. Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.

    Science.gov (United States)

    Sawai, Yugo; Kodama, Yuzo; Shimizu, Takahiro; Ota, Yuji; Maruno, Takahisa; Eso, Yuji; Kurita, Akira; Shiokawa, Masahiro; Tsuji, Yoshihisa; Uza, Norimitsu; Matsumoto, Yuko; Masui, Toshihiko; Uemoto, Shinji; Marusawa, Hiroyuki; Chiba, Tsutomu

    2015-08-15

    Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC.

  2. PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis.

    Science.gov (United States)

    Izaguirre, Daisy I; Zhu, Wen; Hai, Tao; Cheung, Hannah C; Krahe, Ralf; Cote, Gilbert J

    2012-11-01

    Aberrant RNA splicing is thought to play a key role in tumorigenesis. The assessment of its specific contributions is limited by the complexity of information derived from genome-wide array-based approaches. We describe how performing splicing factor-specific comparisons using both tumor and cell line data sets may more readily identify physiologically relevant tumor-specific splicing events. Affymetrix exon array data derived from glioblastoma (GBM) tumor samples with defined polypyrimidine tract-binding protein 1 (PTBP1) levels were compared with data from U251 GBM cells with and without PTBP1 knockdown. This comparison yielded overlapping gene sets that comprised only a minor fraction of each data set. The identification of a novel GBM-specific splicing event involving the USP5 gene led us to further examine its role in tumorigenesis. In GBM, USP5 generates a shorter isoform 2 through recognition of a 5' splice site within exon 15. Production of the USP5 isoform 2 was strongly correlated with PTBP1 expression in GBM tumor samples and cell lines. Splicing regulation was consistent with the presence of an intronic PTBP1 binding site and could be modulated through antisense targeting of the isoform 2 splice site to force expression of isoform 1 in GBM cells. The forced expression of USP5 isoform 1 in two GBM cell lines inhibited cell growth and migration, implying an important role for USP5 splicing in gliomagenesis. These results support a role for aberrant RNA splicing in tumorigenesis and suggest that changes in relatively few genes may be sufficient to drive the process.

  3. An inducible krasV12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening

    Directory of Open Access Journals (Sweden)

    Anh Tuan Nguyen

    2012-01-01

    Because Ras signaling is frequently activated by major hepatocellular carcinoma etiological factors, a transgenic zebrafish constitutively expressing the krasV12 oncogene in the liver was previously generated by our laboratory. Although this model depicted and uncovered the conservation between zebrafish and human liver tumorigenesis, the low tumor incidence and early mortality limit its use for further studies of tumor progression and inhibition. Here, we employed a mifepristone-inducible transgenic system to achieve inducible krasV12 expression in the liver. The system consisted of two transgenic lines: the liver-driver line had a liver-specific fabp10 promoter to produce the LexPR chimeric transactivator, and the Ras-effector line contained a LexA-binding site to control EGFP-krasV12 expression. In double-transgenic zebrafish (driver-effector embryos and adults, we demonstrated mifepristone-inducible EGFP-krasV12 expression in the liver. Robust and homogeneous liver tumors developed in 100% of double-transgenic fish after 1 month of induction and the tumors progressed from hyperplasia by 1 week post-treatment (wpt to carcinoma by 4 wpt. Strikingly, liver tumorigenesis was found to be ‘addicted’ to Ras signaling for tumor maintenance, because mifepristone withdrawal led to tumor regression via cell death in transgenic fish. We further demonstrated the potential use of the transparent EGFP-krasV12 larvae in inhibitor treatments to suppress Ras-driven liver tumorigenesis by targeting its downstream effectors, including the Raf-MEK-ERK and PI3K-AKT-mTOR pathways. Collectively, this mifepristone-inducible and reversible krasV12 transgenic system offers a novel model for understanding hepatocarcinogenesis and a high-throughput screening platform for anti-cancer drugs.

  4. Co-infection ofEpstein-Barr virus andhuman papillomavirus inhuman tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    YingShi; SongLingPeng; LiFangYang; XueChen; YongGuangTao; YaCao

    2016-01-01

    Viral infections contribute to approximately 12% of cancers worldwide, with the vast majority occurring in developing countries and areas. Two DNA viruses, Epstein‑Barr virus (EBV) and human papillomavirus (HPV), are associated with 38% of all virus‑associated cancers. The probability of one patient infected with these two distinct types of viruses is increasing. Here, we summarize the co‑infection of EBV and HPV in human malignancies and address the possible mechanisms for the co‑infection of EBV and HPV during tumorigenesis.

  5. MicroRNA in Metabolic Re-Programming and Their Role in Tumorigenesis

    Science.gov (United States)

    Tomasetti, Marco; Amati, Monica; Santarelli, Lory; Neuzil, Jiri

    2016-01-01

    The process of metabolic re-programing is linked to the activation of oncogenes and/or suppression of tumour suppressor genes, which are regulated by microRNAs (miRNAs). The interplay between oncogenic transformation-driven metabolic re-programming and modulation of aberrant miRNAs further established their critical role in the initiation, promotion and progression of cancer by creating a tumorigenesis-prone microenvironment, thus orchestrating processes of evasion to apoptosis, angiogenesis and invasion/migration, as well metastasis. Given the involvement of miRNAs in tumour development and their global deregulation, they may be perceived as biomarkers in cancer of therapeutic relevance. PMID:27213336

  6. The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis.

    Science.gov (United States)

    Wellberg, Elizabeth A; Johnson, Stevi; Finlay-Schultz, Jessica; Lewis, Andrew S; Terrell, Kristina L; Sartorius, Carol A; Abel, E Dale; Muller, William J; Anderson, Steven M

    2016-12-20

    Altered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis. To determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 (Flox/Flox) (GLUT1(Flox/Flox)) mice to generate NIC-GLUT1(+/+), NIC-GLUT1(Flox/+), and NIC-GLUT1(Flox/Flox) mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis. All of the NIC-GLUT1(+/+) mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1(Flox/Flox) mouse and 1 NIC-GLUT1(Flox/+) mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1(Flox/+) mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress. This study demonstrates a strict requirement for GLUT1 in the early stages of

  7. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity

    DEFF Research Database (Denmark)

    Fedele, Monica; Visone, Rosa; De Martino, Ivana

    2006-01-01

    HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we......2 mice. Thus, HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors in transgenic mice and probably also in human prolactinomas....

  8. The Role of Skp2 in the Prostate Tumorigenesis Following Rb and p53 Loss

    Science.gov (United States)

    2015-12-01

    9 mM NaCl, 40 mM citric acid /sodium phosphate buffer pH6.0, and 1 mg/ml X-gal) for 16 hr (MEFs) and 5 hr (human cancer cell lines) at 37C...2012). Activated p53 switches on its target genes to induce cell- cycle arrest, senescence, and apoptosis to safe- guard against tumorigenesis. In...blot analysis. The cyclin A protein level is shown to indicate cell- cycle progression, and the tubulin level is shown to indicate loading amounts. FBS

  9. Inflammation, aging, and cancer: tumoricidal versus tumorigenesis of immunity: a common denominator mapping chronic diseases.

    Science.gov (United States)

    Khatami, Mahin

    2009-01-01

    Acute inflammation is a highly regulated defense mechanism of immune system possessing two well-balanced and biologically opposing arms termed apoptosis ('Yin') and wound healing ('Yang') processes. Unresolved or chronic inflammation (oxidative stress) is perhaps the loss of balance between 'Yin' and 'Yang' that would induce co-expression of exaggerated or 'mismatched' apoptotic and wound healing factors in the microenvironment of tissues ('immune meltdown'). Unresolved inflammation could initiate the genesis of many age-associated chronic illnesses such as autoimmune and neurodegenerative diseases or tumors/cancers. In this perspective 'birds' eye' view of major interrelated co-morbidity risk factors that participate in biological shifts of growth-arresting ('tumoricidal') or growth-promoting ('tumorigenic') properties of immune cells and the genesis of chronic inflammatory diseases and cancer will be discussed. Persistent inflammation is perhaps a common denominator in the genesis of nearly all age-associated health problems or cancer. Future challenging opportunities for diagnosis, prevention, and/or therapy of chronic illnesses will require an integrated understanding and identification of developmental phases of inflammation-induced immune dysfunction and age-associated hormonal and physiological readjustments of organ systems. Designing suitable cohort studies to establish the oxido-redox status of adults may prove to be an effective strategy in assessing individual's health toward developing personal medicine for healthy aging.

  10. Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway.

    Science.gov (United States)

    Zhang, Qian-Qian; Zhou, Da-Lei; Lei, Yan; Zheng, Li; Chen, Sheng-Xia; Gou, Hong-Ju; Gu, Qu-Liang; He, Xiao-Dong; Lan, Tian; Qi, Cui-Ling; Li, Jiang-Chao; Ding, Yan-Qing; Qiao, Liang; Wang, Li-Jing

    2015-02-20

    Slit2 is often overexpressed in cancers. Slit2 is a secreted protein that binds to Roundabout (Robo) receptors to regulate cell growth and migration. Here, we employed several complementary mouse models of intestinal cancers, including the Slit2 transgenic mice, the ApcMin/+ spontaneous intestinal adenoma mouse model, and the DMH/DSS-induced colorectal carcinoma model to clarify function of Slit2/Robo1 signaling in intestinal tumorigenesis. We showed that Slit2 and Robo1 are overexpressed in intestinal tumors and may contribute to tumor generation. The Slit2/Robo1 signaling can induce precancerous lesions of the intestine and tumor progression. Ectopic expression of Slit2 activated Slit2/Robo1 signaling and promoted tumorigenesis and tumor growth. This was mediated in part through activation of the Src signaling, which then down-regulated E-cadherin, thereby activating Wnt/β-catenin signaling. Thus, Slit2/Robo1 signaling is oncogenic in intestinal tumorigenesis.

  11. Loss of p53 Ser18 and Atm results in embryonic lethality without cooperation in tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Heather L Armata

    Full Text Available Phosphorylation at murine Serine 18 (human Serine 15 is a critical regulatory process for the tumor suppressor function of p53. p53Ser18 residue is a substrate for ataxia-telangiectasia mutated (ATM and ATM-related (ATR protein kinases. Studies of mice with a germ-line mutation that replaces Ser18 with Ala (p53(S18A mice have demonstrated that loss of phosphorylation of p53Ser18 leads to the development of tumors, including lymphomas, fibrosarcomas, leukemia and leiomyosarcomas. The predominant lymphoma is B-cell lymphoma, which is in contrast to the lymphomas observed in Atm(-/- animals. This observation and the fact that multiple kinases phosphorylate p53Ser18 suggest Atm-independent tumor suppressive functions of p53Ser18. Therefore, in order to examine p53Ser18 function in relationship to ATM, we analyzed the lifespan and tumorigenesis of mice with combined mutations in p53Ser18 and Atm. Surprisingly, we observed no cooperation in survival and tumorigenesis in compound p53(S18A and Atm(-/- animals. However, we observed embryonic lethality in the compound mutant animals. In addition, the homozygous p53Ser18 mutant allele impacted the weight of Atm(-/- animals. These studies examine the genetic interaction of p53Ser18 and Atm in vivo. Furthermore, these studies demonstrate a role of p53Ser18 in regulating embryonic survival and motor coordination.

  12. Elevated NIBP/TRAPPC9 mediates tumorigenesis of cancer cells through NFκB signaling.

    Science.gov (United States)

    Zhang, Yonggang; Liu, Shu; Wang, Hong; Yang, Wensheng; Li, Fang; Yang, Fan; Yu, Daohai; Ramsey, Frederick V; Tuszyski, George P; Hu, Wenhui

    2015-03-20

    Regulatory mechanisms underlying constitutive and inducible NFκB activation in cancer remain largely unknown. Here we investigated whether a novel NIK- and IKK2-binding protein (NIBP) is required for maintaining malignancy of cancer cells in an NFκB-dependent manner. Real-time polymerase chain reaction analysis of a human cancer survey tissue-scan cDNA array, immunostaining of a human frozen tumor tissue array and immunoblotting of a high-density reverse-phase cancer protein lysate array showed that NIBP is extensively expressed in most tumor tissues, particularly in breast and colon cancer. Lentivirus-mediated NIBP shRNA knockdown significantly inhibited the growth/proliferation, invasion/migration, colony formation and xenograft tumorigenesis of breast (MDA-MB-231) or colon (HCT116) cancer cells. NIBP overexpression in HCT116 cells promoted cell proliferation, migration and colony formation. Mechanistically, NIBP knockdown in cancer cells inhibited cytokine-induced activation of NFκB luciferase reporter, thus sensitizing the cells to TNFα-induced apoptosis. Endogenous NIBP bound specifically to the phosphorylated IKK2 in a TNFα-dependent manner. NIBP knockdown transiently attenuated TNFα-stimulated phosphorylation of IKK2/p65 and degradation of IκBα. In contrast, NIBP overexpression enhanced TNFα-induced NFκB activation, thus inhibiting constitutive and TNFα-induced apoptosis. Collectively, our data identified important roles of NIBP in promoting tumorigenesis via NFκΒ signaling, spotlighting NIBP as a promising target in cancer therapeutic intervention.

  13. miR-92a family and their target genes in tumorigenesis and metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Li, Molin, E-mail: molin_li@hotmail.com [Department of Pathophysiology, Basic Medical Science of Dalian Medical University, Dalian 116044 (China); Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian 116044 (China); Guan, Xingfang; Sun, Yuqiang [Department of Pathophysiology, Basic Medical Science of Dalian Medical University, Dalian 116044 (China); Mi, Jun [Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian 116044 (China); Shu, Xiaohong [College of Pharmacy, Dalian Medical University Cancer Center, Dalian 116044 (China); Liu, Fang [Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027 (China); Li, Chuangang, E-mail: li_chuangang@sina.com [Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027 (China)

    2014-04-15

    The miR-92a family, including miR-25, miR-92a-1, miR-92a-2 and miR-363, arises from three different paralog clusters miR-17-92, miR-106a-363, and miR-106b-25 that are highly conservative in the process of evolution, and it was thought as a group of microRNAs (miRNAs) correlated with endothelial cells. Aberrant expression of miR-92a family was detected in multiple cancers, and the disturbance of miR-92a family was related with tumorigenesis and tumor development. In this review, the progress on the relationship between miR-92a family and their target genes and malignant tumors will be summarized. - Highlights: • Aberrant expression of miR-92a, miR-25 and miR-363 can be observed in many kinds of malignant tumors. • The expression of miR-92a family is regulated by LOH, epigenetic alteration, transcriptional factors such as SP1, MYC, E2F, wild-type p53 etc. • Roles of miR-92a family in tumorigenesis and development: promoting cell proliferation, invasion and metastasis, inhibiting cell apoptosis.

  14. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis.

    Science.gov (United States)

    Goodwin, Andrew C; Destefano Shields, Christina E; Wu, Shaoguang; Huso, David L; Wu, XinQun; Murray-Stewart, Tracy R; Hacker-Prietz, Amy; Rabizadeh, Shervin; Woster, Patrick M; Sears, Cynthia L; Casero, Robert A

    2011-09-13

    It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) up-regulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N(1),N(4)-bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.

  15. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis

    Science.gov (United States)

    Goodwin, Andrew C.; Shields, Christina E. Destefano; Wu, Shaoguang; Huso, David L.; Wu, XinQun; Murray-Stewart, Tracy R.; Hacker-Prietz, Amy; Rabizadeh, Shervin; Woster, Patrick M.; Sears, Cynthia L.; Casero, Robert A.

    2011-01-01

    It is estimated that the etiology of 20–30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) up-regulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N1,N4-bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention. PMID:21876161

  16. Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1.

    Science.gov (United States)

    Joo, Nam E; Ritchie, Kathryn; Kamarajan, Pachiyappan; Miao, Di; Kapila, Yvonne L

    2012-12-01

    Nisin, a bacteriocin and commonly used food preservative, may serve as a novel potential therapeutic for treating head and neck squamous cell carcinoma (HNSCC), as it induces preferential apoptosis, cell cycle arrest, and reduces cell proliferation in HNSCC cells, compared with primary keratinocytes. Nisin also reduces HNSCC tumorigenesis in vivo. Mechanistically, nisin exerts these effects on HNSCC, in part, through CHAC1, a proapoptotic cation transport regulator, and through a concomitant CHAC1-independent influx of extracellular calcium. In addition, although CHAC1 is known as an apoptotic mediator, its effects on cancer cell apoptosis have not been examined. Our studies are the first to report CHAC1's new role in promoting cancer cell apoptosis under nisin treatment. These data support the concept that nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC, and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated.

  17. Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis.

    Science.gov (United States)

    Lunardi, Andrea; Varmeh, Shohreh; Chen, Ming; Taulli, Riccardo; Guarnerio, Jlenia; Ala, Ugo; Seitzer, Nina; Ishikawa, Tomoki; Carver, Brett S; Hobbs, Robin M; Quarantotti, Valentina; Ng, Christopher; Berger, Alice H; Nardella, Caterina; Poliseno, Laura; Montironi, Rodolfo; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Signoretti, Sabina; Pandolfi, Pier Paolo

    2015-05-01

    The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members, such as ERG, ETV1, ETV4, and ETV5, are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here, we show that ETS family members, such as ERG and ETV1, directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell-cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia into prostatic invasive carcinoma in Pten(+) (/-) mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications. Genetic translocation and aberrant expression of ETS family members is a common event in different types of human tumors. Here, we show that through the transcriptional repression of CHK1, ETS factors may favor DNA damage accumulation and consequent genetic instability in proliferating cells. Importantly, our findings provide a rationale for testing DNA replication inhibitor agents in ETS-positive TP53-proficient tumors. ©2015 American Association for Cancer Research.

  18. Genetic mapping of Mom5, a novel modifier of Apc(Min)-induced intestinal tumorigenesis.

    Science.gov (United States)

    Oikarinen, Seija I; Cleveland, Alicia G; Cork, Karlene M; Bynoté, Kimberly K; Rafter, Joseph J; Gustafsson, Jan-Ake; Mutanen, Marja; Gould, Karen A

    2009-09-01

    The initial purpose of this study was to assess the role of estrogen receptor beta (ERbeta) in intestinal tumorigenesis by examining the effects of an ERbeta knockout (ERbeta(-/-)) on Apc(Min) mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERbeta knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N(5) backcross generation of the ERbeta knockout strain were intercrossed with Apc(Min/+) mice to obtain Apc(Min/+) ERbeta(+/+), Apc(Min/+) ERbeta(+/-) and Apc(Min/+) ERbeta(-/-) mice. Intestinal tumorigenesis in the N(5)F(2) mice was evaluated at 14 weeks of age. The analysis of the impact of ERbeta in the N(5) cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERbeta. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc(Min/+) mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.

  19. miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion.

    Directory of Open Access Journals (Sweden)

    Dahu Chen

    2014-02-01

    Full Text Available Whether epithelial-mesenchymal transition (EMT is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.

  20. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

    Science.gov (United States)

    Wassef, Michel; Rodilla, Veronica; Teissandier, Aurélie; Zeitouni, Bruno; Gruel, Nadege; Sadacca, Benjamin; Irondelle, Marie; Charruel, Margaux; Ducos, Bertrand; Michaud, Audrey; Caron, Matthieu; Marangoni, Elisabetta; Chavrier, Philippe; Le Tourneau, Christophe; Kamal, Maud; Pasmant, Eric; Vidaud, Michel; Servant, Nicolas; Reyal, Fabien; Meseure, Dider; Vincent-Salomon, Anne; Fre, Silvia; Margueron, Raphaël

    2015-01-01

    Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications. PMID:26637281

  1. Diet induced obesity increases the risk of colonic tumorigenesis in mice.

    Science.gov (United States)

    Sikalidis, Angelos K; Fitch, Mark D; Fleming, Sharon E

    2013-10-01

    A large body of epidemiological data indicates that obesity increases the risk of colon cancer in humans. There are limited studies using rodent models where the relationship between obesity and colon cancer has been studied. In this study, wild-type diet-induced obese (DIO) mice and lean wild-type controls were used to investigate the influence of obesity on the risk of colon cancer. We hypothesized that the obese phenotype would exhibit increased colonic tumorigenesis. Colon cancer was chemically induced by injecting the mice with azoxymethane (AOM) at levels that we experimentally determined to result in equivalent AOM concentrations in circulating blood. Risk of colon cancer was assessed via microscopic examination of entire colons for aberrant crypts, aberrant crypt foci and proliferation levels. The DIO mice were found to have significantly more aberrant crypts and aberrant crypt foci as well as increased proliferation of colonocytes per mouse compared to wild-type control mice, supporting the epidemiological data that obesity increases the risk of colonic tumorigenesis.

  2. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Phuoc T Tran

    Full Text Available KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

  3. Mechanisms by Which Interleukin-6 Attenuates Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Ke-Hung Tsui

    2013-01-01

    Full Text Available Interleukin-6, a multifunctional cytokine, contributes to tumor cell proliferation and differentiation. However, the biological mechanisms that are affected by the expression of interleukin-6 in bladder cancer cells remain unclear. We evaluated the effects of interleukin-6 expression in human bladder carcinoma cells in vitro and in vivo. The results of interleukin-6-knockdown experiments in T24 cells and interleukin-6-overexpression experiments in HT1376 cells revealed that interleukin-6 reduced cell proliferation, migration, and invasion in vitro. Xenograft animal studies indicated that the overexpression of interleukin-6 downregulated tumorigenesis of bladder cells and that interleukin-6 knockdown reversed this effect. The results of RT-PCR, immunoblotting, and reporter assays indicated that the overexpression of interleukin-6 upregulated the expression of the mammary serine protease inhibitor (MASPIN, N-myc downstream gene 1 (NDRG1, and KAI1 proteins in HT1376 cells and that interleukin-6 knockdown reduced the expression of these proteins in T24 cells. In addition, results of immunoblotting assays revealed that interleukin-6 modulated epithelial-mesenchymal transitions by upregulating the expression of the E-cadherin, while downregulation N-cadherin and vimentin proteins. Our results suggest that the effects of interleukin-6 on the regulation of epithelial-mesenchymal transitions and the expressions of the MASPIN, NDRG1, and KAI1 genes attribute to the modulation of tumorigenesis in human bladder carcinoma cells.

  4. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.

    Science.gov (United States)

    Wassef, Michel; Rodilla, Veronica; Teissandier, Aurélie; Zeitouni, Bruno; Gruel, Nadege; Sadacca, Benjamin; Irondelle, Marie; Charruel, Margaux; Ducos, Bertrand; Michaud, Audrey; Caron, Matthieu; Marangoni, Elisabetta; Chavrier, Philippe; Le Tourneau, Christophe; Kamal, Maud; Pasmant, Eric; Vidaud, Michel; Servant, Nicolas; Reyal, Fabien; Meseure, Dider; Vincent-Salomon, Anne; Fre, Silvia; Margueron, Raphaël

    2015-12-15

    Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.

  5. Diverse roles of C-terminal Hsp70-interacting protein (CHIP) in tumorigenesis.

    Science.gov (United States)

    Sun, Chao; Li, Hai-Long; Shi, Mei-Lin; Liu, Qing-Hua; Bai, Jin; Zheng, Jun-Nian

    2014-02-01

    The carboxyl terminus of Hsp70-interacting protein (CHIP) is a member of E3 ubiquitin ligase, functioning as a link between the chaperone (heat shock protein 70/90) and proteasome systems, playing a vital role in maintaining the protein homeostasis in the cytoplasm. CHIP has been demonstrated to be involved in tumorigenesis, proliferation and invasion in several malignancies, regulating a number of oncogenic proteins. However, CHIP has also been implicated in the modulation of tumor suppressor proteins. The pathogenic mechanism of CHIP expression in human malignancy is not yet clear, and a number of studies have suggested that CHIP may have opposing roles in different cancers. Therefore, many studies have focused on the relationship between CHIP and carcinoma. A literature search focusing on regulation network, biological function and clinical significance of CHIP in connection with its role in cancer development was performed on the MEDLINE databases. CHIP may be a potential diagnostic biomarker and therapeutic target for human cancer, and may play different roles in different human cancers. This inconsistence might be induced by the diversity of CHIP downstream targeting proteins. Therefore, the phenotypes determined by CHIP should be dependent on the function of its specific targets in a specific type of cancer cells. Whether CHIP contributes to tumor progression or suppression in various human cancers remains unclear, suggesting the necessity of further extensive investigation of its role in tumorigenesis.

  6. The Rab2A GTPase Promotes Breast Cancer Stem Cells and Tumorigenesis via Erk Signaling Activation

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    Man-Li Luo

    2015-04-01

    Full Text Available Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs. Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients. Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.

  7. "The Lower Threshold" phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis?

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    Heidrun Weidemann

    2012-01-01

    Full Text Available Since their first discovery as potential anti-cancer drugs decades ago, there is increasing evidence that digitalis-like compounds (DLC have anti-tumor effects. Less is known about endogenous DLC (EDLC metabolism and regulation. As stress hormones synthesized in and secreted from the adrenal gland, they likely take part in the hypothalamo-pituitary-adrenal (HPA axis. In a previous study, we revealed reduced EDLC concentrations in plasma and organs from immune-compromised animals and proposed that a similar situation of a deregulated HPA axis with "adrenal EDLF exhaustion" may contribute to tumorigenesis in chronic stress situations. Here, we put forward the hypothesis that a lowered EDLC response threshold of tumor cells as compared with normal cells increases the risk of tumorigenesis, especially in those individuals with reduced EDLC plasma concentrations after chronic stress exposure. We will evaluate this hypothesis by (a summarizing the effects of different DLC concentrations on tumor as compared with normal cells and (b reviewing some essential differences in the Na/K-ATPase of tumor as compared with normal cells (isoform pattern, pump activity, mutations of other signalosome receptors. We will conclude that (1 tumor cells, indeed, seem to have their individual "physiologic" EDLC response range that already starts at pmolar levels and (2 that individuals with markedly reduced (pmolar EDLC plasma levels are predisposed to cancer because these EDLC concentrations will predominantly stimulate the proliferation of tumor cells. Finally, we will summarize preliminary results from our department supporting this hypothesis.

  8. Angiogenesis is a link between atherosclerosis and tumorigenesis: role of LOX-1.

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    Jiang, Junlin; Yan, Meiling; Mehta, Jawahar L; Hu, Changping

    2011-10-01

    Angiogenesis is defined as the formation of new blood vessels sprouting from pre-existing vessels. It plays an important role not only in physiological situations such as embryonic vascular development and wound healing, but also in pathological conditions including atherogenesis and evolution and spread of certain tumors. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low density lipoprotein (ox-LDL), is mainly expressed in endothelial cells. It has diverse physiological functions and it could be a link between atherogenesis and tumorigenesis. The risk factors for atherosclerosis like hypertension, diabetes mellitus and hyperlipidemia are associated with LOX-1. Dyslipidemia and obesity are also being recognized as risk factor for certain tumors. LOX-1 is also found to be important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth. There is emerging evidence that LOX-1 plays an important role in the angiogenesis process. In this review, we outline the roles of angiogenesis in atherogenesis and tumorigenesis, and describe the role of LOX-1 as a potential molecular target for blocking angiogenesis.

  9. Lymphotoxin signaling is initiated by the viral polymerase in HCV-linked tumorigenesis.

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    Yannick Simonin

    2013-03-01

    Full Text Available Exposure to hepatitis C virus (HCV typically results in chronic infection that leads to progressive liver disease ranging from mild inflammation to severe fibrosis and cirrhosis as well as primary liver cancer. HCV triggers innate immune signaling within the infected hepatocyte, a first step in mounting of the adaptive response against HCV infection. Persistent inflammation is strongly associated with liver tumorigenesis. The goal of our work was to investigate the initiation of the inflammatory processes triggered by HCV viral proteins in their host cell and their possible link with HCV-related liver cancer. We report a dramatic upregulation of the lymphotoxin signaling pathway and more specifically of lymphotoxin-β in tumors of the FL-N/35 HCV-transgenic mice. Lymphotoxin expression is accompanied by activation of NF-κB, neosynthesis of chemokines and intra-tumoral recruitment of mononuclear cells. Spectacularly, IKKβ inactivation in FL-N/35 mice drastically reduces tumor incidence. Activation of lymphotoxin-β pathway can be reproduced in several cellular models, including the full length replicon and HCV-infected primary human hepatocytes. We have identified NS5B, the HCV RNA dependent RNA polymerase, as the viral protein responsible for this phenotype and shown that pharmacological inhibition of its activity alleviates activation of the pro-inflammatory pathway. These results open new perspectives in understanding the inflammatory mechanisms linked to HCV infection and tumorigenesis.

  10. DNA Methylation Dynamics During Differentiation, Proliferation, and Tumorigenesis in the Intestinal Tract

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    Huang, Can-Ze

    2015-01-01

    DNA methylation, an epigenetic control mechanism in mammals, is widely present in the intestinal tract during the differentiation and proliferation of epithelial cells. Cells in stem cell pools or villi have different patterns of DNA methylation. The process of DNA methylation is dynamic and occurs at many relevant regulatory elements during the rapid transition of stem cells into fully mature, differentiated epithelial cells. Changes in DNA methylation patterns most often take place in enhancer and promoter regions and are associated with transcription factor binding. During differentiation, enhancer regions associated with genes important to enterocyte differentiation are demethylated, activating gene expression. Abnormal patterns of DNA methylation during differentiation and proliferation in the intestinal tract can lead to the formation of aberrant crypt foci and destroy the barrier and absorptive functions of the intestinal epithelium. Accumulation of these epigenetic changes may even result in tumorigenesis. In the current review, we discuss recent findings on the association between DNA methylation and cell differentiation and proliferation in the small intestine and highlight the possible links between dysregulation of this process and tumorigenesis. PMID:26413818

  11. Functional characterization of AMP-activated protein kinase signaling in tumorigenesis.

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    Cheng, Ji; Zhang, Tao; Ji, Hongbin; Tao, Kaixiong; Guo, Jianping; Wei, Wenyi

    2016-12-01

    AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.

  12. A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Wang; Haiyang Liu; Sheng Wang; Xiaojiang Hao; Lin Li

    2011-01-01

    The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis.In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone(NC043)that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin Dl and Survivin, as well as decreases in the protein levels of Cdc25c and Cdc2.NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of P-catenin stability and may be a potential compound for treating colorectal cancer.

  13. Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression

    Institute of Scientific and Technical Information of China (English)

    Dan Xie; Liang Hu; Xin-Yuan Guan; Jonathan S.T. Sham; Wei-Fen Zeng; Li-Hong Che; Meng Zhang; Hui-Xi Wu; Han-Liang Lin; Jian-Ming Wen; Sze Hang Lau

    2005-01-01

    AIM: To investigate the expression pattern of clusterin in colorectal adenoma-carcinoma-metastasis series, and to explore the potential role of dusterin in multistage colorectal tumorigenesis and progression.METHOD:S: A colorectal carcinoma (CRC)-tissue microarray (TMA), which contained 85 advanced CRCs including 43 cases of Dukes B, 21 of Dukes C and 21 of Dukes D tumors, were used for assessing the expression of clusterin (clone 41D) and tumor cell apoptotic index (AI) by immunohistochemistry and TUNEL assay, respectively. Moreover the potential correlation of dusterin expression with the patient'sclinical-pathological features were also examined. RESULTS: The positive staining of clusterin in different colorectal tissues was primarily a cytoplasmic pattern. Cytoplasmic overexpression of clusterin was detected in none of the normal coloredal mucosa, 17% of the adenomas, 46% of the primary CRCs, and 57% of the CRC metastatic lesions. In addition, a significant positive correlation between overexpression of clusterin and advanced clinical (Dukes) stage was observed (P<0.01). Overexpression of cytoplasmic clusterin in CRCs was inversely correlated with tumor apoptotic index (P<0.01), indicating the anti apoptotic function of cytoplasmic clusterin in CRCs.CONCLUSION: These data suggests that overexpression of cytoplasmic dustin might be involved in the tumorigenesis and/or progression of CRCs. The anti-apoptotic function of cytoplasmic dusterin may be responsible, at least in part, for the development and biologically aggressive behavior of CRC.

  14. Synergistic interaction of Rnf8 and p53 in the protection against genomic instability and tumorigenesis.

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    Marie-Jo Halaby

    Full Text Available Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8(-/- mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8(-/- mice in a tissue- and cell type-specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8(-/- mice, we have generated Rnf8(-/-p53(-/- mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8(-/- mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8(-/- mice. Similarly, the senescence phenotype of Rnf8(-/- mouse embryonic fibroblasts was rescued in p53 null background. Rnf8(-/-p53(-/- cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8(-/-p53(-/- mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8(-/- or p53(-/- mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis.

  15. Angiogenin contributes to bladder cancer tumorigenesis by DNMT3b-mediated MMP2 activation.

    Science.gov (United States)

    Peres, Rafael; Furuya, Hideki; Pagano, Ian; Shimizu, Yoshiko; Hokutan, Kanani; Rosser, Charles J

    2016-07-12

    Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG) and matrix metalloproteinase-2 (MMP2) leading to pronounced tumorigenesis. Here we provide multiple lines of evidence further indicating ANG oncogenic potential. ANG expression resulted in the hypomethylated state of the MMP2 gene, which led to increased gene expression of MMP2. More than that, our global DNA methylation microarray analysis showed that gene manipulation of ANG affected a variety of pathways, such as cell migration, angiogenesis and specifically, tumor suppressor genes. Mechanistically, ANG negatively regulated DNA methyltransferase 3b (DNMT3b) enzymatic activity by down-regulating its expression and inhibiting its recruitment to the MMP2 promoter. Consistent with this, ANG-MMP2 overexpression and DNMT3b underexpression correlated with reduction in disease free survival of human bladder cancer patients. Together, the results continue to establish ANG as an oncoprotein and further reveal that ANG contributes to oncogenesis by the activation of MMP2 through modulation of DNMT3b functions.

  16. Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis.

    Science.gov (United States)

    Kümper, Sandra; Mardakheh, Faraz K; McCarthy, Afshan; Yeo, Maggie; Stamp, Gordon W; Paul, Angela; Worboys, Jonathan; Sadok, Amine; Jørgensen, Claus; Guichard, Sabrina; Marshall, Christopher J

    2016-01-14

    Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here, we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while the loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility.

  17. Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis.

    Science.gov (United States)

    Lan, Sheng-Hui; Wu, Shan-Ying; Zuchini, Roberto; Lin, Xi-Zhang; Su, Ih-Jen; Tsai, Ting-Fen; Lin, Yen-Ju; Wu, Cheng-Tao; Liu, Hsiao-Sheng

    2014-09-01

    Autophagy and microRNA (miRNA) are important regulators during cancer cell tumorigenesis. Impaired autophagy and high expression of the oncogenic microRNA MIR224 are prevalent in hepatocellular carcinoma (HCC); however, the relationship between the 2 phenomena remains elusive. In this study, we are the first to reveal that autophagy selectively regulates MIR224 expression through an autophagosome-mediated degradation system. Based on this finding, we further demonstrated that in hepatitis B virus (HBV)-related HCC, aberrant autophagy (low autophagic activity) results in accumulation of MIR224 and decreased expression of the target gene Smad4, which leads to increased cell migration and tumor formation. Preferential recruitment of MIR224 into the autophagosome was clearly demonstrated by a) miRNA in situ hybridization under confocal microscopy, and b) immunogold labeling of MIR224 under electron microscopy compared with a ubiquitously expressed microRNA MIRlet7e/let-7. Furthermore, we found that off-label use of amiodarone, an antiarrhythmic agent, effectively suppressed HCC tumorigenesis through autophagy-mediated MIR224 degradation both in vitro and in vivo. In summary, we identified amiodarone as a new autophagy inducer, which may provide an alternative approach in HCC therapy through a novel tumor suppression mechanism.

  18. Overexpression of Id1 in transgenic mice promotes mammary basal stem cell activity and breast tumorigenesis.

    Science.gov (United States)

    Shin, Dong-Hui; Park, Ji-Hye; Lee, Jeong-Yeon; Won, Hee-Young; Jang, Ki-Seok; Min, Kyueng-Whan; Jang, Si-Hyong; Woo, Jong-Kyu; Oh, Seung Hyun; Kong, Gu

    2015-07-10

    Inhibitor of differentiation/DNA binding (Id)1 is a crucial regulator of mammary development and breast cancer progression. However, its effect on stemness and tumorigenesis in mammary epithelial cells remains undefined. Herein, we demonstrate that Id1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities in transgenic mice. MaSC-enriched basal cell expansion and increased self-renewal and in vivo regenerative capacity of MaSCs are observed in the mammary glands of MMTV-Id1 transgenic mice. Furthermore, MMTV-Id1 mice develop ductal hyperplasia and mammary tumors with highly expressed basal markers. Id1 also increases breast cancer stem cell (CSC) population and activity in human breast cancer lines. Moreover, the effects of Id1 on normal and malignant stem cell activities are mediated by the Wnt/c-Myc pathway. Collectively, these findings provide in vivo genetic evidence of Id1 functions as an oncogene in breast cancer and indicate that Id1 regulates mammary basal stem cells by activating the Wnt/c-Myc pathway, thereby contributing to breast tumor development.

  19. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

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    Victoria L Herrera

    Full Text Available Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL. We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R-intercross rats. Tumorigenesis was measured as tumor burden index (TBI after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs with significant linkage: Mts-1 on chromosome-9 (LOD-2.98 and Mts-2 on chromosome-1 (LOD-2.61, as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93 and Mts-4 on chromosome-18 (LOD-1.54. Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3 reported for 7,12-dimethylbenz-[α]antracene (DMBA-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for

  20. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

    Science.gov (United States)

    Herrera, Victoria L; Ponce, Lorenz R; Ruiz-Opazo, Nelson

    2013-01-01

    Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation

  1. Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats

    Science.gov (United States)

    Herrera, Victoria L.; Ponce, Lorenz R.; Ruiz-Opazo, Nelson

    2013-01-01

    Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via 127Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation

  2. Ectopic expression of PTTG1/securin promotes tumorigenesis in human embryonic kidney cells

    Directory of Open Access Journals (Sweden)

    Malik Mohammed T

    2005-01-01

    Full Text Available Abstract Background Pituitary tumor transforming gene1 (PTTG1 is a novel oncogene that is expressed in most tumors. It encodes a protein that is primarily involved in the regulation of sister chromatid separation during cell division. The oncogenic potential of PTTG1 has been well characterized in the mouse, particularly mouse fibroblast (NIH3T3 cells, in which it induces cell proliferation, promotes tumor formation and angiogenesis. Human tumorigenesis is a complex and a multistep process often requiring concordant expression of a number of genes. Also due to differences between rodent and human cell biology it is difficult to extrapolate results from mouse models to humans. To determine if PTTG1 functions similarly as an oncogene in humans, we have characterized its effects on human embryonic kidney (HEK293 cells. Results We report that introduction of human PTTG1 into HEK293 cells through transfection with PTTG1 cDNA resulted in increased cell proliferation, anchorage-independent growth in soft agar, and formation of tumors after subcutaneous injection of nu/nu mice. Pathologic analysis revealed that these tumors were poorly differentiated. Both analysis of HEK293 cells transiently transfected with PTTG1 cDNA and analysis of tumors developed on injection of HEK293 cells that had been stably transfected with PTTG1 cDNA indicated significantly higher levels of secretion and expression of bFGF, VEGF and IL-8 compared to HEK293 cells transfected with pcDNA3.1 vector or uninvolved tissues collected from the mice. Mutation of the proline-rich motifs at the C-terminal of PTTG1 abolished its oncogenic properties. Mice injected with this mutated PTTG1 either did not form tumors or formed very small tumors. Taken together our results suggest that PTTG1 is a human oncogene that possesses the ability to promote tumorigenesis in human cells at least in part through the regulation of expression or secretion of bFGF, VEGF and IL-8. Conclusions Our results

  3. Calcium sensing receptor suppresses human pancreatic tumorigenesis through a novel NCX1/Ca(2+)/β-catenin signaling pathway.

    Science.gov (United States)

    Tang, Bo; Chow, Jimmy Y C; Dong, Tobias Xiao; Yang, Shi-Ming; Lu, De-Sheng; Carethers, John M; Dong, Hui

    2016-07-10

    The calcium sensing receptor (CaSR) is functionally expressed in normal human pancreases, but its pathological role in pancreatic tumorigenesis is currently unknown. We sought to investigate the role of CaSR in pancreatic cancer (PC) and the underlying molecular mechanisms. We revealed that the expression of CaSR was consistently downregulated in the primary cancer tissues from PC patients, which was correlated with tumor size, differentiation and poor survival of the patients. CaSR activation markedly suppressed pancreatic tumorigenesis in vitro and in vivo likely through the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger 1 (NCX1) to induce Ca(2+) entry into PC cells. Moreover, NCX1-mediated Ca(2+) entry resulted in Ca(2+)-dependent inhibition of β-catenin signaling in PC cells, eventually leading to the inhibition of pancreatic tumorigenesis. Collectively, we demonstrate for the first time that CaSR exerts a suppressive function in pancreatic tumorigenesis through a novel NCX1/Ca(2+)/β-catenin signaling pathway. Targeting this specific signaling pathway could be a potential therapeutic strategy for PC.

  4. Breast cancer cell behaviors on staged tumorigenesis-mimicking matrices derived from tumor cells at various malignant stages.

    Science.gov (United States)

    Hoshiba, Takashi; Tanaka, Masaru

    2013-09-20

    Extracellular matrix (ECM) has been focused to understand tumor progression in addition to the genetic mutation of cancer cells. Here, we prepared "staged tumorigenesis-mimicking matrices" which mimic in vivo ECM in tumor tissue at each malignant stage to understand the roles of ECM in tumor progression. Breast tumor cells, MDA-MB-231 (invasive), MCF-7 (non-invasive), and MCF-10A (benign) cells, were cultured to form their own ECM beneath the cells and formed ECM was prepared as staged tumorigenesis-mimicking matrices by decellularization treatment. Cells showed weak attachment on the matrices derived from MDA-MB-231 cancer cells. The proliferations of MDA-MB-231 and MCF-7 was promoted on the matrices derived from MDA-MB-231 cancer cells whereas MCF-10A cell proliferation was not promoted. MCF-10A cell proliferation was promoted on the matrices derived from MCF-10A cells. Chemoresistance of MDA-MB-231 cells against 5-fluorouracil increased on only matrices derived from MDA-MB-231 cells. Our results showed that the cells showed different behaviors on staged tumorigenesis-mimicking matrices according to the malignancy of cell sources for ECM preparation. Therefore, staged tumorigenesis-mimicking matrices might be a useful in vitro ECM models to investigate the roles of ECM in tumor progression.

  5. The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis.

    Science.gov (United States)

    Yi, Chunling; Shen, Zhewei; Stemmer-Rachamimov, Anat; Dawany, Noor; Troutman, Scott; Showe, Louise C; Liu, Qin; Shimono, Akihiko; Sudol, Marius; Holmgren, Lars; Stanger, Ben Z; Kissil, Joseph L

    2013-09-03

    The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, and tumorigenesis. Members of the scaffold protein angiomotin (Amot) family interact with several Hippo pathway components, including Yap (Yes-associated protein), and either stimulate or inhibit Yap activity. We used a combination of genetic, biochemical, and transcriptional approaches to assess the functional consequences of the Amot-Yap interaction in mice and in human cells. Mice with a liver-specific Amot knockout exhibited reduced hepatic "oval cell" proliferation and tumorigenesis in response to toxin-induced injury or when crossed with mice lacking the tumor suppressor Nf2. Biochemical examination of the Amot-Yap interaction revealed that the p130 splicing isoform of Amot (Amot-p130) and Yap interacted in both the cytoplasm and nucleus, which involved binding of PPxY and LPxY motifs in Amot-p130 to WW domains of Yap. In the cytoplasm, Amot-p130 prevented the phosphorylation of Yap by blocking access of the WW domains to the kinase Lats1. Within the nucleus, Amot-p130 was associated with the transcriptional complex containing Yap and Teads (TEA domain family members) and contributed to the regulation of a subset of Yap target genes, many of which are associated with tumorigenesis. These findings indicated that Amot acts as a Yap cofactor, preventing Yap phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis.

  6. Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis

    Science.gov (United States)

    Ma, Li; Tao, Yongzhen; Duran, Angeles; Llado, Victoria; Galvez, Anita; Barger, Jennifer F.; Castilla, Elias A.; Chen, Jing; Yajima, Tomoko; Porollo, Aleksey; Medvedovic, Mario; Brill, Laurence M.; Plas, David R.; Riedl, Stefan J.; Leitges, Michael; Diaz-Meco, Maria T.; Richardson, Adam D.; Moscat, Jorge

    2013-01-01

    SUMMARY Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer. PMID:23374352

  7. Over-expression of ST3Gal-I promotes mammary tumorigenesis

    DEFF Research Database (Denmark)

    Picco, Gianfranco; Julien, Sylvain; Brockhausen, Inka

    2010-01-01

    3Gal-I adds sialic acid to the galactose residue of core 1 (Galbeta1,3GalNAc) O-glycans and this enzyme is over-expressed in breast cancer resulting in the expression of sialylated core 1 glycans. In order to study the role of ST3Gal-I in mammary tumor development, we developed transgenic mice...... and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background....... These results indicate that ST3Gal-I is acting as a tumor promoter in this model of breast cancer. This, we believe, is the first demonstration that over-expression of a glycosyltransferase involved in mucin-type O-linked glycosylation can promote tumorigenesis....

  8. Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis.

    Science.gov (United States)

    Ferretti, Roberta; Palumbo, Valeria; Di Savino, Augusta; Velasco, Silvia; Sbroggiò, Mauro; Sportoletti, Paolo; Micale, Lucia; Turco, Emilia; Silengo, Lorenzo; Palumbo, Gioacchino; Hirsch, Emilio; Teruya-Feldstein, Julie; Bonaccorsi, Silvia; Pandolfi, Pier Paolo; Gatti, Maurizio; Tarone, Guido; Brancaccio, Mara

    2010-03-16

    Centrosome abnormalities lead to genomic instability and are a common feature of many cancer cells. Here we show that mutations in morgana/chp-1 result in centrosome amplification and lethality in both Drosophila and mouse, and that the fly centrosome phenotype is fully rescued by the human ortholog of morgana. In mouse cells, morgana forms a complex with Hsp90 and ROCK I and II, and directly binds ROCK II. Morgana downregulation promotes the interaction between ROCK II and nucleophosmin (NPM), leading to an increased ROCK II kinase activity, which results in centrosome amplification. Morgana(+/-) primary cells and mice display an increased susceptibility to neoplastic transformation. In addition, tumor tissue array histochemical analysis revealed that morgana is underexpressed in a large fraction of breast and lung human cancers. Thus, morgana/chp-1 appears to prevent both centrosome amplification and tumorigenesis. Copyright 2010 Elsevier Inc. All rights reserved.

  9. IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells

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    Serkan I. Göktuna

    2014-06-01

    Full Text Available The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC therapy.

  10. Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice

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    Bi Xiuli

    2013-01-01

    Full Text Available Abstract Background Both selenium and non-steroidal anti-inflammatory drug (NSAID sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. Results We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p Conclusions The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.

  11. piggyBac mediates efficient in vivo CRISPR library screening for tumorigenesis in mice.

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    Xu, Chunlong; Qi, Xiaolan; Du, Xuguang; Zou, Huiying; Gao, Fei; Feng, Tao; Lu, Hengxing; Li, Shenglan; An, Xiaomeng; Zhang, Lijun; Wu, Yuanyuan; Liu, Ying; Li, Ning; Capecchi, Mario R; Wu, Sen

    2017-01-24

    CRISPR/Cas9 is becoming an increasingly important tool to functionally annotate genomes. However, because genome-wide CRISPR libraries are mostly constructed in lentiviral vectors, in vivo applications are severely limited as a result of difficulties in delivery. Here, we examined the piggyBac (PB) transposon as an alternative vehicle to deliver a guide RNA (gRNA) library for in vivo screening. Although tumor induction has previously been achieved in mice by targeting cancer genes with the CRISPR/Cas9 system, in vivo genome-scale screening has not been reported. With our PB-CRISPR libraries, we conducted an in vivo genome-wide screen in mice and identified genes mediating liver tumorigenesis, including known and unknown tumor suppressor genes (TSGs). Our results demonstrate that PB can be a simple and nonviral choice for efficient in vivo delivery of CRISPR libraries.

  12. The Role of HPV in Head and Neck Cancer Stem Cell Formation and Tumorigenesis

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    Mark S. Swanson

    2016-02-01

    Full Text Available The cancer stem cell (CSC theory proposes that a minority of tumor cells are capable of self-replication and tumorigenesis. It is these minority of cells that are responsible for cancer metastasis and recurrence in head and neck squamous cell cancers (HNSCC. Human papilloma virus (HPV-related cancer of the oropharynx is becoming more prevalent, which makes understanding of the relationship between HPV and CSCs more important than ever. This relationship is critical because CSC behavior can be predicted based on cell surface markers, which makes them a suitable candidate for targeted therapy. New therapies are an exciting opportunity to advance past the stalled outcomes in HNSCC that have plagued patients and clinicians for several decades.

  13. Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis

    Science.gov (United States)

    Zeitels, Lauren R.; Acharya, Asha; Shi, Guanglu; Chivukula, Divya; Chivukula, Raghu R.; Anandam, Joselin L.; Abdelnaby, Abier A.; Balch, Glen C.; Mansour, John C.; Yopp, Adam C.; Richardson, James A.

    2014-01-01

    Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apcmin/+ mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type. PMID:25395662

  14. Correlation of the nuclear accumulation of CTNNB1 and colonic tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    QIU Zhe-fu; Maruyama Keiji; HAN De-min; Nakamura Satoshi

    2006-01-01

    @@ CTNNB1 (or beta-catenin) is regarded as a central effecter in molecules of the wingless/Wnt signalling pathway. It is a key component of the cadherin mediated cell to cell adhesion system and forms a complex with the protein product of adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β) and conductin.1 One mutation of APC is also responsible for activation of wingless/Wnt signalling pathway and accumulation of free beta-catenin in the cell. Beta-catenin upregulates oncogenes, such as cyclin D1 and c-myc.2 Beta-catenin expression in cytoplasm and nuclei was reported to increase in many cases of intestinal tumorigenesis.3,4 In addition, the hyperexpression of integrin linked kinase (ILK) in colonic polyposis has been demonstrated.5

  15. Brain diseases and tumorigenesis: The good and bad cops of pentraxin3.

    Science.gov (United States)

    Fornai, Francesco; Carrizzo, Albino; Ferrucci, Michela; Damato, Antonio; Biagioni, Francesca; Gaglione, Anderson; Puca, Annibale Alessandro; Vecchione, Carmine

    2015-12-01

    The prototype of long pentraxins, Pentraxin 3 (PTX3), is an evolutionarily conserved multifunctional, pattern-recognition protein constituted by a cyclic multimeric structure. PTX3 interacts with a variety of ligands, such as growth factors, extracellular matrix components, molecules of the complement cascade, pathogens recognition proteins, angiogenetic and adhesion molecules. PTX3 could be considered as a molecular link between innate and adaptive immunity as well as between focal and circulating responses during inflammation. In fact, it modulates the functions of resident dendritic cells and circulating lymphocytes. Recent evidence demonstrates that manipulation of PTX3 may produce even opposite effects depending on which target organ is considered and the physiopathological context. In the present review we discuss the good and bad cops of PTX3 concerning multifacted effects on inflammation, innate immunity, brain diseases and tumorigenesis. Finally, a perspective on PTX3 and autophagy is provided as a convergent pathway.

  16. Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Zhimin Lu

    2012-01-01

    Pyruvate kinase catalyzes the rate-limiting final step of glycolysis,generating adenosine triphosphate (ATP) and pyruvate.The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptake and lactate production in the presence of oxygen,known as aerobic glycolysis or the Warburg effect.As recently reported in Nature,PKM2,besides its metabolic function,has a nonmetabolic function in the direct control of cell cycle progression by activating β-catenin and inducing expression of the β-catenin downstream gene CCND1 (encoding for cyclin D1).This nonmetabolic function of PKM2 is essential for epidermal growth factor receptor (EGFR) activation-induced tumorigenesis.

  17. Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Khan, Galam; Davis, Jennifer

    2011-01-01

    Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either...... whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p vaginal...... or apoptosis were seen. IGF-1 mRNA levels were reduced on PND 50 in the mammary glands of rats exposed to milk at puberty. Our results suggest that drinking milk before puberty reduces later risk of developing mammary cancer in rats. This might be mediated by a reduction in the number of TEBs and lower...

  18. Suppression of tumorigenesis in mitochondrial NADP(+)-dependent isocitrate dehydrogenase knock-out mice.

    Science.gov (United States)

    Kim, Seontae; Kim, Sung Youl; Ku, Hyeong Jun; Jeon, Yong Hyun; Lee, Ho Won; Lee, Jaetae; Kwon, Taeg Kyu; Park, Kwon Moo; Park, Jeen-Woo

    2014-02-01

    The tumor host microenvironment is increasingly viewed as an important contributor to tumor growth and suppression. Cellular oxidative stress resulting from high levels of reactive oxygen species (ROS) contributes to various processes involved in the development and progress of malignant tumors including carcinogenesis, aberrant growth, metastasis, and angiogenesis. In this regard, the stroma induces oxidative stress in adjacent tumor cells, and this in turn causes several changes in tumor cells including modulation of the redox status, inhibition of cell proliferation, and induction of apoptotic or necrotic cell death. Because the levels of ROS are determined by a balance between ROS generation and ROS detoxification, disruption of this system will result in increased or decreased ROS level. Recently, we demonstrated that the control of mitochondrial redox balance and cellular defense against oxidative damage is one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) that supplies NADPH for antioxidant systems. To explore the interactions between tumor cells and the host, we evaluated tumorigenesis between IDH2-deficient (knock-out) and wild-type mice in which B16F10 melanoma cells had been implanted. Suppression of B16F10 cell tumorigenesis was reproducibly observed in the IDH2-deficient mice along with significant elevation of oxidative stress in both the tumor and the stroma. In addition, the expression of angiogenesis markers was significantly down-regulated in both the tumor and the stroma of the IDH2-deficient mice. These results support the hypothesis that redox status-associated changes in the host environment of tumor-bearing mice may contribute to cancer progression.

  19. Germline Mutations in Mtap Cooperate with Myc to Accelerate Tumorigenesis in Mice.

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    Yuwaraj Kadariya

    Full Text Available The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers. In this study, we have examined if heterozygosity for a null mutation in Mtap (Mtap(lacZ could accelerate tumorigenesis development in two different mouse cancer models, Eμ-myc transgenic and Pten(+/- .Mtap Eμ-myc and Mtap Pten mice were generated and tumor-free survival was monitored over time. Tumors were also examined for a variety of histological and protein markers. In addition, microarray analysis was performed on the livers of Mtap(lacZ/+ and Mtap (+/+ mice.Survival in both models was significantly decreased in Mtap(lacZ/+ compared to Mtap(+/+ mice. In Eµ-myc mice, Mtap mutations accelerated the formation of lymphomas from cells in the early pre-B stage, and these tumors tended to be of higher grade and have higher expression levels of ornithine decarboxylase compared to those observed in control Eµ-myc Mtap(+/+ mice. Surprisingly, examination of Mtap status in lymphomas in Eµ-myc Mtap(lacZ/+ and Eµ-myc Mtap(+/+ animals did not reveal significant differences in the frequency of loss of Mtap protein expression, despite having shorter latency times, suggesting that haploinsufficiency of Mtap may be playing a direct role in accelerating tumorigenesis. Consistent with this idea, microarray analysis on liver tissue from age and sex matched Mtap(+/+ and Mtap(lacZ/+ animals found 363 transcripts whose expression changed at least 1.5-fold (P<0.01. Functional categorization of these genes reveals enrichments in several pathways involved in growth control and cancer.Our findings show that germline inactivation of a single Mtap allele alters gene expression and enhances lymphomagenesis in Eµ-myc mice.

  20. ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis

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    Mark Z. Ma

    2015-10-01

    Full Text Available Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. We have previously shown that ∆DNMT3B is the predominantly expressed form of DNMT3B. In this study, we found that most of the lung cancer cell lines tested predominantly expressed DNMT3B isoforms without exons 21, 22 or both 21 and 22 (a region corresponding to the enzymatic domain of DNMT3B termed DNMT3B/∆DNMT3B-del. In normal bronchial epithelial cells, DNMT3B/ΔDNMT3B and DNMT3B/∆DNMT3B-del displayed equal levels of expression. In contrast, in patients with non-small cell lung cancer NSCLC, 111 (93% of the 119 tumors predominantly expressed DNMT3B/ΔDNMT3B-del, including 47 (39% tumors with no detectable DNMT3B/∆DNMT3B. Using a transgenic mouse model, we further demonstrated the biological impact of ∆DNMT3B4-del, the ∆DNMT3B-del isoform most abundantly expressed in NSCLC, in global DNA methylation patterns and lung tumorigenesis. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation patterns during lung tumorigenesis and suggest that ∆DNMT3B4-del may be a target for lung cancer prevention.

  1. N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways.

    Science.gov (United States)

    Da, Chenxing; Wu, Kexia; Yue, Chenli; Bai, Peisong; Wang, Rong; Wang, Guanjie; Zhao, Man; Lv, Yanyan; Hou, Peng

    2017-01-31

    Epithelial-mesenchymal transition (EMT), a crucial step in disease progression, plays a key role in tumor metastasis. N-cadherin, a well-known EMT marker, acts as a major oncogene in diverse cancers, whereas its functions in thyroid cancer remains largely unclear. This study was designed to explore the biological roles and related molecular mechanism of N-cadherin in thyroid tumorigenesis. Quantitative RT-PCR (qRT-PCR) and immunohistochemistry assays were used to evaluate N-cadherin expression. A series of in vitro studies such as cell proliferation, colony formation, cell cycle, apoptosis, migration and invasion assays were performed to determine the effect of N-cadherin on malignant behavior of thyroid cancer cells. Our results showed that N-cadherin was significantly upregulated in papillary thyroid cancers (PTCs) as compared with non-cancerous thyroid tissues. N-cadherin knockdown markedly inhibited cell proliferation, colony formation, cell migration and invasion, and induced cell cycle arrest and apoptosis. On the other hand, ectopic expression of N-cadherin promoted thyroid cancer cell growth and invasiveness. Mechanically, our data demonstrated that tumor-promoting role of N-cadherin in thyroid cancer was closely related to the activities of the MAPK/Erk, the phosphatidylinositol-3-kinase (PI3K)/Akt and p16/Rb signaling pathways in addition to affecting the EMT process. Altogether, our findings suggest that N-cadherin promotes thyroid tumorigenesis by modulating the activities of major signaling pathways and EMT process, and may represent a potential therapeutic target for this cancer.

  2. The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation.

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    Reem Malek

    Full Text Available Disruption of cerebellar granular neuronal precursor (GNP maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro, which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/- mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.

  3. FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo.

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    Julia Brun

    Full Text Available BACKGROUND: The molecular mechanisms that are involved in the growth and invasiveness of osteosarcoma, an aggressive and invasive primary bone tumor, are not fully understood. The transcriptional co-factor FHL2 (four and a half LIM domains protein 2 acts as an oncoprotein or as a tumor suppressor depending on the tissue context. In this study, we investigated the role of FHL2 in tumorigenesis in osteosarcoma model. METHODOLOGY/PRINCIPAL FINDINGS: Western blot analyses showed that FHL2 is expressed above normal in most human and murine osteosarcoma cells. Tissue microarray analysis revealed that FHL2 protein expression is high in human osteosarcoma and correlates with osteosarcoma aggressiveness. In murine osteosarcoma cells, FHL2 silencing using shRNA decreased canonical Wnt/β-catenin signaling and reduced the expression of Wnt responsive genes as well as of the key Wnt molecules Wnt5a and Wnt10b. This effect resulted in inhibition of osteosarcoma cell proliferation, invasion and migration in vitro. Using xenograft experiments, we showed that FHL2 silencing markedly reduced tumor growth and lung metastasis occurence in mice. The anti-oncogenic effect of FHL2 silencing in vivo was associated with reduced cell proliferation and decreased Wnt signaling in the tumors. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that FHL2 acts as an oncogene in osteosarcoma cells and contributes to tumorigenesis through Wnt signaling. More importantly, FHL2 depletion greatly reduces tumor cell growth and metastasis, which raises the potential therapeutic interest of targeting FHL2 to efficiently impact primary bone tumors.

  4. Tumorigenesis and spontaneous metastasis by luciferase-labeled human xenograft osteosarcoma cells in nude mice.

    Science.gov (United States)

    Du, Lin; Xu, Wen-ting; Fan, Qi-ming; Tu, Bing; Shen, Yang; Yan, Wei; Tang, Ting-ting; Wang, You

    2012-11-01

    Osteosarcoma (OS) is the most common primary malignant tumor of bone. Mouse models of human OS can invariably provide greater insight into the complex mechanisms that underlie the development and pathogenesis of this aggressive tumor. Bioluminescence technology favored tracing cancer cells in vivo. In this study, an OS model was described and evaluated using human OS cell line, Saos2, labeled with luciferase (Saos2-luc). Saos2 cells were infected by lentivirus loading a firefly luciferase gene. Luciferase expression of Saos2-luc cells was characterized both in vitro and in vivo. Specific biologic and oncologic features of Saos2-luc cells were analyzed. The OS was established as orthotopic xenografts in nude mice. Both orthotopic tumors and spontaneous lung metastasis were analyzed. Tumorigenesis and spontaneous lung metastasis in nude mice could be monitored in vivo through in vivo imaging system. The enhancement in proliferation, migration and invasion abilities and the attenuation in adhesion ability were observed in Saos2-luc cells compared with Saos2 cells. Furthermore, there were the up-regulation of Osteocalcin, CCR10, CXCR1 and ID1 and the down-regulation of ALP, collagen I, CCR1, CCR3, CXCR3, NID and N-cadherin in Saos2-luc cells compare to Saos2 cells. The rate of spontaneous lung metastasis in Saos2-luc cells was higher than that in Saos2 cells, although without significant difference. Lentivirus transfection may cause alteration of gene expression profiles and further biological functions. This model can be used in the elucidation of molecular mechanisms of tumorigenesis and the screening of new therapeutic agents.

  5. Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis.

    Science.gov (United States)

    He, Feng; Mo, Lan; Zheng, Xiao-Yong; Hu, Changkun; Lepor, Herbert; Lee, Eva Y-H P; Sun, Tung-Tien; Wu, Xue-Ru

    2009-12-15

    Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.

  6. The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis.

    Science.gov (United States)

    Snapkov, Igor; Öqvist, Carl Otto; Figenschau, Yngve; Kogner, Per; Johnsen, John Inge; Sveinbjørnsson, Baldur

    2016-07-18

    Formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor mainly expressed by the cells of myeloid origin, where it mediates the innate immune response to bacterial formylated peptides. High expression of FPR1 has been detected in various cancers but the function of FPR1 in tumorigenesis is poorly understood. Expression of FPR1 in neuroblastoma cell lines and primary tumors was studied using RT-PCR, western blotting, immunofluorescence and immunohistochemistry. Calcium mobilization assays and western blots with phospho-specific antibodies were used to assess the functional activity of FPR1 in neuroblastoma. The tumorigenic capacity of FPR1 was assessed by xenografting of neuroblastoma cells expressing inducible FPR1 shRNA, FPR1 cDNA or control shRNA in nude mice. FPR1 is expressed in neuroblastoma primary tumors and cell lines. High expression of FPR1 corresponds with high-risk disease and poor patient survival. Stimulation of FPR1 in neuroblastoma cells using fMLP, a selective FPR1 agonist, induced intracellular calcium mobilization and activation of MAPK/Erk, PI3K/Akt and P38-MAPK signal transduction pathways that were inhibited by using Cyclosporin H, a selective receptor antagonist for FPR1. shRNA knock-down of FPR1 in neuroblastoma cells conferred a delayed xenograft tumor development in nude mice, whereas an ectopic overexpression of FPR1 promoted augmented tumorigenesis in nude mice. Our data demonstrate that FPR1 is involved in neuroblastoma development and could represent a therapy option for the treatment of neuroblastoma.

  7. Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis.

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    Caitlyn W Barrett

    Full Text Available Selenium (Se is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD. Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS-induced colitis, and azoxymethane (AOM followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.

  8. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis

    Science.gov (United States)

    Waldman, Scott A

    2010-01-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer. PMID:20592492

  9. Rewiring drug-activated p53-regulatory network from suppressing to promoting tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Song; Jiguang Wang; Ying Yang; Naihe Jing; Xiangsun Zhang; Luonan Chen; Jiarui Wu

    2012-01-01

    Many of oncogenes and tumor suppressor genes have been found to exert variable and even opposing roles in different kinds of tumors or at different stages of cancer development.Here we showed that tumorigenic potential of mouse embryonic carcinoma P19 cells cultured in adherent plates (attached-P19-cells) was suppressed by a chemotherapeutic agent,5-aza-2'-deoxycytidine (ZdCyd),whereas the higher pro-tumorigenicity of P19 cells growing in suspension (detached-P19-cells) was generated by the ZdCyd treatment.Surprisingly,p53 activity was highly up-regulated by ZdCyd in both growing conditions.By our developed computational approaches,we revealed that there was a significant enrichment of apoptotic pathways in the ZdCyd-induced p53-dominant gene-regulatory network in attached P19 cells,whereas the pro-survival genes were significantly enriched in the ZdCyd-induced p53 network in detached P19 cells.The protein-protein interaction network of the ZdCyd-treated detached P19 cells was significantly different from that of ZdCyd-treated attached P19 cells.On the other hand,inhibition of pS3 expression by siRNA suppressed the ZdCyd-induced tumorigenesis of detached P19 cells,suggesting that the ZdCyd-activated p53 plays oncogenic function in detached P19 cells.Taken together,these results indicate a context-dependent role for the ZdCyd-activated p53-dominant network in tumorigenesis.

  10. Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Bo Gun Jang

    Full Text Available Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates that Lgr5(+ cells may not only be the cells responsible for the origin of tumors; they may also be the so-called cancer stem cells. In the present study, we investigated the presence of Lgr5(+ cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled Lgr5(+ cells at the basal glands of the gastric antrum. Notably, the number of Lgr5(+ cells was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas and 43% of early gastric carcinomas were positive for LGR5. Lgr5(+ cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, Lgr5(+ cells were often restricted to the base of the tumor glands, and such Lgr5(+ restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2. Thus, our findings show that Lgr5(+ cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5(+ cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5(+ cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis.

  11. PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Lin Yang; Li-Ge Kuang; Hua-Chuan Zheng; Jin-Yi Li; Dong-Ying Wu; Su-Min Zhang; Yan Xin

    2003-01-01

    AIM: To detect the expression of PTEN encoding productin normal mucosa, intestinal metaplasia (IM), dysplasia andcarcinoma of the stomach, and to investigate its clinicalimplication in tumorigenesis and progression of gastriccarcinoma.METHODS: Formalin-fixed paraffin embedded specimens from184 cases of gastric carcinoma, their adjacent normal mucosa,IM and dysplasia were evaluated for PTEN protein expressionby SABC immunohistochemistry. PTEN expression wascompared with tumor stage, lymph node metastasis, Lauren'sand WHO's histological classification of gastric carcinoma.Expression of VEGF was also detected in 60 cases of gastriccarcinoma and its correlation with PTEN was concerned.RESULTS: The positive rates of PTEN protein were 100 %(102/102), 98.5 %(65/66), 66.7 % (4/6) and 47.8 %(88/184)in normal mucosa, IM, dysplasia and carcinoma of the stomach,respectively. The positive rates in dysplasia and carcinomawere lower than in normal mucosa and IM (P<0.01).Advanced gastric cancers expressed less frequent PTEN thanearly gastric cancer (42.9 % v567.6 %, P<0.01). The positiverate of PTEN protein was lower in gastric cancer with thanwithout lymph node metastasis (40.3 % v563.3 %, P<0.01).PTEN was less expressed in diffuse-type than in intestinal-type gastric cancer (41.5 % v557.8 %,P<0.05). Signet ringcell carcinoma showed the expression of PTEN at the lowestlevel (25.0 %, 7/28); less than well and moderatelydifferentiated ones (P<0.01). Expression of PTEN was notcorrelated with expression of VEGF (P>0.05).CONCLUSION: Loss or reduced expression of PTEN proteinoccures commonly in tumorigenesis and progression of gastriccarcinoma. It is suggested that PTEN can be an objective markerfor pathologically biological behaviors of gastric carcinoma.

  12. Deletion of Forkhead Box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis.

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    I-Ching Wang

    Full Text Available The Forkhead Box m1 (Foxm1 protein is induced in a majority of human non-small cell lung cancers and its expression is associated with poor prognosis. However, specific requirements for the Foxm1 in each cell type of the cancer lesion remain unknown. The present study provides the first genetic evidence that the Foxm1 expression in respiratory epithelial cells is essential for lung tumorigenesis. Using transgenic mice, we demonstrated that conditional deletion of Foxm1 from lung epithelial cells (epFoxm1(-/- mice prior to tumor initiation caused a striking reduction in the number and size of lung tumors, induced by either urethane or 3-methylcholanthrene (MCA/butylated hydroxytoluene (BHT. Decreased lung tumorigenesis in epFoxm1(-/- mice was associated with diminished proliferation of tumor cells and reduced expression of Topoisomerase-2alpha (TOPO-2alpha, a critical regulator of tumor cell proliferation. Depletion of Foxm1 mRNA in cultured lung adenocarcinoma cells significantly decreased TOPO-2alpha mRNA and protein levels. Moreover, Foxm1 directly bound to and induced transcription of the mouse TOPO-2alpha promoter region, indicating that TOPO-2alpha is a direct target of Foxm1 in lung tumor cells. Finally, we demonstrated that a conditional deletion of Foxm1 in pre-existing lung tumors dramatically reduced tumor growth in the lung. Expression of Foxm1 in respiratory epithelial cells is critical for lung cancer formation and TOPO-2alpha expression in vivo, suggesting that Foxm1 is a promising target for anti-tumor therapy.

  13. A Requirement for SOCS-1 and SOCS-3 Phosphorylation in Bcr-Abl-Induced Tumorigenesis

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    Xiaoxue Qiu

    2012-06-01

    Full Text Available Suppressors of cytokine signaling 1 and 3 (SOCS-1 and SOCS-3 are inhibitors of the Janus tyrosine kinase (JAK/signal transducers and activators of transcription (STAT pathway and function in a negative feedback loop during cytokine signaling. Abl transformation is associated with constitutive activation of JAK/STAT-dependent signaling. However, the mechanism by which Abl oncoproteins bypass SOCS inhibitory regulation remains poorly defined. Here, we demonstrate that coexpression of Bcr-Abl with SOCS-1 or SOCS-3 results in tyrosine phosphorylation of these SOCS proteins. Interestingly, SOCS-1 is highly tyrosine phosphorylated in one of five primary chronic myelogenous leukemia samples. Bcr-Abl-dependent tyrosine phosphorylation of SOCS-1 and SOCS-3 occurs mainly on Tyr 155 and Tyr 204 residues of SOCS-1 and on Tyr 221 residue of SOCS-3. We observed that phosphorylation of these SOCS proteins was associated with their binding to Bcr-Abl. Bcr-Abl-dependent phosphorylation of SOCS-1 and SOCS-3 diminished their inhibitory effects on the activation of JAK and STAT5 and thereby enhanced JAK/STAT5 signaling. Strikingly, disrupting the tyrosine phosphorylation of SOCS-1 or SOCS-3 impaired the expression of Bcl-XL protein and sensitized K562 leukemic cells to undergo apoptosis. Moreover, selective mutation of tyrosine phosphorylation sites of SOCS-1 or SOCS-3 significantly blocked Bcr-Abl-mediated tumorigenesis in nude mice and inhibited Bcr-Abl-mediated murine bone marrow transformation. Together, these results reveal a mechanism of how Bcr-Abl may overcome SOCS-1 and SOCS-3 inhibition to constitutively activate the JAK/STAT-dependent signaling, and suggest that Bcr-Abl may critically requires tyrosine phosphorylation of SOCS-1 and SOCS-3 to mediate tumorigenesis when these SOCS proteins are present in cells.

  14. Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis.

    Science.gov (United States)

    van der Weyden, Louise; Papaspyropoulos, Angelos; Poulogiannis, George; Rust, Alistair G; Rashid, Mamunur; Adams, David J; Arends, Mark J; O'Neill, Eric

    2012-08-01

    The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a-null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A-mediated tumor suppression. ©2012 AACR.

  15. Dose and Spatial Effects in Long-Distance Radiation Signaling In Vivo: Implications for Abscopal Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Mancuso, Mariateresa, E-mail: mariateresa.mancuso@enea.it [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche Casaccia, Rome (Italy); Giardullo, Paola [Guglielmo Marconi University, Rome (Italy); Leonardi, Simona [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche Casaccia, Rome (Italy); Pasquali, Emanuela [Guglielmo Marconi University, Rome (Italy); Casciati, Arianna [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche Casaccia, Rome (Italy); De Stefano, Ilaria [Guglielmo Marconi University, Rome (Italy); Tanori, Mirella; Pazzaglia, Simonetta [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche Casaccia, Rome (Italy); Saran, Anna, E-mail: anna.saran@enea.it [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche Casaccia, Rome (Italy)

    2013-03-01

    Purpose: To investigate the dose and spatial dependence of abscopal radiation effects occurring in vivo in the mouse, along with their tumorigenic potential in the central nervous system (CNS) of a radiosensitive mouse model. Methods and Materials: Patched1 (Ptch1){sup +/−} mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene and uniquely susceptible to radiation damage in neonatal cerebellum, were exposed directly to ionizing radiation (1, 2, or 3 Gy of x-rays) or treated in a variety of partial-body irradiation protocols, in which the animals' head was fully protected by suitable lead cylinders while the rest of the body was exposed to x-rays in full or in part. Apoptotic cell death was measured in directly irradiated and shielded cerebellum shortly after irradiation, and tumor development was monitored in lifetime groups. The same endpoints were measured using different shielding geometries in mice irradiated with 3 or 10 Gy of x-rays. Results: Although dose-dependent cell death was observed in off-target cerebellum for all doses and shielding conditions tested, a conspicuous lack of abscopal response for CNS tumorigenesis was evident at the lowest dose of 1 Gy. By changing the amount of exposed body volume, the shielding geometry could also significantly modulate tumorigenesis depending on dose. Conclusions: We conclude that interplay between radiation dose and exposed tissue volume plays a critical role in nontargeted effects occurring in mouse CNS under conditions relevant to humans. These findings may help understanding the mechanisms of long-range radiation signaling in harmful effects, including carcinogenesis, occurring in off-target tissues.

  16. Arsenic-induced Aurora-A activation contributes to chromosome instability and tumorigenesis

    Science.gov (United States)

    Wu, Chin-Han; Tseng, Ya-Shih; Yang, Chao-Chun; Kao, Yu-Ting; Sheu, Hamm-Ming; Liu, Hsiao-Sheng

    2013-11-01

    Arsenic may cause serious environmental pollution and is a serious industrial problem. Depending on the dosage, arsenic may trigger the cells undergoing either proliferation or apoptosis-related cell death. Because of lack of the proper animal model to study arsenic induced tumorigenesis, the accurate risk level of arsenic exposure has not been determined. Arsenic shows genotoxic effect on human beings who uptake water contaminated by arsenic. Chromosome aberration is frequently detected in arsenic exposure-related diseases and is associated with increased oxidative stress and decreased DNA repairing activity, but the underlying mechanism remains elusive. Aurora-A is a mitotic kinase, over-expression of Aurora-A leads to centrosome amplification, chromosomal instability and cell transformation. We revealed that Aurora-A is over-expressed in the skin and bladder cancer patients from blackfoot-disease endemic areas. Our cell line studies reveal that arsenic exposure between 0.5 μM and 1 μM for 2-7 days are able to induce Aurora-A expression and activation based on promoter activity, RNA and protein analysis. Aurora-A overexpression further increases the frequency of unsymmetrical chromosome segregation through centrosome amplification followed by cell population accumulated at S phase in immortalized keratinocyte (HaCaT) and uroepithelial cells (E7). Furthermore, Aurora-A over-expression was sustained for 1-4 weeks by chronic treatment of immortalized bladder and skin cells with NaAsO2. Aurora-A promoter methylation and gene amplification was not detected in the long-term arsenic treated E7 cells. Furthermore, the expression level of E2F1 transcription factor (E2F1) is increased in the presence of arsenic, and arsenic-related Aurora-A over-expression is transcriptionally regulated by E2F1. We further demonstrated that overexpression of Aurora-A and mutant Ha-ras or Aurora-A and mutant p53 may act additively to trigger arsenic-related bladder and skin cancer

  17. Suppression of colorectal tumorigenesis by recombinant Bacteroides fragilis enterotoxin-2 in vivo

    Science.gov (United States)

    Lv, You; Ye, Tao; Wang, Hui-Peng; Zhao, Jia-Ying; Chen, Wen-Jie; Wang, Xin; Shen, Chen-Xia; Wu, Yi-Bin; Cai, Yuan-Kun

    2017-01-01

    AIM To evaluate the impact of recombinant Bacteroides fragilis enterotoxin-2 (BFT-2, or Fragilysin) on colorectal tumorigenesis in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS). METHODS Recombinant proBFT-2 was expressed in Escherichia coli strain Rosetta (DE3) and BFT-2 was obtained and tested for its biological activity via colorectal adenocarcinoma cell strains SW-480. Seventy C57BL/6J mice were randomly divided into a blank (BC; n = 10), model (AD; n = 20), model + low-dose toxin (ADLT; n = 20, 10 μg), and a model + high-dose toxin (ADHT; n = 20, 20 μg) group. Mice weight, tumor formation and pathology were analyzed. Immunohistochemistry determined Ki-67 and Caspase-3 expression in normal and tumor tissues of colorectal mucosa. RESULTS Recombinant BFT-2 was successfully obtained, along with its biological activity. The most obvious weight loss occurred in the AD group compared with the ADLT group (21.82 ± 0.68 vs 23.23 ± 0.91, P < 0.05) and the ADHT group (21.82 ± 0.68 vs 23.57 ± 1.06, P < 0.05). More tumors were found in the AD group than in the ADLT and ADHT groups (19.75 ± 3.30 vs 6.50 ± 1.73, P < 0.05; 19.75 ± 3.30 vs 6.00 ± 2.16, P < 0.05). Pathology showed that 12 mice had adenocarcinoma and 6 cases had adenoma in the AD group. Five mice had adenocarcinoma and 15 had adenoma in the ADLT group. Four mice had adenocarcinoma and 16 had adenoma in the ADHT group. The incidence of colorectal adenocarcinoma in both the ADHT group and the ADHT group was reduced compared to that in the AD group (P < 0.05, P < 0.05). The positive rate of Ki-67 in the ADLT group and the ADHT group was 50% and 40%, respectively, both of which were lower than that found in the AD group (94.44%, P < 0.05, P < 0.05). Caspase-3 expression in the ADLT group and the ADHT group was 45% and 55%, both of which were higher than that found in the BC group (16.67%, P < 0.05, P < 0.05). CONCLUSION Oral administration with lower-dose biologically active recombinant BFT-2

  18. Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models.

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    Carmen Blanco-Aparicio

    Full Text Available Elevated expression of AKT has been noted in a significant percentage of primary human breast cancers, mainly as a consequence of the PTEN/PI3K pathway deregulation. To investigate the mechanistic basis of the AKT gain of function-dependent mechanisms of breast tumorigenesis, we explored the phenotype induced by activated AKT transgenes in a quantitative manner. We generated several transgenic mice lines expressing different levels of constitutively active AKT in the mammary gland. We thoroughly analyzed the preneoplastic and neoplastic mammary lesions of these mice and correlated the process of tumorigenesis to AKT levels. Finally, we analyzed the impact that a possible senescent checkpoint might have in the tumor promotion inhibition observed, crossing these lines to mammary specific p53(R172H mutant expression, and to p27 knock-out mice. We analyzed the benign, premalignant and malignant lesions extensively by pathology and at molecular level analysing the expression of proteins involved in the PI3K/AKT pathway and in cellular senescence. Our findings revealed an increased preneoplastic phenotype depending upon AKT signaling which was not altered by p27 or p53 loss. However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype. Molecular analysis suggest that tumors from double myrAKT;p53(R172H mice result from acceleration of initiated p53(R172H tumors and not from bypass of AKT-induced oncogenic senescence. Our work suggests that tumors are not the consequence of the bypass of senescence in MIN. We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53. Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors. Finally, our

  19. The functional and structural characterization of a novel oncogene GIG47 involved in the breast tumorigenesis

    Directory of Open Access Journals (Sweden)

    Han Kyou-Hoon

    2012-07-01

    Full Text Available Abstract Background A candidate oncogene GIG47, previously known as a neudesin with a neurotrophic activity, was identified by applying the differential expression analysis method. Methods As a first step to understand the molecular role of GIG47, we analyzed the expression profile of GIG47 in multiple human cancers including the breast cancer and characterized its function related to human carcinogenesis. Based on this oncogenic role of GIG47, we then embarked on determining the high-resolution structure of GIG47. We have applied multidimensional heteronuclear NMR methods to GIG47. Results GIG47 was over-expressed in primary breast tumors as well as other human tumors including carcinomas of the uterine cervix, malignant lymphoma, colon, lung, skin, and leukemia. To establish its role in the pathogenesis of breast cancer in humans, we generated stable transfectants of MCF7 cells. The ectopic expression of GIG47 in MCF7 cells promoted the invasiveness in the presence of 50% serum. In addition, it also resulted in the increased tumorigenicity in in vivo tumor formation assay. The tumorigenesis mechanism involving GIG47 might be mediated by the activation of MAPK and PI3K pathways. These results indicate that GIG47 plays a role in the breast tumorigenesis, thus representing a novel target for the treatment of breast cancer. To facilitate the development of GIG47-targeted therapeutics, we determined the structural configuration of GIG47. The high-resolution structure of GIG47 was obtained by combination of NMR and homology modeling. The overall structure of GIG47 has four α-helices and 6 β-strands, arranged in a β1-α1-β2-β3-α2-β4-α3-α4-β5-β6 topology. There is a potential heme/steroid binding pocket formed between two helices α2 and α3. Conclusion The determined three-dimensional structure of GIG47 may facilitate the development of potential anti-cancer agents.

  20. Overexpression of ligase defective E6-associated protein, E6-AP, results in mammary tumorigenesis.

    Science.gov (United States)

    Ramamoorthy, Sivapriya; Tufail, Rozina; Hokayem, Jimmy El; Jorda, Mercy; Zhao, Wei; Reis, Zizi; Nawaz, Zafar

    2012-02-01

    E6-associated protein (E6-AP) is a dual function protein. It acts as an E3 ubiquitin-protein ligase enzyme and coactivator of steroid hormone receptors such as estrogen (ERα) and progesterone (PR) receptors. It promotes the degradation of ERα and PR through the ubiquitin-proteasome pathway. Furthermore, it has been shown that the levels of E6-AP are inversely associated with that of ERα in human breast tumors. But the role of wild-type human E6-AP and its ubiquitin-protein ligase activity in mammary tumorigenesis is still unknown. To investigate this role, the authors utilized transgenic mice lines that specifically overexpress either the wild-type human E6-AP (E6-AP(WT)) or the ubiquitin-protein ligase defective E6-AP that contains C833S mutation (E6-AP(C833S)) in the mammary gland. To further substantiate the role of E6-AP in the development of breast tumorigenesis, it was also examined the expression of E6-AP in a large cohort of human breast cancer samples. The transgenic mice that overexpress wild-type E6-AP (E6-AP(WT)) fail to develop mammary tumors. Unlike the E6-AP(WT) mice, the E6-AP(C833S) mice that overexpress ubiquitin-protein ligase defective E6-AP protein develop mammary hyperplasia with a median latency of 18 months. These observations suggest that the inactivation of the ubiquitin-protein ligase function of E6-AP is sufficient to initiate the process of mammary tumor development. Furthermore, the data also suggests that E6-AP exerts its effects on target cells by modulating the protein levels and functions of ERα and PR. In addition, it was found in human breast cancer patients that the level of E6-AP is decreased in invasive breast tumors compared to normal breast tissue. Moreover, the authors also show that the survival patterns for E6-AP negative patients were worse compared to E6-AP positive patients. Taken together, these data suggests that E6-AP may act as a tumor suppressor in breast.

  1. Activation of p21(CIP1/WAF1) in mammary epithelium accelerates mammary tumorigenesis and promotes lung metastasis.

    Science.gov (United States)

    Cheng, Xiaoyun; Xia, Weiya; Yang, Jer-Yen; Hsu, Jennifer L; Chou, Chao-Kai; Sun, Hui-Lung; Wyszomierski, Shannon L; Mills, Gordon B; Muller, William J; Yu, Dihua; Hung, Mien-Chie

    2010-12-03

    While p21 is well known to inhibit cyclin-CDK activity in the nucleus and it has also been demonstrated to have oncogenic properties in different types of human cancers. In vitro studies showed that the oncogenic function of p21is closely related to its cytoplasmic localization. However, it is unclear whether cytoplasmic p21 contributes to tumorigenesis in vivo. To address this question, we generated transgenic mice expressing the Akt-phosphorylated form of p21 (p21T145D) in the mammary epithelium. The results showed that Akt-activated p21 was expressed in the cytoplasm of mammary epithelium. Overexpression of Akt-activated p21 accelerated tumor onset and promoted lung metastasis in MMTV/neu mice, providing evidence that p21, especially cytoplasmic phosphorylated p21, has an oncogenic role in promoting mammary tumorigenesis and metastasis.

  2. Neudesin as a unique secreted protein with multi-functional roles in neural functions, energy metabolism, and tumorigenesis

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    Hiroya eOhta

    2015-05-01

    Full Text Available Neudesin was originally identified as a secreted protein with neurotrophic activity, and, thereafter, was also termed neuron-derived neurotrophic factor (NENF or the candidate oncogene GIG47. Neudesin with a conserved cytochrome 5-like heme/steroid-binding domain activates intracellular signaling pathways possibly through the activation of G protein-coupled receptors. In the brain, hypothalamic Neudesin decreases food intake. Neudesin knockout mice also exhibit anxiety-like behavior, indicating its roles in the hippocampal anxiety circuitry. Neudesin is also expressed in various peripheral tissues. Neudesin knockout mice are strongly resistant to high-fat diet-induced obesity due to elevated systemic sympathetic activity, heat production, and adipocytic lipolysis. Neudesin, which is over-expressed or induced by DNA hypomethylation in multiple human cancers, also stimulates tumorigenesis. These findings indicate that Neudesin plays roles in neural functions, energy metabolism, and tumorigenesis and is expected to be a novel target for obesity and anti-cancer treatments.

  3. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.

    Science.gov (United States)

    Weaver, Kelly L; Alves-Guerra, Marie-Clotilde; Jin, Ke; Wang, Zhiqiang; Han, Xiaoqing; Ranganathan, Prathibha; Zhu, Xiaoxia; DaSilva, Thiago; Liu, Wei; Ratti, Francesca; Demarest, Renee M; Tzimas, Cristos; Rice, Meghan; Vasquez-Del Carpio, Rodrigo; Dahmane, Nadia; Robbins, David J; Capobianco, Anthony J

    2014-09-01

    The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development.

  4. A zebrafish transgenic model of Ewing’s sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis

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    Stefanie W. Leacock

    2012-01-01

    Ewing’s sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing’s sarcoma family tumors (ESFTs, which include peripheral primitive neuroectodermal tumors (PNETs, are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing’s sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing’s sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing’s sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.

  5. Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription.

    OpenAIRE

    Shimon, I; Hüttner, A; Said, J; Spirina, O M; Melmed, S

    1996-01-01

    We have shown previously that human prolactinomas express transforming sequences of the heparin-binding secretory transforming gene (hst) which encodes fibroblast growth factor-4 (FGF-4). To elucidate the role of hst in pituitary tumorigenesis we treated primary rat pituitary and pituitary tumor cell cultures with recombinant FGF-4 and also stably transfected pituitary cell lines with full-length human hst cDNA. Transfectants were screened for hst mRNA expression and FGF-4 production. FGF-4 (...

  6. Prepubertal exposure to cow’s milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    OpenAIRE

    Nielsen, Tina S.; Khan, Galam; Davis, Jennifer; Michels, Karin B; Hilakivi-Clarke, Leena

    2011-01-01

    Cow’s milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague Dawley rats were given either whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene (DMBA) on P...

  7. Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells

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    Cai Shao-xi

    2011-03-01

    Full Text Available Abstract Background Conflicting research has identified METCAM/MUC18, an integral membrane cell adhesion molecule (CAM in the Ig-like gene super-family, as both a tumor promoter and a tumor suppressor in the development of breast cancer. To resolve this, we have re-investigated the role of this CAM in the progression of human breast cancer cells. Methods Three breast cancer cell lines were used for the tests: one luminal-like breast cancer cell line, MCF7, which did not express any METCAM/MUC18, and two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which expressed moderate levels of the protein. MCF7 cells were transfected with the human METCAM/MUC18 cDNA to obtain G418-resistant clones which expressed the protein and were used for testing effects of human METCAM/MUC18 expression on in vitro motility and invasiveness, and in vitro and in vivo tumorigenesis. Both MDA-MB-231 and MDA-MB-468 cells already expressed METCAM/MUC18. They were directly used for in vitro tests in the presence and absence of an anti-METCAM/MUC18 antibody. Results In MCF7 cells, enforced METCAM/MUC18 expression increased in vitro motility, invasiveness, anchorage-independent colony formation (in vitro tumorigenesis, and in vivo tumorigenesis. In both MDA-MB-231 and MDA-MB-468 cells, the anti-METCAM/MUC18 antibody inhibited both motility and invasiveness. Though both MDA-MB-231 and MDA-MB-468 cells established a disorganized growth in 3D basement membrane culture assay, the introduction of the anti-METCAM/MUC18 antibody completely destroyed their growth in the 3D culture. Conclusion These findings support the notion that human METCAM/MUC18 expression promotes the progression of human breast cancer cells by increasing their motility, invasiveness and tumorigenesis.

  8. Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway.

    Science.gov (United States)

    Liu, G; Yu, F-X; Kim, Y C; Meng, Z; Naipauer, J; Looney, D J; Liu, X; Gutkind, J S; Mesri, E A; Guan, K-L

    2015-07-01

    Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.

  9. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation.

    Science.gov (United States)

    Yang, Qi; Du, William W; Wu, Nan; Yang, Weining; Awan, Faryal Mehwish; Fang, Ling; Ma, Jian; Li, Xiangmin; Zeng, Yan; Yang, Zhenguo; Dong, Jun; Khorshidi, Azam; Yang, Burton B

    2017-09-01

    Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm(3) in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.

  10. JNK2 downregulation promotes tumorigenesis and chemoresistance by decreasing p53 stability in bladder cancer

    Science.gov (United States)

    Zhao, Yu; Qian, Chenchen; Wang, Liguo; Qi, Jun

    2016-01-01

    Bladder cancer is one of the most common malignancies of the urinary system, and the 5-year survival rate remains low. A comprehensive understanding of the carcinogenesis and progression of bladder cancer is urgently needed to advance treatment. c-Jun N-terminal kinase-2 (JNK2) exhibits both tumor promoter and tumor suppressor actions, depending on tumor type. Here, we analyzed the JNK2 function in bladder cancer. Using gene expression microarrays, we demonstrated that JNK2 mRNA is downregulated in an orthotopic rat model of bladder cancer. JNK2 protein levels were lower in rat and human bladder cancer tissues than in normal tissues, and the levels correlated with those of p53. Moreover, JNK2 phosphorylated p53 at Thr-81, thus protecting p53 from MDM2-induced proteasome degradation. Decreased expression of JNK2 in T24 cells conferred resistance to cell death induced by mitomycin C. Furthermore, lower JNK2 expression was associated with poorer overall survival among patients who underwent radical cystectomy. These results indicate that JNK2 acts as a tumor suppressor in bladder cancer, and that decreased JNK2 expression promotes bladder cancer tumorigenesis. PMID:27147566

  11. RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.

    Science.gov (United States)

    Taulli, Riccardo; Accornero, Paolo; Follenzi, Antonia; Mangano, Tony; Morotti, Alessandro; Scuoppo, Claudio; Forni, Paolo E; Bersani, Francesca; Crepaldi, Tiziana; Chiarle, Roberto; Naldini, Luigi; Ponzetto, Carola

    2005-05-01

    Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele. In this work, we report specific suppression of Tpr-Met expression and inhibition of Tpr-Met-mediated transformation and tumorigenesis by means of a short interfering RNA (siRNA) directed toward the Tpr-Met junction (anti-TM2). When delivered by a lentiviral vector, anti-TM2 siRNA was effective also in mouse embryonal fibroblasts or epithelial cells expressing high levels of Tpr-Met. Our results suggest that lentiviral-mediated delivery of anti-TM2 siRNA may be developed into a powerful tool to treat Tpr-Met-positive cancers.

  12. Nisin ZP, a Bacteriocin and Food Preservative, Inhibits Head and Neck Cancer Tumorigenesis and Prolongs Survival.

    Science.gov (United States)

    Kamarajan, Pachiyappan; Hayami, Takayuki; Matte, Bibiana; Liu, Yang; Danciu, Theodora; Ramamoorthy, Ayyalusamy; Worden, Francis; Kapila, Sunil; Kapila, Yvonne

    2015-01-01

    The use of small antimicrobial peptides or bacteriocins, like nisin, to treat cancer is a new approach that holds great promise. Nisin exemplifies this new approach because it has been used safely in humans for many years as a food preservative, and recent laboratory studies support its anti-tumor potential in head and neck cancer. Previously, we showed that nisin (2.5%, low content) has antitumor potential in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. The current studies explored a naturally occurring variant of nisin (nisin ZP; 95%, high content) for its antitumor effects in vitro and in vivo. Nisin ZP induced the greatest level of apoptosis in HNSCC cells compared to low content nisin. HNSCC cells treated with increasing concentrations of nisin ZP exhibited increasing levels of apoptosis and decreasing levels of cell proliferation, clonogenic capacity, and sphere formation. Nisin ZP induced apoptosis through a calpain-dependent pathway in HNSCC cells but not in human oral keratinocytes. Nisin ZP also induced apoptosis dose-dependently in human umbilical vein endothelial cells (HUVEC) with concomitant decreases in vascular sprout formation in vitro and reduced intratumoral microvessel density in vivo. Nisin ZP reduced tumorigenesis in vivo and long-term treatment with nisin ZP extended survival. In addition, nisin treated mice exhibited normal organ histology with no evidence of inflammation, fibrosis or necrosis. In summary, nisin ZP exhibits greater antitumor effects than low content nisin, and thus has the potential to serve as a novel therapeutic for HNSCC.

  13. Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.

    Science.gov (United States)

    Ferreira, Humberto J; Heyn, Holger; Garcia del Muro, Xavier; Vidal, August; Larriba, Sara; Muñoz, Clara; Villanueva, Alberto; Esteller, Manel

    2014-01-01

    Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia. Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development. We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines. Most importantly, these epigenetic lesions occur in a context of piRNA downregulation and loss of DNA methylation of the LINE-1 repetitive sequences, one of the target genomic loci where the PIWI/piRNA machinery acts as a caretaker in non-transformed cells.

  14. Astrocyte Elevated Gene-1 Mediates Glycolysis and Tumorigenesis in Colorectal Carcinoma Cells via AMPK Signaling

    Directory of Open Access Journals (Sweden)

    Hong-tao Song

    2014-01-01

    Full Text Available To investigate the role of AEG-1 in glycolysis and tumorigenesis, we construct myc-AEG-1 expression vector and demonstrate a novel mechanism that AEG-1 may increase the activity of AMPK by Thr172 phosphorylation. The higher expression levels of AEG-1 in colorectal carcinoma cells were found but showed significant difference in different cell lines. To study the role of AEG-1 in colorectal cells, myc-AEG-1 vector was constructed and transfected into NCM460 colonic epithelial cells. We observed consistent increasing of glucose consumption and lactate production, typical features of anaerobic glycolysis, suggesting that AEG-1 may promote anaerobic glycolysis. Moreover, we noted that AMPK phosphorylation at Thr172 as well as pPFK2 (Ser466 was increased in NCM460 cells overexpressing AEG-1. Compound C may block AMPK and PFK2 phosphorylation in both control and AEG-1-overexpressed cells and decrease the glucose consumption and lactate production. The present findings indicated that reduced AEG-1 protein levels by RNAi may decrease the glucose consumption and lactate production in HCT116 colorectal carcinoma cells. The present identified AEG-1/AMPK/PFK2 glycolysis cascade may be essential to cell proliferation and tumor growth. The present results may provide us with a mechanistic insight into novel targets controlled by AEG-1, and the components in the AEG-1/AMPK/PFK2 glycolysis process may be targeted for the clinical treatment of cancer.

  15. Long-chain fatty acid analogues suppress breast tumorigenesis and progression.

    Science.gov (United States)

    Gluschnaider, Udi; Hertz, Rachel; Ohayon, Sarit; Smeir, Elia; Smets, Martha; Pikarsky, Eli; Bar-Tana, Jacob

    2014-12-01

    Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither β-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydrate-restricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src-transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction.

  16. Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis

    Science.gov (United States)

    Marusiak, Anna A.; Stephenson, Natalie L.; Baik, Hayeon; Trotter, Eleanor W.; Li, Yaoyong; Blyth, Karen; Mason, Susan; Chapman, Phil; Puto, Lorena A.; Read, Jon A.; Brassington, Claire; Pollard, Hannah K.; Phillips, Chris; Green, Isabelle; Overman, Ross; Collier, Matthew; Testoni, Ewelina; Miller, Crispin J.; Hunter, Tony; Sansom, Owen J.; Brognard, John

    2015-01-01

    MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers including frequently in colorectal cancer, where their function and pathobiological importance has been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain the tumorigenic phenotype, we reconstituted its signaling axis in colon cancer cells harboring MLK4 inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3 and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer. PMID:26637668

  17. Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Jin Woo Choi

    2011-03-01

    Full Text Available Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38 was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2 is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.

  18. Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats.

    Directory of Open Access Journals (Sweden)

    Jun-Chao Guo

    Full Text Available The extremely dismal prognosis of pancreatic cancer (PC is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation.

  19. Knockdown of DDX46 Inhibits the Invasion and Tumorigenesis in Osteosarcoma Cells.

    Science.gov (United States)

    Jiang, Feng; Zhang, Dengfeng; Li, Guojun; Wang, Xiao

    2017-03-13

    DDX46, a member of the DEAD-box (DDX) helicase family, is involved in the development of several tumors. However, the exact role of DDX46 in osteosarcoma and the underlying mechanisms in tumorigenesis remain poorly understood. Thus, in the present study, we explored the role of DDX46 in osteosarcoma and the underlying mechanisms. Our results demonstrated that the expression levels of DDX46 in both mRNA and protein were greatly elevated in human osteosarcoma tissues and cell lines. Knockdown of DDX46 obviously inhibited osteosarcoma cell proliferation and tumor growth in vivo. In addition, knockdown of DDX46 also significantly suppressed migration and invasion in osteosarcoma cells. Furthermore, knockdown of DDX46 substantially downregulated the phosphorylation levels of PI3K and Akt in SaOS2 cells. In summary, the present results have revealed that DDX46 plays an important role in osteosarcoma growth and metastasis. Knockdown of DDX46 inhibited osteosarcoma cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Therefore, DDX46 may be a potential therapeutic target for the treatment of osteosarcoma.

  20. A potential role for Helicobacter pylori heat shock protein 60 in gastric tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chen-Si [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); He, Pei-Juin [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Tsai, Nu-Man [School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Li, Chi-Han; Yang, Shang-Chih; Hsu, Wei-Tung [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Wu, Ming-Shiang [Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Wu, Chang-Jer [Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan (China); Cheng, Tain-Lu [Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Liao, Kuang-Wen, E-mail: kitchhen@yahoo.com.tw [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China)

    2010-02-05

    Helicobacter pylori has been found to promote the malignant process leading to gastric cancer. Heat shock protein 60 of H. pylori (HpHSP60) was previously been identified as a potent immunogene. This study investigates the role of HpHSP60 in gastric cancer carcinogenesis. The effect of HpHSP60 on cell proliferation, anti-death activity, angiogenesis and cell migration were explored. The results showed that HpHSP60 enhanced migration by gastric cancer cells and promoted tube formation by umbilical vein endothelial cells (HUVECs); however, HpHSP60 did not increase cell proliferation nor was this protein able to rescue gastric cancer cells from death. Moreover, the results also indicated HpHSP60 had different effects on AGS gastric cancer cells or THP-1 monocytic cells in terms of their expression of pro-inflammatory cytokines, which are known to be important to cancer development. We propose that HpHSP60 may trigger the initiation of carcinogenesis by inducing pro-inflammatory cytokine release and by promoting angiogenesis and metastasis. Thus, this extracellular pathogen-derived HSP60 is potentially a vigorous virulence factor that can act as a carcinogen during gastric tumorigenesis.

  1. Extraintestinal Helminth Infection Reduces the Development of Colitis-Associated Tumorigenesis

    Science.gov (United States)

    León-Cabrera, Sonia; Callejas, Blanca E.; Ledesma-Soto, Yadira; Coronel, Jossimar; Pérez-Plasencia, Carlos; Gutiérrez-Cirlos, Emma B.; Ávila-Moreno, Federico; Rodríguez-Sosa, Miriam; Hernández-Pando, Rogelio; Marquina-Castillo, Brenda; Chirino, Yolanda I.; Terrazas, Luis I.

    2014-01-01

    Colitis-associated colorectal cancer (CAC) is one of the most common cancers and is closely related to chronic or deregulated inflammation. Helminthic infections can modulate inflammatory responses in some diseases, but their immunomodulatory role during cancer development remains completely unknown. We have analyzed the role of Taenia crassiceps-induced anti-inflammatory response in determining the outcome of CAC. We show that extraintestinal T. crassiceps infection in CAC mice inhibited colonic inflammatory responses and tumor formation and prevented goblet cell loss. There was also increased expression of IL-4 and alternatively activated macrophages markers in colonic tissue and negative immunomodulation of pro-inflammatory cytokine expression. In addition, T. crassiceps infection prevented the upregulation of β-catenin and CXCR2 expression observed in the CAC mice, which are both markers associated with CAC-tumorigenesis, and reduced the numbers of circulating and colonic CD11b+Ly6ChiCCR2+ monocytes. Thus, immunomodulatory activities induced by helminth infections may have a role in the progression of CAC. PMID:25210492

  2. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Kay Andrea

    2009-10-01

    Full Text Available Abstract The mammalian target of rapamycin (mTOR is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA and the European Medicines Agency (EMEA for the treatment of advanced renal cell carcinoma (RCC. Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

  3. Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis and viral infection

    Directory of Open Access Journals (Sweden)

    YASUO eARIUMI

    2014-12-01

    Full Text Available The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in all aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. In addition, DDX3 is also implicated in cell cycle regulation, apoptosis, Wnt-ß-catenin signaling, tumorigenesis, and viral infection. Notably, recent studies suggest that DDX3 is a component of anti-viral innate immune signaling pathways. Indeed, DDX3 contributes to enhance the induction of anti-viral mediators, interferon regulatory factor (IRF 3 and type I interferon (IFN. However, DDX3 seems to be an important target for several viruses, such as human immunodeficiency virus (HIV-1, hepatitis C virus (HCV, hepatitis B virus (HBV, and poxvirus. DDX3 interacts with HIV-1 Rev or HCV Core protein and modulates its function. At least, DDX3 is required for both HIV-1 and HCV replication. Therefore, DDX3 could be a novel therapeutic target for the development of drug against HIV-1 and HCV.

  4. Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis, and viral infection.

    Science.gov (United States)

    Ariumi, Yasuo

    2014-01-01

    The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in all aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. In addition, DDX3 is also implicated in cell cycle regulation, apoptosis, Wnt-β-catenin signaling, tumorigenesis, and viral infection. Notably, recent studies suggest that DDX3 is a component of anti-viral innate immune signaling pathways. Indeed, DDX3 contributes to enhance the induction of anti-viral mediators, interferon (IFN) regulatory factor 3 and type I IFN. However, DDX3 seems to be an important target for several viruses, such as human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV), hepatitis B virus (HBV), and poxvirus. DDX3 interacts with HIV-1 Rev or HCV Core protein and modulates its function. At least, DDX3 is required for both HIV-1 and HCV replication. Therefore, DDX3 could be a novel therapeutic target for the development of drug against HIV-1 and HCV.

  5. Detection of tumorigenesis in urinary bladder with optical coherence tomography: optical characterization of morphological changes

    Science.gov (United States)

    Xie, T.-Q.; Zeidel, M. L.; Pan, Yingtian

    2002-12-01

    Most transitional cell tumorigenesis involves three stages of subcellular morphological changes: hyperplasia, dysplasia and neoplasia. Previous studies demonstrated that owing to its high spatial resolution and intermediate penetration depth, current OCT technology including endoscopic OCT could delineate the urothelium, submucosa and the upper muscular layers of the bladder wall. In this paper, we will discuss the sensitivity and limitations of OCT in diagnosing and staging bladder cancer. Based on histomorphometric evaluations of nuclear morphology, we modeled the resultant backscattering changes and the characteristic changes in OCT image contrast. In the theoretical modeling, we assumed that nuclei were the primary sources of scattering and were uniformly distributed in the uroepithelium, and compared with the results of the corresponding prior OCT measurements. According to our theoretical modeling, normal bladder shows a thin, uniform and low scattering urothelium, so does an inflammatory lesion except thickening in the submucosa. Compared with a normal bladder, a hyperplastic lesion exhibits a thickened, low scattering urothelium whereas a neoplastic lesion shows a thickened urothelium with increased backscattering. These results support our previous animal study that OCT has the potential to differentiate inflammation, hyperplasia, and neoplasia by quantifying the changes in urothelial thickening and backscattering. The results also suggest that OCT might not have the sensitivity to differentiate the subtle morphological changes between hyperplasia and dysplasia based on minor backscattering differences.

  6. Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis

    Indian Academy of Sciences (India)

    Niladri Ganguly; Suraj P Parihar

    2009-03-01

    Human papillomavirus (HPV) is small, double-stranded DNA virus that infects mucosal and cutaneous epithelial tissue. HPV is sexually transmitted and the viral DNA replicates extrachromosomally. The virus is non-enveloped and has an icosahedral capsid. There are approximately 118 types of HPV, which are characterized as high-risk or low-risk types. High-risk HPVs cause malignant transformation while the low-risk ones cause benign warts and lesions. The expression of E6 and E7 is normally controlled during the normal viral life cycle when viral DNA replicates extrachromosomally. HPV E6 and E7 oncoproteins are overexpressed when the viral genome integrates into the host DNA. Deregulated overexpression of E6 and E7 oncoproteins can cause several changes in cellular pathways and functions leading to malignant transformation of cells and tumorigenesis. In this review, we focus on several cellular mechanisms and pathways that are altered in the presence of E6 and E7, the target proteins of E6 and E7 inside the host cell and how they contribute to the development of the transformed phenotype..

  7. Influence of dietary menhaden oil on 7,12-dimethylbenzanthracene induced mammary tumorigenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, T.P.; Peterson, F.; Campbell, T.C.

    1986-03-05

    The effect of dietary menhaden oil on 7,12-dimethylbenzanthracene (DMBA) induced mammary tumorigenesis was examined in female Sprague-Dawley rats. Rats were obtained at age 28 days and acclimated until age 50 days when they received a single i.g. dose of 5 mg DMBA dissolved in 1 ml corn oil. Rats were then randomly assigned to one of four treatment groups with 25 rats per group. One group was fed a diet based on fish protein (freeze-dried cod) and corn oil (F/C). The second group received a diet based on fish protein and menhaden oil (F/M). The third group received a casein based diet with corn oil as the lipid source (C/C). The fourth group was fed a casein based diet with menhaden oil as the lipid source (C/M). Both the protein and lipid sources were fed at a level of 20% by weight of the diets. Rats were palpated weekly to check for mammary tumor development and the experiment was terminated 24 weeks after DMBA administration. Rats fed menhaden oil as a lipid source (F/M and C/M groups) developed significantly fewer mammary tumors than animals on the corn oil based diets (F/C and C/C groups, respectively). Thus, menhaden oil, rich in omega-3 fatty acids, significantly inhibited the development of DMBA induced mammary tumors in this experiment.

  8. Intestinal tumorigenesis is not affected by progesterone signaling in rodent models.

    Directory of Open Access Journals (Sweden)

    Jarom Heijmans

    Full Text Available Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO to the Apc(Min/+ mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+ mice exhibited no change in polyp number, size or localization compared to Apc(Min/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

  9. β-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

    Directory of Open Access Journals (Sweden)

    Noriko Okumura

    Full Text Available The canonical Wnt/β-catenin signaling pathway plays a crucial role in the maintenance of the balance between proliferation and differentiation throughout embryogenesis and tissue homeostasis. β-Catenin, encoded by the Ctnnb1 gene, mediates an intracellular signaling cascade activated by Wnt. It also plays an important role in the maintenance of various types of stem cells including adult stem cells and cancer stem cells. However, it is unclear if β-catenin is required for the derivation of mouse embryo-derived stem cells. Here, we established β-catenin-deficient (β-cat(Δ/Δ mouse embryo-derived stem cells and showed that β-catenin is not essential for acquiring self-renewal potential in the derivation of mouse embryonic stem cells (ESCs. However, teratomas formed from embryo-derived β-cat(Δ/Δ ESCs were immature germ cell tumors without multilineage differentiated cell types. Re-expression of functional β-catenin eliminated their neoplastic, transformed phenotype and restored pluripotency, thereby rescuing the mutant ESCs. Our findings demonstrate that β-catenin has pleiotropic effects in ESCs; it is required for the differentiation of ESCs and prevents them from acquiring tumorigenic character. These results highlight β-catenin as the gatekeeper in differentiation and tumorigenesis in ESCs.

  10. EMP-1 promotes tumorigenesis of NSCLC through PI3K/AKT pathway.

    Science.gov (United States)

    Lai, Senyan; Wang, Guihua; Cao, Xiaonian; Li, Zhaoming; Hu, Junbo; Wang, Jing

    2012-12-01

    This study examined the role of EMP-1 in tumorigenesis of non-small cell lung carcinoma (NSCLC) and the possible mechanism. Specimens were collected from 28 patients with benign lung diseases and 28 with NSCLC, and immunohistochemically detected to evaluate the correlation of EMP-1 expression to the clinical features of NSCLC. Recombinant adenovirus was constructed to over-express EMP-1 and then infect PC9 cells. Cell proliferation was measured by Ki67 staining. Western blotting was performed to examine the effect of EMP-1 on the PI3K/AKT signaling. Moreover, tumor xenografts were established by subcutaneous injection of PC9 cell suspension (about 5×10(7)/mL in 100 μL of PBS) into the right hind limbs of athymic nude mice. The results showed EMP-1 was significantly up-regulated in NSCLC patients as compared with those with benign lung diseases. Over-expression of EMP-1 promoted proliferation of PC9 cells, which coincided with the activation of the PI3K/AKT pathway. EMP-1 promoted the growth of xenografts of PC9 cells in athymic nude mice. It was concluded that EMP-1 expression may contribute to the development and progress of NSCLC by activating PI3K/AKT pathway.

  11. HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis.

    Science.gov (United States)

    Choi, Seo-Hyun; Nam, Jae-Kyung; Kim, Bu-Yeo; Jang, Junho; Jin, Young-Bae; Lee, Hae-June; Park, Seungwoo; Ji, Young Hoon; Cho, Jaeho; Lee, Yoon-Jin

    2016-03-01

    The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFβ or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.

  12. Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis.

    Science.gov (United States)

    Mancini, Maria L; Lien, Evan C; Toker, Alex

    2016-04-05

    One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1(E17K).

  13. Partial Hepatectomy in Acetylation-Deficient Mice Corroborates that Chromosome Missegregation Initiates Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yoo-Kyung Lee

    2014-12-01

    Full Text Available BackgroundAneuploidy has been suggested as one of the major causes of cancer from the time of Boveri. In support of this notion, many studies have shown that cancer cells exhibit aneuploidy. However, there are evidences that do not support the aneuploidy hypothesis. We have previously reported that the spindle assembly checkpoint protein BubR1 is acetylated in mitosis and that the acetylation of BubR1 is crucial for checkpoint maintenance and chromosome-spindle attachment. Mice heterozygous for acetylation-deficient BubR1 (K243R/+ spontaneously develop cancer with chromosome instability. As K243R/+ mice develop hepatocellular carcinoma, we set out to test if chromosome mis-segregation was the cause of their liver cancer.MethodsPrimary hepatocytes in the regenerating liver after partial hepatectomy (PH were analyzed and compared for various mitotic parameters.ResultsPrimary hepatocytes isolated from K243R/+ mice after PH displayed a marked increase of chromosome misalignment, accompanied by an increase of micronuclei. In comparison, the number of nuclei per cell and the centrosome numbers were not different between wild-type and K243R/+ mice. Taken together, chromosome mis-segregation provokes tumorigenesis in mouse liver.ConclusionOur results corroborate that PH provides a reliable tool for assessing mitotic infidelity and cancer in mice.

  14. Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis.

    Science.gov (United States)

    Maruyama, Eri Ohfuchi; Yu, H-M Ivy; Jiang, Ming; Fu, Jiang; Hsu, Wei

    2013-01-01

    Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.

  15. Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Eri Ohfuchi Maruyama

    Full Text Available Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.

  16. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis

    Science.gov (United States)

    Seo, Bo Ri; Bhardwaj, Priya; Choi, Siyoung; Gonzalez, Jacqueline; Andresen Eguiluz, Roberto C.; Wang, Karin; Mohanan, Sunish; Morris, Patrick G.; Du, Baoheng; Zhou, Xi K.; Vahdat, Linda T.; Verma, Akanksha; Elemento, Olivier; Hudis, Clifford A.; Williams, Rebecca M.; Gourdon, Delphine; Dannenberg, Andrew J.; Fischbach, Claudia

    2016-01-01

    Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies. PMID:26290412

  17. Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis.

    Science.gov (United States)

    Lu, Jingjun; Mitra, Sona; Wang, Xianwei; Khaidakov, Magomed; Mehta, Jawahar L

    2011-10-15

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been identified as a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, monocytes, platelets, cardiomyocytes, and vascular smooth muscle cells. Its expression is minimal under physiological conditions but can be induced under pathological conditions. The upregulation of LOX-1 by ox-LDL appears to be important for physiologic processes, such as endothelial cell proliferation, apoptosis, and endothelium remodeling. Pathophysiologic effects of ox-LDL in atherogenesis have also been firmly established, including endothelial cell dysfunction, smooth muscle cell growth and migration, monocyte transformation into macrophages, and finally platelet aggregation-seen in atherogenesis. Recent studies show a positive correlation between increased serum ox-LDL levels and an increased risk of colon, breast, and ovarian cancer. As in atherosclerosis, ox-LDL and its receptor LOX-1 activate the inflammatory pathway through nuclear factor-kappa B, leading to cell transformation. LOX-1 is important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth, suggesting a molecular connection between atherogenesis and tumorigenesis.

  18. Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis

    Science.gov (United States)

    Qin, Hai-De; Liao, Xiao-Yu; Chen, Yuan-Bin; Huang, Shao-Yi; Xue, Wen-Qiong; Li, Fang-Fang; Ge, Xiao-Song; Liu, De-Qing; Cai, Qiuyin; Long, Jirong; Li, Xi-Zhao; Hu, Ye-Zhu; Zhang, Shao-Dan; Zhang, Lan-Jun; Lehrman, Benjamin; Scott, Alan F.; Lin, Dongxin; Zeng, Yi-Xin; Shugart, Yin Yao; Jia, Wei-Hua

    2016-01-01

    The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets. PMID:27058444

  19. JAC, a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis.

    Science.gov (United States)

    Hartl, M; Reiter, F; Bader, A G; Castellazzi, M; Bister, K

    2001-11-20

    Using subtractive hybridization techniques, we have isolated a gene termed JAC that is strongly and specifically activated in avian fibroblasts transformed by the v-jun oncogene of avian sarcoma virus 17 (ASV17), but not in cells transformed by other oncogenic agents. Furthermore, JAC is highly expressed in cell lines derived from jun-induced avian fibrosarcomas. Kinetic analysis using a doxycycline-controlled conditional cell transformation system showed that expression of the 0.8-kb JAC mRNA is induced rapidly upon activation of the oncogenic v-jun allele. Nucleotide sequence analysis and transcriptional mapping revealed that the JAC gene contains two exons, with the longest ORF confined to exon 2. The deduced 68-amino acid chicken JAC protein is rich in cysteine residues and displays 37% sequence identity to mammalian high-sulfur keratin-associated proteins. The promoter region of JAC contains a consensus (5'-TGACTCA-3') and a nonconsensus (5'-TGAGTAA-3') AP-1 binding site in tandem, which are both specifically bound by the Gag-Jun hybrid protein encoded by ASV17. Mutational analysis revealed that the two AP-1 sites confer strong transcriptional activation by Gag-Jun in a synergistic manner. Ectopic expression of JAC in avian fibroblasts leads to anchorage-independent growth, strongly suggesting that deregulation of JAC is an essential event in jun-induced cell transformation and tumorigenesis.

  20. Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis

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    Ahmed Kheimar

    2017-07-01

    Full Text Available Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGGn that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek’s disease virus (MDV, harbor telomeric repeats (TMR identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR that shares 88% sequence identity with the telomerase RNA in chicken (chTR. vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.

  1. Telomeres and Telomerase: Role in Marek's Disease Virus Pathogenesis, Integration and Tumorigenesis.

    Science.gov (United States)

    Kheimar, Ahmed; Previdelli, Renato L; Wight, Darren J; Kaufer, Benedikt B

    2017-07-04

    Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek's disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.

  2. Effects of hemin and nitrite on intestinal tumorigenesis in the A/J Min/+ mouse model.

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    Marianne Sødring

    Full Text Available Red and processed meats are considered risk factors for colorectal cancer (CRC; however, the underlying mechanisms are still unclear. One cause for the potential link between CRC and meat is the heme iron in red meat. Two pathways by which heme and CRC promotion may be linked have been suggested: fat peroxidation and N-nitrosation. In the present work we have used the novel A/J Min/+ mouse model to test the effects of dietary hemin (a model of red meat, and hemin in combination with nitrite (a model of processed meat on intestinal tumorigenesis. Mice were fed a low Ca2+ and vitamin D semi-synthetic diet with added hemin and/or nitrite for 8 weeks post weaning, before termination followed by excision and examination of the intestinal tract. Our results indicate that dietary hemin decreased the number of colonic lesions in the A/J Min/+ mouse. However, our results also showed that the opposite occurred in the small intestine, where dietary hemin appeared to stimulate tumor growth. Furthermore, we find that nitrite, which did not have an effect in the colon, appeared to have a suppressive effect on tumor growth in the small intestine.

  3. Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats.

    Science.gov (United States)

    Guo, Jun-Chao; Li, Jian; Yang, Ying-Chi; Zhou, Li; Zhang, Tai-Ping; Zhao, Yu-Pei

    2013-01-01

    The extremely dismal prognosis of pancreatic cancer (PC) is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA)-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes) were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation.

  4. Absence of ERK5/MAPK7 delays tumorigenesis in Atm-/- mice.

    Science.gov (United States)

    Granados-Jaén, Alba; Angulo-Ibáñez, Maria; Rovira-Clavé, Xavier; Gamez, Celina Paola Vasquez; Soriano, Francesc X; Reina, Manuel; Espel, Enric

    2016-11-15

    Ataxia-telangiectasia mutated (ATM) is a cell cycle checkpoint kinase that upon activation by DNA damage leads to cell cycle arrest and DNA repair or apoptosis. The absence of Atm or the occurrence of loss-of-function mutations in Atm predisposes to tumorigenesis. MAPK7 has been implicated in numerous types of cancer with pro-survival and pro-growth roles in tumor cells, but its functional relation with tumor suppressors is not clear. In this study, we show that absence of MAPK7 delays death due to spontaneous tumor development in Atm-/- mice. Compared with Atm-/- thymocytes, Mapk7-/-Atm-/- thymocytes exhibited an improved response to DNA damage (increased phosphorylation of H2AX) and a restored apoptotic response after treatment of mice with ionizing radiation. These findings define an antagonistic function of ATM and MAPK7 in the thymocyte response to DNA damage, and suggest that the lack of MAPK7 inhibits thymic lymphoma growth in Atm-/- mice by partially restoring the DNA damage response in thymocytes.

  5. GATA4 is a critical regulator of gonadectomy-induced adrenocortical tumorigenesis in mice.

    Science.gov (United States)

    Krachulec, Justyna; Vetter, Melanie; Schrade, Anja; Löbs, Ann-Kathrin; Bielinska, Malgorzata; Cochran, Rebecca; Kyrönlahti, Antti; Pihlajoki, Marjut; Parviainen, Helka; Jay, Patrick Y; Heikinheimo, Markku; Wilson, David B

    2012-06-01

    In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4(+/-) B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4(F)) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4(F) dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.

  6. SIRT1 and Tumorigenesis%SIRT1与肿瘤发生

    Institute of Scientific and Technical Information of China (English)

    赵志强; 毛文琼

    2011-01-01

    Sirtuin l(SIRT1)inactivates proteins involved in tumor suppression and DNA damage repair )by deacetylation and it has long been considered as a tumor promoter. However, recent studies demonstrated that SIRT1 expression levels are reduced in some other types of cancers, and that SIRT1 deficiency results in genetic instability and tumorigenesis,while overexpression of SIRT1 attenuates cancer formation. The dual role that SIRT1 plays may depend on the temporal and special distribution of different SIRT1 upand downstream factors in different tissue contexts.%SIRT1(sirtuin 1)通过对肿瘤抑制蛋白和DNA损伤修复蛋白去乙酰化而使之失活。因此,SIRT1早期被认为是肿瘤促进因子。近来研究又表明SIRT1在某些肿瘤中表达降低且SIRT1缺乏导致遗传不稳定和肿瘤发生。超表达SIRT1可降低癌变风险。SIRT1的这种双重作用可能与其组织中SIRT1上游和下游因子的时空分布不同有关。

  7. Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis.

    Science.gov (United States)

    Safaee, Michael; Oh, Michael C; Bloch, Orin; Sun, Matthew Z; Kaur, Gurvinder; Auguste, Kurtis I; Tihan, Tarik; Parsa, Andrew T

    2013-03-01

    Choroid plexus papillomas are rare, benign tumors originating from the choroid plexus. Although generally found within the ventricular system, they can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. We sought to review recent advances in our understanding of the molecular biology and oncogenic pathways associated with this disease. A comprehensive PubMed literature review was conducted to identify manuscripts discussing the clinical, molecular, and genetic features of choroid plexus papillomas. Articles concerning diagnosis, treatment, and long-term patient outcomes were also reviewed. The introduction of atypical choroid plexus papilloma as a distinct entity has increased the need for accurate histopathologic diagnosis. Advances in immunohistochemical staining have improved our ability to differentiate choroid plexus papillomas from other intracranial tumors or metastatic lesions using combinations of key markers and mitotic indices. Recent findings have implicated Notch3 signaling, the transcription factor TWIST1, platelet-derived growth factor receptor, and the tumor necrosis factor-related apoptosis-inducing ligand pathway in choroid plexus papilloma tumorigenesis. A combination of commonly occurring chromosomal duplications and deletions has also been identified. Surgical resection remains the standard of care, although chemotherapy and radiotherapy may be considered for recurrent or metastatic lesions. While generally considered benign, these tumors possess a complex biology that sheds insight into other choroid plexus tumors, particularly malignant choroid plexus carcinomas. Improving our understanding of the molecular biology, genetics, and oncogenic pathways associated with this tumor will allow for the development of targeted therapies and improved outcomes for patients with this disease.

  8. Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart.

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    Yuzhen Zhang

    Full Text Available BACKGROUND: Induced pluripotent stem cells (iPSCs are a novel candidate for use in cardiac stem cell therapy. However, their intrinsic tumorigenicity requires further investigation prior to use in a clinical setting. In this study we investigated whether undifferentiated iPSCs are tumorigenic after intramyocardial transplantation into immunocompetent allogeneic recipients. METHODOLOGY/PRINCIPAL FINDINGS: We transplanted 2 × 10(4, 2 × 10(5, or 2 × 10(6 cells from the established rat iPSC line M13 intramyocardially into intact or infarcted hearts of immunocompetent allogeneic rats. Transplant duration was 2, 4, or 6 weeks. Histological examination with hematoxylin-eosin staining confirmed that undifferentiated rat iPSCs could generate heterogeneous tumors in both intracardiac and extracardiac sites. Furthermore, tumor incidence was independent of cell dose, transplant duration, and the presence or absence of myocardial infarction. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that allogeneic iPSC transplantation in the heart will likely result in in situ tumorigenesis, and that cells leaked from the beating heart are a potential source of tumor spread, underscoring the importance of evaluating the safety of future iPSC therapy for cardiac disease.

  9. Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι

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    Yuki Nakanishi

    2016-09-01

    Full Text Available Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5+ stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease. Kaplan-Meier survival analysis of colorectal cancer (CRC patients revealed that low PRKCI levels correlated with significantly worse patient survival rates. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.

  10. MicroRNA-24 Modulates Aflatoxin B1-Related Hepatocellular Carcinoma Prognosis and Tumorigenesis

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    Yi-Xiao Liu

    2014-01-01

    Full Text Available MicroRNA-24 (miR-24 may be involved in neoplastic process; however, the role of this microRNA in the hepatocellular carcinoma (HCC related to aflatoxin B1 (AFB1 has not been well elaborated. Here, we tested miR-24 expression in 207 pathology-diagnosed HCC cases from high AFB1 exposure areas and HCC cells. We found that miR-24 was upregulated in HCC tumor tissues relative to adjacent noncancerous tissue samples, and that the high expression of miR-24 was significantly correlated with larger tumor size, higher microvessel density, and tumor dedifferentiation. Additionally, this microRNA overexpression modified the recurrence-free survival (relative hazard ratio [HR], 4.75; 95% confidence interval [CI], 2.66–8.47 and overall survival (HR=3.58, 95% CI = 2.34–5.46 of HCC patients. Furthermore, we observed some evidence of joint effects between miR-24 and AFB1 exposure on HCC prognosis. Functionally, miR-24 overexpression progressed tumor cells proliferation, inhibited cell apoptosis, and developed the formation of AFB1-DNA adducts. These results indicate for the first time that miR-24 may modify AFB1-related HCC prognosis and tumorigenesis.

  11. Protein Kinase C alpha (PKCα) dependent signaling mediates endometrial cancer cell growth and tumorigenesis

    Science.gov (United States)

    Haughian, James M.; Reno, Elaine M.; Thorne, Alicia M.; Bradford, Andrew P.

    2009-01-01

    Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCα, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCα protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCα knockdown increased levels of the cyclin dependent kinase (CDK) inhibitors p21Cip1/WAF1 (p21) and p27Kip1 (p27). Despite the absence of functional phosphatase and tensin homologue (PTEN) protein in Ishikawa cells, PKCα knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3β (GSK-3β). PKCα knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting PKCα regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of grade 1 endometrioid adenocarcinoma revealed aberrant PKCα expression, with foci of elevated PKCα staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCα signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK dependent proliferative pathways. Thus, targeting PKCα may provide novel therapeutic options in endometrial tumors. PMID:19672862

  12. Dmp1α inhibits HER2/neu-induced mammary tumorigenesis.

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    Elizabeth A Fry

    Full Text Available Our recent study shows a pivotal role of Dmp1 in quenching hyperproliferative signals from HER2 to the Arf-p53 pathway as a safety mechanism to prevent breast carcinogenesis. To directly demonstrate the role of Dmp1 in preventing HER2/neu-driven oncogenic transformation, we established Flag-Dmp1α transgenic mice (MDTG under the control of the mouse mammary tumor virus (MMTV promoter. The mice were viable but exhibited poorly developed mammary glands with markedly reduced milk production; thus more than half of parous females were unable to support the lives of new born pups. The mammary glands of the MDTG mice had very low Ki-67 expression but high levels of Arf, Ink4a, p53, and p21(Cip1, markers of senescence and accelerated aging. In all strains of generated MDTG;neu mice, tumor development was significantly delayed with decreased tumor weight. Tumors from MDTG;neu mice expressed Flag-Dmp1α and Ki-67 in a mutually exclusive fashion indicating that transgenic Dmp1α prevented tumor growth in vivo. Genomic DNA analyses showed that the Dmp1α transgene was partially lost in half of the MDTG;neu tumors, and Western blot analyses showed Dmp1α protein downregulation in 80% of the cases. Our data demonstrate critical roles of Dmp1 in preventing mammary tumorigenesis and raise the possibility of treating breast cancer by restoring Dmp1α expression.

  13. Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis.

    Science.gov (United States)

    Chung, Chi-Yeh; Sun, Zhen; Mullokandov, Gavriel; Bosch, Almudena; Qadeer, Zulekha A; Cihan, Esma; Rapp, Zachary; Parsons, Ramon; Aguirre-Ghiso, Julio A; Farias, Eduardo F; Brown, Brian D; Gaspar-Maia, Alexandre; Bernstein, Emily

    2016-07-12

    Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.

  14. Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Chi-Yeh Chung

    2016-07-01

    Full Text Available Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.

  15. Diallyl sulfide protects against N-nitrosodiethylamine-induced liver tumorigenesis: Role of aldose reductase

    Institute of Scientific and Technical Information of China (English)

    Safinaz S Ibrahim; Noha N Nassar

    2008-01-01

    AIM: To evaluate the protective effect of diallyl sulfide (DAS) against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis. METHODS: Male Wistar rats received either NDEA or NDEA together with DAS as protection. Liver energy metabolism was assessed in terms of lactate, pyruvate, lactate/pyruvate, ATP levels, lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD) activities. In addition, membrane disintegration of the liver cells was evaluated by measuring lipid-peroxidation products, measured as malondialdehyde (MDA); nitric oxide (NO) levels; glucose-6-phosphatase (G6Pase), catalase (CAT) and superoxide dismutase (SOD) activities. Uver DNA level, glutathione-S-transferase (GST) and cytochrome c oxidase activities were used as DNA fragmentation indices. Aldose reductase (AR) activity was measured as an index for cancer cells resistant to chemotherapy and histopathological examination was performed on liver sections from different groups. RESULTS: NDEA significantly disturbed liver functions and most of the aforementioned indices. Treatment with DAS significantly restored liver functions and hepatocellular integrity; improved parameters of energy metabolism and suppressed free-radical generation. CONCLUSION: We provide evidence that DAS exerts a protective role on liver functions and tissue integrity in face of enhanced tumorigenesis caused by NDEA, as well as improving cancer-cell sensitivity to chemotherapy. This is mediated through combating oxidative stress of free radicals, improving the energy metabolic state of the cell, and enhancing the activity of G6Pase, GST and AR enzymes.

  16. The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis.

    Science.gov (United States)

    Gu, X; Xing, L; Shi, G; Liu, Z; Wang, X; Qu, Z; Wu, X; Dong, Z; Gao, X; Liu, G; Yang, L; Xu, Y

    2012-03-01

    Circadian oscillation and cell cycle progression are the two most essential rhythmic events present in almost all organisms. Circadian rhythms keep track of time and provide temporal regulation with a period of about 24 h. The cell cycle is optimized for growth and division, but not for time keeping. Circadian gated cell divisions are observed in nearly all organisms. However, the implications of this coupling to the physiology of mammals are unknown. A mutation (S662G) in the clock protein PERIOD2 (PER2) is responsible for familial advanced sleep phase syndrome in which sleep onset occurs in the early evening and wakefulness occurs in the early morning. Here, we provide evidence that the PER2(S662) mutation leads to enhanced resistance to X-ray-induced apoptosis and increased E1A- and RAS-mediated oncogenic transformation. Accordingly, the PER2(S662) mutation affects tumorigenesis in cancer-sensitized p53(R172H/+) mice. Finally, analyzing the clock-controlled cell cycle genes p21, c-Myc, Cyclin D1 and p27, we found that the relative phases between p21 and Cyclin D expression profiles have been changed significantly in these Per2 allele mutant mouse embryonic fibroblasts. This key role of the Per2-mediated phase alteration of p21 provides what we believe to be a novel mechanism in understanding cell cycle progression, its plasticity and its resistance to interference.

  17. T-cell activation promotes tumorigenesis in inflammation-associated cancer

    Directory of Open Access Journals (Sweden)

    Lairmore Michael

    2009-12-01

    Full Text Available Abstract Chronic inflammation has long been associated with a wide range of malignancies, is now widely accepted as a risk factor for development of cancer, and has been implicated as a promoter of a variety of cancers including hematopoietic malignancies. We have described a mouse model uniquely suited to examine the link between inflammation and lymphoma in which the Tax oncogene, expressed in activated T and NK cells, perpetuates chronic inflammation that begins as microscopic intraepithelial lesions and develops into inflammatory nodules, subcutaneous tumors, and large granular lymphocytic leukemia. The use of bioluminescent imaging in these mice has expanded our ability to interrogate aspects of inflammation and tumorigenesis non-invasively. Here we demonstrate that bioluminescence induction in these mice correlated with inflammation resulting from wounding, T cell activation, and exposure to chemical agents. In experiments in which long-term effects of inflammation on disease outcome were monitored, the development of lymphoma was promoted by an inflammatory stimulus. Finally we demonstrated that activation of T-cells in T-cell receptor (TCR transgenic TAX-LUC animals dramatically exacerbated the development of subcutaneous TCR- CD16+ LGL tumors. The role of activated T-cells and acquired immunity in inflammation-associated cancers is broadly applicable to hematopoietic malignancies, and we propose these mice will be of use in dissecting mechanisms by which activated T-cells promote lymphomagenesis in vivo.

  18. Telomere regulation during ageing and tumorigenesis of the grey mouse lemur.

    Science.gov (United States)

    Trochet, Delphine; Mergui, Xénia; Ivkovic, Ivana; Porreca, Rosa Maria; Gerbault-Seureau, Michèle; Sidibe, Assitan; Richard, Florence; Londono-Vallejo, Arturo; Perret, Martine; Aujard, Fabienne; Riou, Jean-François

    2015-06-01

    Telomere erosion leading to replicative senescence has been well documented in human and anthropoid primates, and provides a clue against tumorigenesis. In contrast, other mammals, such as laboratory mice, with short lifespan and low body weight mass have different telomere biology without replicative senescence. We analyzed telomere biology in the grey mouse lemur, a small prosimian model with a relative long lifespan currently used in ageing research. We report an average telomere length by telomere restriction fragment (TRF) among the longest reported so far for a primate species (25-30 kb), but without detectable overall telomere shortening with ageing on blood samples. However, we demonstrate using universal STELA (Single Telomere Length Amplification) the existence of short telomeres, the increase of which, while correlating with ageing might be related to another mechanism than replicative senescence. We also found a low stringency of telomerase restriction in tissues and an ease to immortalize fibroblasts in vitro upon spontaneous telomerase activation. Finally, we describe the first grey mouse lemur cancer cell line showing a dramatic telomere shortening and high telomerase activity associated with polyploidy. Our overall results suggest that telomere biology in grey mouse lemur is an exception among primates, with at best a physiologically limited replicative telomere ageing and closest to that observed in small rodents.

  19. Electroporation markedly improves Sleeping Beauty transposon-induced tumorigenesis in mice.

    Science.gov (United States)

    Jung, S; Choi, H-J; Park, H-K; Jo, W; Jang, S; Ryu, J-E; Kim, W-J; Yu, E-S; Son, W-C

    2014-08-01

    The Sleeping Beauty (SB) transposon system is an important tool for genetic studies. It is used to insert a gene of interest into the host chromosome, thus enabling permanent gene expression. However, this system is less useful in higher eukaryotes because the transposition frequency is low. Efforts to improve the efficacy of the SB transposon system have focused on the method of gene delivery, but although electroporation has recently attracted much attention as an in vivo gene delivery tool, the simultaneous use of electroporation and the SB transposon system has not been studied for gene transfer in mice. In this study, electroporation was used in a model of SB transposon-induced insertional tumorigenesis. Electroporation increased the rate of tumor development to three times that of the control group. There was no difference in phenotype between tumors induced with the SB transposon system alone and those induced by the SB transposon and electroporation. Electroporation therefore may be an efficient means of improving the efficacy of gene transfer via the SB transposon system.

  20. PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

    Energy Technology Data Exchange (ETDEWEB)

    Swindall, Amanda F.; Stanley, Jennifer A. [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Yang, Eddy S., E-mail: eyang@uab.edu [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States); Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States)

    2013-07-26

    Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

  1. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Qing; Yu, Tao; Ren, Yao-Yao; Gong, Ting; Zhong, Dian-Sheng, E-mail: zhongdsyx@126.com

    2014-11-07

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression.

  2. The role of microRNAs in the tumorigenesis of ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Gianpiero eDi Leva

    2013-06-01

    Full Text Available Epithelial ovarian cancer (EOC is a complex disease, with multiple histological subtypes recognized. There have been major advances in the understanding of the cellular and molecular biology of this human malignancy, however the survival rate of women with epithelial ovarian cancer has changed little since platinum based-treatment was introduced more than 30 years ago. Since 2006, an increasing number of studies have indicated an essential role for microRNAs in ovarian cancer tumorigenesis. Several microRNA profiling studies have shown that they associate with different aspects of ovarian cancer (tumor subtype, stage, histological grade, prognosis and therapy resistance and pointed to a critical role for microRNAs in the pathogenesis and progression of EOC. In this review, we discuss the current data concerning the accumulating evidence of the modulated expression of microRNAs in EOC, their role in diagnosis, prognosis and prediction of response to therapy. Given the heterogeneity of this disease, it is likely that increases in long-term survival might be also achieved by translating the recent insights of miRNAs involvement in EOC into novel targeted therapies that will have a major impact on the management of ovarian cancer.

  3. Characterization of a dominant-active STAT that promotes tumorigenesis in Drosophila

    Science.gov (United States)

    Ekas, Laura A.; Cardozo, Timothy J.; Flaherty, Maria Sol; McMillan, Elizabeth A.; Gonsalves, Foster C.; Bach, Erika A.

    2010-01-01

    Little is known about the molecular mechanisms by which STAT proteins promote tumorigenesis. Drosophila is an ideal system for investigating this issue, as there is a single STAT (Stat92E), and its hyperactivation causes overgrowths resembling human tumors. Here we report the first identification of a dominant-active Stat92E protein, Stat92EΔNΔC, which lacks both N- and C-termini. Mis-expression of Stat92EΔNΔC in vivo causes melanotic tumors, while in vitro it transactivates a Stat92E-luciferase reporter in the absence of stimulation. These gain-of-function phenotypes require phosphorylation of Y711 and dimer formation with full-length Stat92E. Furthermore, a single point mutation, an R442P substitution in the DNA-binding domain, abolishes Stat92E function. Recombinant Stat92ER442P translocates to the nucleus following activation but fails to function in all assays tested. Interestingly, R442 is conserved in most STATs in higher organisms, suggesting conservation of function. Modeling of Stat92E indicates that R442 may contact the minor groove of DNA via invariant TC bases in the consensus binding element bound by all STAT proteins. We conclude that the N- and C- termini function unexpectedly in negatively regulating Stat92E activity, possibly by decreasing dimer dephosphorylation or increasing stability of DNA interaction, and that Stat92ER442 has a nuclear function by altering dimer:DNA binding. PMID:20501334

  4. The Role of c-KIT in Tumorigenesis: Evaluation in Canine Cutaneous Mast Cell Tumors

    Directory of Open Access Journals (Sweden)

    Joshua D. Webster

    2006-02-01

    Full Text Available The c-KIT proto-oncogene has been implicated in the pathogenesis of several neoplastic diseases, including gastrointestinal stromal tumors and mastocytosis in humans, and mast cell tumors (MCTs in canines. Cutaneous MCTs are common neoplasms in dogs and have a variable biologic behavior. The goal of this study was to define the prognostic significance of c-KIT mutations identified in canine MCTs and the associations between c-KIT mutations, KIT localization, and KIT expression levels. Microdissection and polymerase chain reaction were performed on 60 MCTs to identify c-KIT mutations. Anti-KIT antibodies were used for immunohistochemical evaluation of KIT localization. Forty-two MCTs were included in a tissue microarray, and KIT expression was quantified using immunofluorescence. Canine MCTs with c-KIT mutations were significantly associated with an increased incidence of recurrent disease and death. c-KIT mutations were also significantly associated with aberrant protein localization; however, the level of KIT expression did not correlate with either c-KIT mutations or changes in protein localization. Considering the high prevalence of canine MCTs and the central role of c-KIT in the tumorigenesis of certain tumors, canine MCTs are an excellent model for characterizing the role of c-KIT in neoplastic diseases and is a potential target for novel therapeutic agents in clinical trials.

  5. EXPRESSION OF ANNEXIN I IN TUMORIGENESIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    吕宁; 薛丽燕; 林冬梅; 谢永强; 温芃; 何祖根

    2004-01-01

    Objective: To detect the expression of annexin I in esophageal squamous cell carcinoma and precursor lesions,and evaluate its effect on the tumorigenesis. Methods: The immunohistochemistry S-P method was used to determine the expression of annexin I in 135 cases of esophageal squamous cell carcinoma, in which precursor lesions were found in some cases, and in the corresponding normal controls. Results: Of 135 cases, 35 (25.9%) were strongly positive, 60 (44.4%) were weakly positive and 40 (29.6%)negative, while in the corresponding normal controls, 129(95.6%) were strongly positive, 6 (6.4%) weakly positive.The expression of annexin I was decreased in esophageal squamous cell carcinoma (P<0.0001), and the degree and rate of the decrease did not show correlation with age,gender, differentiation, and lymph node metastasis (P>0.05).The expression of annexin I was also decreased in the lesions of dysplasia and carcinoma in situ, with 2 (4.3%) strongly positive, 17 (37.0%) weakly positive and 27(58.7%) negative (P<0.0001). Conclusion: Annexin I may be useful in early detection of esophageal squamous cell carcinoma and in evaluation of predisposition for the risk of cancerization of precursor lesions.

  6. Unique haploinsufficient role of the microRNA-processing molecule Dicer1 in a murine colitis-associated tumorigenesis model.

    Directory of Open Access Journals (Sweden)

    Takeshi Yoshikawa

    Full Text Available A widespread downregulated expression of microRNAs (miRNAs is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

  7. Distinct functions of epidermal and myeloid-derived VEGF-A in skin tumorigenesis mediated by HPV8.

    Science.gov (United States)

    Ding, Xiaolei; Lucas, Tina; Marcuzzi, Gian P; Pfister, Herbert; Eming, Sabine A

    2015-01-15

    Beta human papillomaviruses (HPV) have been suspected to be carcinogenic in nonmelanoma skin cancers (NMSC), but the basis for potential viral contributions to these cancers is poorly understood. In particular, it is unresolved how HPV-infected keratinocytes escape cell-cycle control and whether their cross-talk with immune cells is critical for tumorigenesis. In nonviral preclinical models, the angiogenic cytokine VEGF-A has been identified as a critical regulator of NMSC. In this study, we dissected the contribution of epidermal versus myeloid cell-derived VEGF-A in HPV-mediated skin cancer by interbreeding an HPV8 transgenic mouse model with a conditional disruption of VEGF-A restricted to either epidermal or myeloid cells. Although only epidermal-derived VEGF-A was essential for initiation of skin tumor development, both spontaneously and UV-light triggered, both epidermal and myeloid cell-derived VEGF-A contributed to regeneration-induced tumorigenesis upon HPV8 overexpression, partly not only through a paracrine effect on endothelial cells, but also most probably through an additional autocrine effect on epidermal cells. Our findings offer new mechanistic insights into distinct functions of epidermal versus myeloid cell-derived VEGF-A during HPV-mediated tumorigenesis, with possible implications for preventing this disease.

  8. O-linked N-acetylglucosamine transferase promotes cervical cancer tumorigenesis through human papillomaviruses E6 and E7 oncogenes.

    Science.gov (United States)

    Kim, Minjun; Kim, Yoon Sook; Kim, Hwajin; Kang, Min Young; Park, Jeongsook; Lee, Dong Hoon; Roh, Gu Seob; Kim, Hyun Joon; Kang, Sang Soo; Cho, Gyeong Jae; Park, Ji Kwon; Cho, Jin Won; Shin, Jeong Kyu; Choi, Wan Sung

    2016-07-12

    O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) increases O-GlcNAc modification (O-GlcNAcylation), and transcriptional co-regulator host cell factor 1 (HCF-1) is one of OGT targets. High-risk Human Papillomaviruses (HPVs) encode E6 and E7 oncoproteins, which promote cervical cancer. Here, we tested whether O-GlcNAc modification of HCF-1 affects HPV E6 and E7 expressions and tumorigenesis of cervical cancer. We found that depleting OGT with OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins, and cervical cancer tumorigenesis, while OGT overexpression greatly increased levels of E6 and E7 oncoproteins. Notably, OGT overexpression caused dose-dependent increases in the transcriptional activity of E6 and E7, and this activity was decreased when HCF-1 was depleted with HCF-1-specific siRNA. Moreover, OGT depletion reduced proliferation, invasion, and metastasis in cervical cancer cells. Further, high glucose enhanced the interaction between OGT and HCF-1, paralleling increased levels of E6 and E7 in cervical cancer cells. Most importantly, we found that reducing OGT in HeLa cells caused decreased tumor growth in vivo. These findings identify OGT as a novel cellular factor involved in E6 and E7 expressions and cervical cancer tumorigenesis, suggesting that targeting OGT in cervical cancer may have potential therapeutic benefit.

  9. Racing to block tumorigenesis after pRb loss: an innocuous point mutation wins with synthetic lethality.

    Science.gov (United States)

    Bauzon, Frederick; Zhu, Liang

    2010-06-01

    A major goal of tumor suppressor research is to neutralize the tumorigenic effects of their loss. Since loss of pRb does not induce tumorigenesis in many types of cells, natural mechanisms may neutralize the tumorigenic effects of pRb loss in these cells. For susceptible cells, neutralizing the tumorigenic effects of pRb loss could logically be achieved by correcting the deregulated activities of pRb targets to render pRb-deficient cells less abnormal. This line of research has unexpectedly revealed that knocking out the pRb target Skp2 did not render Rb1 deficient cells less abnormal but, rather, induced apoptosis in them, thereby completely blocking tumorigenesis in Rb1+/- mice and after targeted deletion of Rb1 in pituitary intermediate lobe (IL). Skp2 is a substrate-recruiting component of the SCFSkp2 E3 biquitin ligase; one of its substrates is Thr187-phosphorylated p27Kip1. A p27T187A knockin (KI) mutation phenocopied Skp2 knockout (KO) in inducing apoptosis following Rb1 loss. Thus, Skp2 KO or p27T187A KI are synthetic lethal with pRb inactivation. Since homozygous p27T187A KI mutations show no adverse effects in mice, inhibiting p27T187 phosphorylation or p27T187p ubiquitination could be a highly therapeutic and minimally toxic intervention strategy for pRb deficiency-induced tumorigenesis.

  10. Pregnancy-dependent initiation in tumorigenesis of Wistar rat mammary glands by sup 60 Co-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Inano, Hiroshi; Suzuki, Keiko; Ishii-Ohba, Hiroko; Ikeda, Kiyomi (National Inst. of Radiological Sciences, Chiba (Japan)); Wakabayashi, Katsumi (Gunma Univ., Maebashi (Japan). Hormone Assay Center)

    1991-06-01

    Pregnant Wistar rats received whole body irradiation with 260 cGy {gamma}-rays at days 7, 14 and 20 of pregnancy and then were treated with diethylstilbestrol (DES) for 1 year. The highest incidence (92.9%) for tumorigenesis of mammary glands was observed in the rats irradiated in late pregnancy. Histological examination showed that tumors were classified as fibroadenoma and adenocarcinoma. To determine the reasons for specific induction of mammary tumors by irradiation in late pregnancy, hormone concentrations in serum and estrogen receptors in mammary glands during pregnancy were measured. Concentrations of estradiol, progesterone, 11-deoxycorticosterone and placental lactogen at day 20 were higher than at days 7 and/or 14, but no difference was observed in the concentrations of prolactin and thyroid-stimulating hormone during pregnancy. The estrogen receptor in mammary glands at day 20 was indicated to have the highest affinity and the highest binding capacity during pregnancy. Normal mammary glands at day 20 were suggested to have more abundant epithelial cells in the mammary lobes than those at days 7 and 14. The data suggest that the critical requirements for the initiation of tumorigenesis by {gamma}-rays are dependent upon the differentiated state of mammary glands exposed to various hormones, and that the concentration and persistence of the synthetic estrogen (DES) are necessary for the promotion of tumorigenesis of the irradiated mammary glands. (Author).

  11. Mammary tumorigenesis in APC{sup min/+} mice is enhanced by X-irradiation with a characteristic age dependence

    Energy Technology Data Exchange (ETDEWEB)

    Tatsuhiko, Imaoka; Mayumi, Nishimura; Shizuko, Kakinuma; Yoshiya, Shimada [National Institute of Radiological Sciences, Experimental Radiobiology for Children' s Health Research Group, Research, Center for Radiation Protection (Japan); Mieko, Okamoto [Tokyo Metropolitan Institute of Medical Science (Japan)

    2006-07-01

    The ApcM{sup min/+} (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7 to 10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type litter-mates did not. Interestingly, irradiation of Min mice at 2 to 5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling. (author)

  12. Pubertal and adult windows of susceptibility to a high animal fat diet in Trp53-null mammary tumorigenesis.

    Science.gov (United States)

    Zhu, Yirong; Aupperlee, Mark D; Zhao, Yong; Tan, Ying Siow; Kirk, Erin L; Sun, Xuezheng; Troester, Melissa A; Schwartz, Richard C; Haslam, Sandra Z

    2016-12-13

    Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.

  13. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yan; Choksi, Swati; Liu, Zheng-Gang, E-mail: zgliu@helix.nih.gov [Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-12-04

    Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80{sup +} macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206{sup +} TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer.

  14. Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.

    Directory of Open Access Journals (Sweden)

    Tomohiko Ohno

    Full Text Available Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR, and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.

  15. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in young but not in old rats

    Science.gov (United States)

    Vinogradova, Irina A.; Anisimov, Vladimir N.; Bukalev, Andrey V.; Ilyukha, Viktor A.; Khizhkin, Evgeniy A.; Lotosh, Tatiana A.; Semenchenko, Anna V.; Zabezhinski, Mark A.

    2010-01-01

    We evaluated the effect of exposure to constant light started at the age of 1 month and at the age of 14 months on the survival, life span, tumorigenesis and age-related dynamics of antioxidant enzymes activity in various organs in comparison to the rats maintained at the standard (12:12 light/dark) light/dark regimen. We found that exposure to constant light started at the age of 1 month accelerated spontaneous tumorigenesis and shortened life span both in male and female rats as compared to the standard regimen. At the same time, the exposure to constant light started at the age of 14 months failed to influence survival of male and female rats. While delaying tumors in males, constant light accelerated tumors in females. We conclude that circadian disruption induced by light-at-night started at the age of 1 month accelerates aging and promotes tumorigenesis in rats, however failed affect survival when started at the age of 14 months. PMID:20354269

  16. Type I Insulin-like Growth Factor Receptor Induces Pulmonary Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Nicolle M. Linnerth

    2009-07-01

    Full Text Available Despite the type I insulin-like growth factor receptor (IGF-IR being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR or Clara cells (CCSP-IGFIR in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGF-IR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.

  17. Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice.

    Science.gov (United States)

    Li, Weidong; Hua, Baojin; Saud, Shakir M; Lin, Hongsheng; Hou, Wei; Matter, Matthias S; Jia, Libin; Colburn, Nancy H; Young, Matthew R

    2015-10-01

    Colorectal cancer, a leading cause of cancer death, has been linked to inflammation and obesity. Berberine, an isoquinoline alkaloid, possesses anti-inflammatory, anti-diabetes and anti-tumor properties. In the azoxymethane initiated and dextran sulfate sodium (AOM/DSS) promoted colorectal carcinogenesis mouse model, berberine treated mice showed a 60% reduction in tumor number (P = 0.009), a 48% reduction in tumors 4 mm (P = 0.02) compared to vehicle treated mice. Berberine also decreased AOM/DSS induced Ki-67 and COX-2 expression. In vitro analysis showed that in addition to its anti-proliferation activity, berberine also induced apoptosis in colorectal cancer cell lines. Berberine activated AMP-activated protein kinase (AMPK), a major regulator of metabolic pathways, and inhibited mammalian target of rapamycin (mTOR), a downstream target of AMPK. Furthermore, 4E-binding protein-1 and p70 ribosomal S6 kinases, downstream targets of mTOR, were down regulated by berberine treatment. Berberine did not affect Liver kinase B1 (LKB1) activity or the mitogen-activated protein kinase pathway. Berberine inhibited Nuclear Factor kappa-B (NF-κB) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro. Berberine inhibition of mTOR activity and p53 phosphorylation was found to be AMPK dependent, while inhibition NF-κB was AMPK independent. In vivo, berberine also activated AMPK, inhibited mTOR and p65 phosphorylation and activated caspase-3 cleavage. Our data suggests that berberine suppresses colon epithelial proliferation and tumorigenesis via AMPK dependent inhibition of mTOR activity and AMPK independent inhibition of NF-κB.

  18. PTEN coding product:a new marker for tumorigenesis and progession of endometrial carcinoma

    Institute of Scientific and Technical Information of China (English)

    Gao Qinglei; Li Jing; Xing Hui; Lu Yunping; Zhou Jianfeng; Ma Ding

    2008-01-01

    Objective :To investigate the expression of PTEN in carcinogenesis and development of endometrial carcinoma.Methods: The expression of PTEN was detected by reverse transcription-polymerase chain reaction(RT-PCR) methods from 24 cases with endometrial carcinoma,10 cases with endometrial atypical hyperplasia,I0 eases with endometrial hyperplasia and I0 cases with normal endometrium and by SP immunohistochemical methods from 73 cases with endometrial carcinoma,25 cases with endometrial atypical hyperplasia,71 cases with endometrial hyperplasia and 31 cases with normal endometrium.Results:PTEN expression of both RNA and protein in patients with endometrial carcinoma and endometrial atypical hyperplasia was significantly lower than that of patients with endometrial hyperplasia and normal endometriurn.mRNA relative value was 0.35±0.13,0.46±0.11,2.32±0.32,2.45±0.51,respectively.Loss of PTEN expression rates were 66.67% (38/57) ,76.00% ( 19/25 ) ,5.63% (4/71 ) ,0 (0/31 ),repeetively.The results were also compared with clinical parameters.Loss of PTEN expression in patients with endometrial carcinoma was significantly related to histological classification ( P < 0.0001 ) and differentiation ( P < 0.05 ).It was not related to depth of myometrium invasion and clinical stage( P >0.05 ).Conclusion:Loss of PTEN expression is an early event in endometrial tumorigenesis.Detection of PTEN protein may be a diagnostic biomarker for endometrial precancers and adenocareinoma.

  19. Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms

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    Lia E. De Faveri

    2015-10-01

    Full Text Available Urothelial carcinoma (UC causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non–muscle-invasive bladder cancer (NMIBC. Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1 in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription.

  20. Expression profiling of CEACAM6 associated with the tumorigenesis and progression in gastric adenocarcinoma.

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    Deng, X; Liu, P; Zhao, Y; Wang, Q

    2014-09-26

    Carcinoembryonic antigen-related cellular adhesion molecule 6 (CEACAM6) is a member of the immunoglobulin superfamily and has been recently reported to affect the neoplastic, metastatic, and invasive ability of malignant cells by regulating intracellular signaling pathways during tumorigenesis and progression. We investigated the expression and amplification of CEACAM6 in relation to the clinicopathological and biological significance of gastric adenocarcinoma. Expression of CEACAM6 mRNA in 75 primary gastric adenocarcinom and 20 adjacent tissues compared to normal gastric mucosas were explored using real-time quantitative-polymerase chain reaction. Immunohistochemical assays were conducted to evaluate the expression and tissue distribution of CEACAM6 protein. Overexpression of CEACAM6 mRNA in both gastric adenocarcinoma (2.513 ± 0.869) and adjacent tissues (1.171 ± 0.428) was significantly higher than the relative expressions in non-neoplastic specimens (0.594 ± 0.513) (P < 0.01). CEACAM6 protein was present in 52 (69.33%) gastric adenocarcinomas, but not in normal gastric tissues. Adenocarcinomas with elevated CEACAM6 expression were significantly associated with lymph node metastases and advanced stages. There were no relationships between CEACAM6 expression and tumor size, histological differentiation, or different subtypes, respectively. Moreover, higher expression of CEACAM6 was found to be correlated with short postoperative survival time of patients with gastric cancer. Amplification and upregulation of CEACAM6 expression was observed in human gastric adenocarcinomas, which may be correlated with the generation or transformation of malignant cells, tumor aggressive progression, and clinical outcome. CEACAM6 may be a valuable biomarker screening for gastric tumor and novel predictor for patients in advanced stages of gastric cancer.

  1. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.

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    Claudia Gaspar

    2009-07-01

    Full Text Available Germline mutations in the adenomatous polyposis coli (APC gene are responsible for familial adenomatous polyposis (FAP, an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/beta-catenin signaling. Notably, genotype-phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/beta-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/beta-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc(+/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc(+/1572T mice suggests that specific dosages of Wnt/beta-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion.

  2. Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.

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    Ip, Blanche C; Liu, Chun; Ausman, Lynne M; von Lintig, Johannes; Wang, Xiang-Dong

    2014-12-01

    Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. ©2014 American Association for Cancer Research.

  3. miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression

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    Yan, Chao [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Yu, Jianchun, E-mail: yu_jchpumch@163.com [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Kang, Weiming [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Liu, Yuqin [Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005 (China); Ma, Zhiqiang; Zhou, Li [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China)

    2016-01-29

    Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma. - Highlights: • The expression of miR-935 is lower in GC tissue than in paired normal tissue. • The expression of miR-935 is lower in GSRCC tissue than in non-GSRCC. • Enhanced expression of miR-935 suppresses tumorigenesis of GSRCC. • Notch1 is a direct target of miR-935.

  4. Loss of p53 Induces Tumorigenesis in p21-Deficient Mesenchymal Stem Cells

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    Rene Rodriguez

    2009-04-01

    Full Text Available There is growing evidence about the role of mesenchymal stem cells (MSCs as cancer stem cells in many sarcomas. Nevertheless, little is still known about the cellular and molecular mechanisms underlying MSCs transformation. We aimed at investigating the role of p53 and p21, two important regulators of the cell cycle progression and apoptosis normally involved in protection against tumorigenesis. Mesenchymal stem cells from wild-type, p21-/-p53+/+, and p21-/-p53+/- mice were cultured in vitro and analyzed for the appearance of tumoral transformation properties after low, medium, and high number of passages both in vitro and in vivo. Wild-type or p21-/-p53+/+ MSCs did not show any sign of tumoral transformation. Indeed, after short-term in vitro culture, wild-type MSCs became senescent, and p21-/-p53+/+ MSCs showed an elevated spontaneous apoptosis rate. Conversely, MSCs carrying a mutation in one allele of the p53 gene (p21-/-p53+/- MSCs completely lost p53 expression after in vitro long-term culture. Loss of p53 was accompanied by a significant increase in the growth rate, gain of karyotypic instability, loss of p16 expression, and lack of senescence response. Finally, these cells were able to form fibrosarcomas partially differentiated into different mesenchymal lineages when injected in immunodeficient mice both after subcutaneous and intrafemoral injection. These findings show that MSCs are very sensitive to mutations in genes involved in cell cycle control and that these deficiencies can be at the origin of some mesodermic tumors.

  5. A protein knockdown strategy to study the function of β-catenin in tumorigenesis

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    Zhou Pengbo

    2003-09-01

    Full Text Available Abstract Background The Wnt signaling pathway plays critical roles in cell proliferation and cell fate determination at many stages of development. A critical downstream target of Wnt signaling is the cytosolic β-catenin, which is stabilized upon Wnt activation and promotes transcription of a variety of target genes including c-myc and cyclin D. Aberrant Wnt signaling, which results from mutations of either β-catenin or adenomatous polyposis coli (APC, renders β-catenin resistant to degradation, and has been associated with multiple types of human cancers. Results A protein knockdown strategy was designed to reduce the cytosolic β-catenin levels through accelerating its turnover rate. By engineering a chimeric protein with the β-catenin binding domain of E-cadherin fused to βTrCP ubiquitin-protein ligase, the stable β-catenin mutant was recruited to the cellular SCF (Skp1, Cullin 1, and F-box-containing substrate receptor ubiquitination machinery for ubiquitination and degradation. The DLD1 colon cancer cells express wild type β-catenin at abnormally high levels due to loss of APC. Remarkably, conditional expression of βTrCP-E-cadherin under the control of a tetracycline-repressive promoter in DLD1 cells selectively knocked down the cytosolic, but not membrane-associated subpopulation of β-catenin. As a result, DLD1 cells were impaired in their growth and clonogenic ability in vitro, and lost their tumorigenic potential in nude mice. Conclusion We have designed a novel approach to induce degradation of stabilized/mutated β-catenin. Our results suggest that a high concentration of cytoplasmic β-catenin is critical for the growth of colorectal tumor cells. The protein knockdown strategy can be utilized not only as a novel method to dissect the role of oncoproteins in tumorigenesis, but also as a unique tool to delineate the function of a subpopulation of proteins localized to a specific subcellular compartment.

  6. In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells.

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    Chien-Chih Ke

    Full Text Available Mesenchymal stromal cells (MSCs are multipotent adult stem cells which are recruited to the tumor microenvironment (TME and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs.

  7. Hypermethylated MAL gene – a silent marker of early colon tumorigenesis

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    Kallioniemi Anne

    2008-03-01

    Full Text Available Abstract Background Tumor-derived aberrantly methylated DNA might serve as diagnostic biomarkers for cancer, but so far, few such markers have been identified. The aim of the present study was to investigate the potential of the MAL (T-cell differentiation protein gene as an early epigenetic diagnostic marker for colorectal tumors. Methods Using methylation-specific polymerase chain reaction (MSP the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44, colorectal adenomas (n = 63, carcinomas (n = 65, and various cancer cell lines (n = 46. Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5 and a tissue microarray with 292 colorectal tumors. Results Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80% as well as in adenomas (45/63, 71%. In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%. The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type. Conclusion Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.

  8. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development

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    Jimann Shin

    2012-11-01

    Neurofibromatosis type 1 (NF1 is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1 gene. Affected individuals demonstrate abnormalities in neural-crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML, optic glioma, glioblastoma, schwannoma and malignant peripheral nerve sheath tumors (MPNSTs. In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs, dysmorphic myelin sheaths and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/−; nf1b−/−; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish.

  9. Over-expression of ST3Gal-I promotes mammary tumorigenesis.

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    Picco, Gianfranco; Julien, Sylvain; Brockhausen, Inka; Beatson, Richard; Antonopoulos, Aristotelis; Haslam, Stuart; Mandel, Ulla; Dell, Anne; Pinder, Sarah; Taylor-Papadimitriou, Joyce; Burchell, Joy

    2010-10-01

    Changes in glycosylation are common in malignancy, and as almost all surface proteins are glycosylated, this can dramatically affect the behavior of tumor cells. In breast carcinomas, the O-linked glycans are frequently truncated, often as a result of premature sialylation. The sialyltransferase ST3Gal-I adds sialic acid to the galactose residue of core 1 (Galbeta1,3GalNAc) O-glycans and this enzyme is over-expressed in breast cancer resulting in the expression of sialylated core 1 glycans. In order to study the role of ST3Gal-I in mammary tumor development, we developed transgenic mice that over-express the sialyltransferase under the control of the human membrane-bound mucin 1 promoter. These mice were then crossed with PyMT mice that spontaneously develop mammary tumors. As expected, ST3Gal-I transgenic mice showed increased activity and expression of the enzyme in the pregnant and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background. These results indicate that ST3Gal-I is acting as a tumor promoter in this model of breast cancer. This, we believe, is the first demonstration that over-expression of a glycosyltransferase involved in mucin-type O-linked glycosylation can promote tumorigenesis.

  10. Nisin ZP, a Bacteriocin and Food Preservative, Inhibits Head and Neck Cancer Tumorigenesis and Prolongs Survival.

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    Pachiyappan Kamarajan

    Full Text Available The use of small antimicrobial peptides or bacteriocins, like nisin, to treat cancer is a new approach that holds great promise. Nisin exemplifies this new approach because it has been used safely in humans for many years as a food preservative, and recent laboratory studies support its anti-tumor potential in head and neck cancer. Previously, we showed that nisin (2.5%, low content has antitumor potential in head and neck squamous cell carcinoma (HNSCC in vitro and in vivo. The current studies explored a naturally occurring variant of nisin (nisin ZP; 95%, high content for its antitumor effects in vitro and in vivo. Nisin ZP induced the greatest level of apoptosis in HNSCC cells compared to low content nisin. HNSCC cells treated with increasing concentrations of nisin ZP exhibited increasing levels of apoptosis and decreasing levels of cell proliferation, clonogenic capacity, and sphere formation. Nisin ZP induced apoptosis through a calpain-dependent pathway in HNSCC cells but not in human oral keratinocytes. Nisin ZP also induced apoptosis dose-dependently in human umbilical vein endothelial cells (HUVEC with concomitant decreases in vascular sprout formation in vitro and reduced intratumoral microvessel density in vivo. Nisin ZP reduced tumorigenesis in vivo and long-term treatment with nisin ZP extended survival. In addition, nisin treated mice exhibited normal organ histology with no evidence of inflammation, fibrosis or necrosis. In summary, nisin ZP exhibits greater antitumor effects than low content nisin, and thus has the potential to serve as a novel therapeutic for HNSCC.

  11. PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis.

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    Claire B Pollock

    Full Text Available Peroxisome proliferator-activated receptorδ (PPARδ is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide-dependent kinase-1 (PDK1. PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPARδ, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα. The transgenic mammary gland also expressed higher levels of PPARδ and a gene expression profile resembling wild-type mice maintained on a diet containing the PPARδ agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPARδ-driven energy metabolism. These results reveal that PPARδ activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling.

  12. The ING gene family in the regulation of cell growth and tumorigenesis.

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    Coles, Andrew H; Jones, Stephen N

    2009-01-01

    The five members of the inhibitor of growth (ING) gene family have garnered significant interest due to their putative roles as tumor suppressors. However, the precise role(s) of these ING proteins in regulating cell growth and tumorigenesis remains uncertain. Biochemical and molecular biological analysis has revealed that all ING members encode a PHD finger motif proposed to bind methylated histones and phosphoinosital, and all ING proteins have been found as components of large chromatin remodeling complexes that also include histone acetyl transferase (HAT) and histone deacetylase (HDAC) enzymes, suggesting a role for ING proteins in regulating gene transcription. Additionally, the results of forced overexpression studies performed in tissue culture have indicated that several of the ING proteins can interact with the p53 tumor suppressor protein and/or the nuclear factor-kappa B (NF-kappaB) protein complex. As these ING-associated proteins play well-established roles in numerous cell processes, including DNA repair, cell growth and survival, inflammation, and tumor suppression, several models have been proposed that ING proteins act as key regulators of cell growth not only through their ability to modify gene transcription but also through their ability to alter p53 and NF-kappaB activity. However, these models have yet to be substantiated by in vivo experimentation. This review summarizes what is currently known about the biological functions of the five ING genes based upon in vitro experiments and recent mouse modeling efforts, and will highlight the potential impact of INGs on the development of cancer.

  13. Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer

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    Meng-Chun Wang; Yan-Min Yang; Xiao-Han Li; Fang Dong; Yan Li

    2004-01-01

    AIM: To investigate maspin expression in tumorigenesis and progression of gastric cancer and to explore its relevant molecular mechanisms.METHODS: Formalin-fixed and paraffin-embedded tissues from normal mucosa (n=182), dysplasia (n=69), cancer (n=113) of the stomach were studied for maspin expression by immunohistochemistry. Microvessel density (MVD) in gastric cancer was labeled using anti-CD34 antibody. Maspin expression was compared with clinical parameters and MVD of tumors. Caspase-3 expression was also detected in gastric carcinoma by immunohistochemistry. The relationship between Caspase-3 and maspin expression was concerned as well.RESULTS: The positive rates of maspin expression were 79.8%(145/182), 75.4%(52/69) and 50.4%(57/113) in normal mucosa, dysplasia and cancer of the stomach,respectively. Cancer less frequently expressed maspin than normal mucosa and dysplasia (P<0.05). Maspin expression showed a significantly negative association with invasive depth, metastasis, Lauren's and Nakamura's classification (P<0.05), but not with tumor size, Borrmann's classification,growth pattern or TNM staging (P>0.05). The positive rate of Caspase-3 was significantly lower in gastric cancer than in normal gastric mucosa (P<0.05,32.7% vs 50.4%). It was noteworthy that maspin expression was negatively correlated with MVD, but positively correlated with expression of Caspase-3 in gastric cancer (P<0.05).CONCLUSION: Down-regulated maspin expression is a late molecular event in gastric carcinogenesis. Reduced expression of maspin contributes to progression of gastric cancer probably by inhibiting cell adhesion, enhancing cell mobility,decreasing cell apoptosis and facilitating angiogenesis.Additionally altered expression of maspin underlies the molecular mechanism of differentiation of gastric cancer and supports the different histogenetic pathways of intestinal and diffuse gastric cancers. Maspin expression can be considered as an effective and objective

  14. Loss of disabled-2 expression is an early event in esophageal squamous tumorigenesis

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    Kumar Anupam; Chatopadhyay Tusharkant; Siddhartha Datta Gupta; Ralhan Ranju

    2006-01-01

    AIM: Disabled-2 (D4B2) is a candidate tumor-suppressor gene identified in ovarian cancer that negatively influences mitogenic signal transduction of growth factors and blocks ras activity. In a recent study, we observed down-regulation of DAB2 transcripts in ESCCs using cDNA microarrays. In the present study, we aimed to determine the clinical significance of loss of DAB2protein in esophageal tumorigenesis, hypothesizing that DAB2 promoter hypermethylation-mediated gene silencing may account for loss of the protein.METHODS: DAB2 expression was analyzed by immunohistochemistry in 50 primary esophageal squamous cell carcinomas (ESCCs), 30 distinct hyperplasia, 15 dysplasia and 10 non-malignant esophageal tissues. To determine whether promoter hypermethylation contributes to loss of DAB2 expression in ESCCs, methylation status of DAB2 promoter was analyzed in DAB2 immuno-negative tumors using methylation-specific PCR.RESULTS: Loss of DAB2 protein was observed in 5/30 (17%) hyperplasia, 10/15 (67%) dysplasia and 34/50 (68%) ESCCs. Significant loss of DAB2 protein was observed from esophageal normal mucosa to hyperplasia, dysplasia and invasive cancer (Ptrend < 0.001).Promoter hypermethylation of DAB2 was observed in 2of 10 (20%) DAB2 immuno-negative ESCCs.CONCLUSION: Loss of DAB2 protein expression occurs in early pre-neoplastic stages of development of esophageal cancer and is sustained down the tumorigenic pathway. Infrequent DAB2 promoter methylation in ESCCs suggests that epigenetic gene silencing is only one of the mechanisms causing loss of DAB2 expression in ESCCs.

  15. Cooperation of the BTB-Zinc finger protein, Abrupt, with cytoskeletal regulators in Drosophila epithelial tumorigenesis

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    Nezaket Turkel

    2015-08-01

    Full Text Available The deregulation of cell polarity or cytoskeletal regulators is a common occurrence in human epithelial cancers. Moreover, there is accumulating evidence in human epithelial cancer that BTB-ZF genes, such as Bcl6 and ZBTB7A, are oncogenic. From our previous studies in the vinegar fly, Drosophila melanogaster, we have identified a cooperative interaction between a mutation in the apico-basal cell polarity regulator Scribble (Scrib and overexpression of the BTB-ZF protein Abrupt (Ab. Herein, we show that co-expression of ab with actin cytoskeletal regulators, RhoGEF2 or Src64B, in the developing eye-antennal epithelial tissue results in the formation of overgrown amorphous tumours, whereas ab and DRac1 co-expression leads to non-cell autonomous overgrowth. Together with ab, these genes affect the expression of differentiation genes, resulting in tumours locked in a progenitor cell fate. Finally, we show that the expression of two mammalian genes related to ab, Bcl6 and ZBTB7A, which are oncogenes in mammalian epithelial cancers, significantly correlate with the upregulation of cytoskeletal genes or downregulation of apico-basal cell polarity neoplastic tumour suppressor genes in colorectal, lung and other human epithelial cancers. Altogether, this analysis has revealed that upregulation of cytoskeletal regulators cooperate with Abrupt in Drosophila epithelial tumorigenesis, and that high expression of human BTB-ZF genes, Bcl6 and ZBTB7A, shows significant correlations with cytoskeletal and cell polarity gene expression in specific epithelial tumour types. This highlights the need for further investigation of the cooperation between these genes in mammalian systems.

  16. Role of PINCH and its partner tumor suppressor Rsu-1 in regulating liver size and tumorigenesis.

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    Shashikiran Donthamsetty

    Full Text Available Particularly interesting new cysteine-histidine-rich protein (PINCH protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK-PINCH-Parvin-α complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1. We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice. PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1 protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype.

  17. Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression.

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    Rudra-Ganguly, Nandini; Lowe, Christine; Mattie, Michael; Chang, Mi Sook; Satpayev, Daulet; Verlinsky, Alla; An, Zili; Hu, Liping; Yang, Peng; Challita-Eid, Pia; Stover, David R; Pereira, Daniel S

    2014-01-01

    Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. The receptor is activated upon binding to its ligand, collagen, and plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Although DDR1 is expressed in many normal tissues, upregulated expression of DDR1 in a variety of human cancers such as lung, colon and brain cancers is known to be associated with poor prognosis. Using shRNA silencing, we assessed the oncogenic potential of DDR1. DDR1 knockdown impaired tumor cell proliferation and migration in vitro and tumor growth in vivo. Microarray analysis of tumor cells demonstrated upregulation of TGFBI expression upon DDR1 knockdown, which was subsequently confirmed at the protein level. TGFBI is a TGFβ-induced extracellular matrix protein secreted by the tumor cells and is known to act either as a tumor promoter or tumor suppressor, depending on the tumor environment. Here, we show that exogenous addition of recombinant TGFBI to BXPC3 tumor cells inhibited clonogenic growth and migration, thus recapitulating the phenotypic effect observed from DDR1 silencing. BXPC3 tumor xenografts demonstrated reduced growth with DDR1 knockdown, and the same xenograft tumors exhibited an increase in TGFBI expression level. Together, these data suggest that DDR1 expression level influences tumor growth in part via modulation of TGFBI expression. The reciprocal expression of DDR1 and TGFBI may help to elucidate the contribution of DDR1 in tumorigenesis and TGFBI may also be used as a biomarker for the therapeutic development of DDR1 specific inhibitors.

  18. Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression.

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    Nandini Rudra-Ganguly

    Full Text Available Discoidin domain receptor 1 (DDR1 is a member of the receptor tyrosine kinase family. The receptor is activated upon binding to its ligand, collagen, and plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Although DDR1 is expressed in many normal tissues, upregulated expression of DDR1 in a variety of human cancers such as lung, colon and brain cancers is known to be associated with poor prognosis. Using shRNA silencing, we assessed the oncogenic potential of DDR1. DDR1 knockdown impaired tumor cell proliferation and migration in vitro and tumor growth in vivo. Microarray analysis of tumor cells demonstrated upregulation of TGFBI expression upon DDR1 knockdown, which was subsequently confirmed at the protein level. TGFBI is a TGFβ-induced extracellular matrix protein secreted by the tumor cells and is known to act either as a tumor promoter or tumor suppressor, depending on the tumor environment. Here, we show that exogenous addition of recombinant TGFBI to BXPC3 tumor cells inhibited clonogenic growth and migration, thus recapitulating the phenotypic effect observed from DDR1 silencing. BXPC3 tumor xenografts demonstrated reduced growth with DDR1 knockdown, and the same xenograft tumors exhibited an increase in TGFBI expression level. Together, these data suggest that DDR1 expression level influences tumor growth in part via modulation of TGFBI expression. The reciprocal expression of DDR1 and TGFBI may help to elucidate the contribution of DDR1 in tumorigenesis and TGFBI may also be used as a biomarker for the therapeutic development of DDR1 specific inhibitors.

  19. Dietary Feeding of Grape Seed Extract Prevents Intestinal Tumorigenesis in APCmin/+ Mice

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    Balaiya Velmurugan

    2010-01-01

    Full Text Available Chemopreventive effects and associated mechanisms of grape seed extract (GSE against intestinal/colon cancer development are largely unknown. Herein, we investigated GSE efficacy against intestinal tumorigenesis in APCmin/+ mice. Female APCmin/+ mice were fed control or 0.5% GSE (wt/wt mixed AIN-76A diet for 6 weeks. At the end of the experiment, GSE feeding decreased the total number of intestinal polyps by 40%. The decrease in polyp formation in the small intestine was 42%, which was mostly in its middle (51% and distal (49% portions compared with the proximal one. GSE also decreased polyp growth where the number of polyps of 1 to 2 mm in size decreased by 42% and greater than 2 mm in size by 71%, without any significant change in polyps less than 1 mm in size. Immunohistochemical analyses of small intestinal tissue samples revealed a decrease (80%–86% in cell proliferation and an increase (four- to eight-fold in apoptosis. GSE feeding also showed decreased protein levels of cyclooxygenase-2 (COX-2 (56%–64%, inducible nitric oxide synthase (iNOS (58%–60%, and β-catenin (43%–59% but an increased Cip1/p21-positive cells (1.9- to 2.6-fold. GSE also decreased cyclin D1 and c-Myc protein levels in small intestine. Together, these findings show the chemopreventive potential of GSE against intestinal polyp formation and growth in APCmin/+ mice, which was accompanied with reduced cell proliferation and increased apoptosis together with down-regulation in COX-2, iNOS, β-catenin, cyclin D1, and c-Myc expression, but increased Cip1/p21. In conclusion, the present study suggests potential usefulness of GSE for the chemoprevention of human intestinal/colorectal cancer.

  20. In Drosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1–Rok–Myosin-II and JNK signalling

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    Peytee Khoo

    2013-05-01

    The Ras oncogene contributes to ∼30% of human cancers, but alone is not sufficient for tumorigenesis. In a Drosophila screen for oncogenes that cooperate with an activated allele of Ras (RasACT to promote tissue overgrowth and invasion, we identified the GTP exchange factor RhoGEF2, an activator of Rho-family signalling. Here, we show that RhoGEF2 also cooperates with an activated allele of a downstream effector of Ras, Raf (RafGOF. We dissect the downstream pathways through which RhoGEF2 cooperates with RasACT (and RafGOF, and show that RhoGEF2 requires Rho1, but not Rac, for tumorigenesis. Furthermore, of the Rho1 effectors, we show that RhoGEF2 + Ras (Raf-mediated tumorigenesis requires the Rho kinase (Rok–Myosin-II pathway, but not Diaphanous, Lim kinase or protein kinase N. The Rho1–Rok–Myosin-II pathway leads to the activation of Jun kinase (JNK, in cooperation with RasACT. Moreover, we show that activation of Rok or Myosin II, using constitutively active transgenes, is sufficient for cooperative tumorigenesis with RasACT, and together with RasACT leads to strong activation of JNK. Our results show that Rok–Myosin-II activity is necessary and sufficient for Ras-mediated tumorigenesis. Our observation that activation of Myosin II, which regulates Filamentous actin (F-actin contractility without affecting F-actin levels, cooperates with RasACT to promote JNK activation and tumorigenesis, suggests that increased cell contractility is a key factor in tumorigenesis. Furthermore, we show that signalling via the Tumour necrosis factor (TNF; also known as Egr-ligand–JNK pathway is most likely the predominant pathway that activates JNK upon Rok activation. Overall, our analysis highlights the need for further analysis of the Rok–Myosin-II pathway in cooperation with Ras in human cancers.

  1. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.

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    Tian, Maozhen; Schiemann, William P

    2010-04-01

    The molecular mechanisms that enable cyclooxygenase-2 (COX-2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor-beta (TGF-beta) signaling during mammary tumorigenesis remain unknown. We show here that TGF-beta selectively stimulated the expression of the PGE2 receptor EP2, which increased normal and malignant mammary epithelial cell (MEC) invasion, anchorage-independent growth, and resistance to TGF-beta-induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF-beta to Smad2/3 activation and plasminogen activator inhibitor-1 (PAI1) expression, while EP2 deficiency in these same MECs augmented Smad2/3 activation and PAI expression stimulated by TGF-beta. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF-beta, decreased their invasiveness in response to TGF-beta, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF-beta. More important, we show that COX-2 or EP2 deficiency both significantly decreased the growth, angiogenesis, and pulmonary metastasis of mammary tumors produced in mice. Collectively, this investigation establishes EP2 as a potent mediator of the anti-TGF-beta activities elicited by COX-2/PGE2 in normal and malignant MECs. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the oncogenic activities of TGF-beta during mammary tumorigenesis.-Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.

  2. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis

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    Tian, Maozhen; Schiemann, William P.

    2010-01-01

    The molecular mechanisms that enable cyclooxygenase-2 (COX-2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor-β (TGF-β) signaling during mammary tumorigenesis remain unknown. We show here that TGF-β selectively stimulated the expression of the PGE2 receptor EP2, which increased normal and malignant mammary epithelial cell (MEC) invasion, anchorage-independent growth, and resistance to TGF-β-induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF-β to Smad2/3 activation and plasminogen activator inhibitor-1 (PAI1) expression, while EP2 deficiency in these same MECs augmented Smad2/3 activation and PAI expression stimulated by TGF-β. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF-β, decreased their invasiveness in response to TGF-β, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF-β. More important, we show that COX-2 or EP2 deficiency both significantly decreased the growth, angiogenesis, and pulmonary metastasis of mammary tumors produced in mice. Collectively, this investigation establishes EP2 as a potent mediator of the anti-TGF-β activities elicited by COX-2/PGE2 in normal and malignant MECs. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the oncogenic activities of TGF-β during mammary tumorigenesis.—Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. PMID:19897661

  3. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells.

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    Si Chen

    Full Text Available Recent studies demonstrated that cancer stem cells (CSCs have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP cells than in non-side population (NSP cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.

  4. TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1.

    Science.gov (United States)

    Yu, Jihang; Alharbi, Adel; Shan, Hongchao; Hao, Yawei; Snetsinger, Brooke; Rauh, Michael J; Yang, Xiaolong

    2017-06-13

    Recent studies suggest that lung cancer stem cells (CSCs) may play major roles in lung cancer. Therefore, identification of lung CSC drivers may provide promising targets for lung cancer. TAZ is a transcriptional co-activator and key downstream effector of the Hippo pathway, which plays critical roles in various biological processes. TAZ has been shown to be overexpressed in lung cancer and involved in tumorigenicity of lung epithelial cells. However, whether TAZ is a driver for lung CSCs and tumor formation in vivo is unknown. In addition, the molecular mechanism underlying TAZ-induced lung tumorigenesis remains to be determined. In this study, we provided evidence that constitutively active TAZ (TAZ-S89A) is a driver for lung tumorigenesis in vivo in mice and formation of lung CSC. Further RNA-seq and qRT-PCR analysis identified Aldh1a1, a well-established CSC marker, as critical TAZ downstream target and showed that TAZ induces Aldh1a1 transcription by activating its promoter activity through interaction with the transcription factor TEAD. Most significantly, inhibition of ALDH1A1 with its inhibitor A37 or CRISPR gene knockout in lung cancer cells suppressed lung tumorigenic and CSC phenotypes in vitro, and tumor formation in mice in vivo. In conclusion, this study identified TAZ as a novel inducer of lung CSCs and the first transcriptional activator of the stem cell marker ALDH1A1. Most significantly, we identified ALDH1A1 as a critical meditator of TAZ-induced tumorigenic and CSC phenotypes in lung cancer. Our studies provided preclinical data for targeting of TAZ-TEAD-ALDH1A1 signaling to inhibit CSC-induced lung tumorigenesis in the future.

  5. EFFECTS OF MUTATION AND EXPRESSION OF PTEN GENE mRNA ON TUMORIGENESIS AND PROGRESSION OF EPITHELIAL OVARIAN CANCER

    Institute of Scientific and Technical Information of China (English)

    陈颖; 郑华川; 杨雪飞; 孙丽梅; 辛彦

    2004-01-01

    Objective To investigate the mutation and expression of tumor suppressor gene-PTEN mRNA and explore their roles in tumorigenesis and progression of ovarian cancer. Methods Mutated exon 5 of PTEN gene was examined in normal ovary (n = 5), ovarian cyst (n =5), ovarian borderline tumor (n=9), epithelial ovarian cancer (n=60), and ovarian cancer cell line (n= 1)by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). mRNA expression of PTEN gene was evaluated in corresponding tissues and cell line by reverse transcription polymerase chain reaction(RT-PCR). The mutation and mRNA expression of PTEN gene were compared with clinicopathological features of ovarian cancer. Results Mutated exon 5 of PTEN gene was detected only in 5 (7.1%) cases of epithelial ovarian cancer. mRNA expression level of PTEN gene in ovarian borderline tumor or ovarian cancer was lower than that in normal ovary or ovarian cyst (P < 0.05). The level of PTEN gene mRNA expression was negatively correlated with clinicopathological staging of ovarian cancer, whereas positively correlated with histological differentiation (P < 0.05). mRNA expression level of PTEN gene in ovarian endometrioid cancer was significantly lower than that in ovarian serous or mucinous cancer (P < 0.05). Conclusions Mutation of PTEN gene occurs in ovarian cancer. Down-regulated expression of PTEN is probably an important molecular event in tumorigenesis of ovarian cancer. Abnormal expression of PTEN gene is involved in progression of ovarian cancer. Reduced expression of PTEN gene is closely associated with tumorigenesis and pathobiological behaviors of ovarian endometrioid cancer.

  6. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells.

    Science.gov (United States)

    Chen, Si; Xu, Yingxi; Chen, Yanan; Li, Xuefei; Mou, Wenjun; Wang, Lina; Liu, Yanhua; Reisfeld, Ralph A; Xiang, Rong; Lv, Dan; Li, Na

    2012-01-01

    Recent studies demonstrated that cancer stem cells (CSCs) have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP) cells than in non-side population (NSP) cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.

  7. Cdk2 deficiency decreases ras/CDK4-dependent malignant progression, but not myc-induced tumorigenesis.

    Science.gov (United States)

    Macias, Everardo; Kim, Yongbaek; Miliani de Marval, Paula L; Klein-Szanto, Andres; Rodriguez-Puebla, Marcelo L

    2007-10-15

    We have previously shown that forced expression of CDK4 in mouse skin (K5CDK4 mice) results in increased susceptibility to squamous cell carcinoma (SCC) development in a chemical carcinogenesis protocol. This protocol induces skin papilloma development, causing a selection of cells bearing activating Ha-ras mutations. We have also shown that myc-induced epidermal proliferation and oral tumorigenesis (K5Myc mice) depends on CDK4 expression. Biochemical analysis of K5CDK4 and K5Myc epidermis as well as skin tumors showed that keratinocyte proliferation is mediated by CDK4 sequestration of p27Kip1 and p21Cip1, and activation of CDK2. Here, we studied the role of CDK2 in epithelial tumorigenesis. In normal skin, loss of CDK2 rescues CDK4-induced, but not myc-induced epidermal hyperproliferation. Ablation of CDK2 in K5CDK4 mice results in decreased incidences and multiplicity of skin tumors as well as malignant progression to SCC. Histopathologic analysis showed that K5CDK4 tumors are drastically more aggressive than K5CDK4/CDK2-/- tumors. On the other hand, we show that CDK2 is dispensable for myc-induced tumorigenesis. In contrast to our previous report of K5Myc/CDK4-/-, K5Myc/CDK2-/- mice developed oral tumors with the same frequency as K5Myc mice. Overall, we have established that ras-induced tumors are more susceptible to CDK2 ablation than myc-induced tumors, suggesting that the efficacy of targeting CDK2 in tumor development and malignant progression is dependent on the oncogenic pathway involved.

  8. Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis and metastasis.

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    Teoh-Fitzgerald, M L; Fitzgerald, M P; Zhong, W; Askeland, R W; Domann, F E

    2014-01-16

    Expression of the antioxidant enzyme EcSOD in normal human mammary epithelial cells was not recognized until recently. Although expression of EcSOD was not detectable in non-malignant human mammary epithelial cells (HMEC) cultured in conventional two-dimensional (2D) culture conditions, EcSOD protein expression was observed in normal human breast tissues, suggesting that the 2D-cultured condition induces a repressive status of EcSOD gene expression in HMEC. With the use of laminin-enriched extracellular matrix (lrECM), we were able to detect expression of EcSOD when HMEC formed polarized acinar structures in a 3D-culture condition. Repression of the EcSOD-gene expression was again seen when the HMEC acini were sub-cultured as a monolayer, implying that lrECM-induced acinar morphogenesis is essential in EcSOD-gene activation. We have further shown the involvement of DNA methylation in regulating EcSOD expression in HMEC under these cell culture conditions. EcSOD mRNA expression was strongly induced in the 2D-cultured HMEC after treatment with a DNA methyltransferase inhibitor. In addition, epigenetic analyses showed a decrease in the degree of CpG methylation in the EcSOD promoter in the 3D versus 2D-cultured HMEC. More importantly, >80% of clinical mammary adenocarcinoma samples showed significantly decreased EcSOD mRNA and protein expression levels compared with normal mammary tissues and there is an inverse correlation between the expression levels of EcSOD and the clinical stages of breast cancer. Combined bisulfite restriction analysis analysis of some of the tumors also revealed an association of DNA methylation with the loss of EcSOD expression in vivo. Furthermore, overexpression of EcSOD inhibited breast cancer metastasis in both the experimental lung metastasis model and the syngeneic mouse model. This study suggests that epigenetic silencing of EcSOD may contribute to mammary tumorigenesis and that restoring the extracellular superoxide scavenging

  9. Changes in mitochondrial DNA alter expression of nuclear encoded genes associated with tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Jandova, Jana; Janda, Jaroslav [Southern Arizona VA Healthcare System, Department of Medicine, Dermatology Division and Arizona Cancer Center, University of Arizona, 1515 N Campbell Avenue, Tucson, AZ 857 24 (United States); Sligh, James E, E-mail: jsligh@azcc.arizona.edu [Southern Arizona VA Healthcare System, Department of Medicine, Dermatology Division and Arizona Cancer Center, University of Arizona, 1515 N Campbell Avenue, Tucson, AZ 857 24 (United States)

    2012-10-15

    genes associated with tumorigenesis. Black-Right-Pointing-Pointer MMP-9 is up-regulated and Col1a1 is down-regulated in mutant cybrids. Black-Right-Pointing-Pointer GM6001 reduced the enhanced motility of mutant cybrids caused by up-regulated MMP-9. Black-Right-Pointing-Pointer The MMP-9 expression and invasiveness of mutant cybrids were reduced by Bay 11-7802.

  10. Modulatory effects of Azadirachta indica on benzo(a)pyrene-induced forestomach tumorigenesis in mice

    Institute of Scientific and Technical Information of China (English)

    Subhash Chander Gangar; Rajat Sandhir; Durg Vijay Rai; Ashwani Koul

    2006-01-01

    AIM: To evaluate the chemopreventive effects of aqueous Azadirachta indica (A indica) leaf extract (AAILE)against benzo(a)pyrene [B(a)P]-induced forestomach tumorigenesis in Balb/c mice.METHODS: Female Balb/c mice were divided into four groups of 10-12 animals each. For induction of forestomach tumors, starting from d 14 of the experiment, mice of B(a)P and B(a)P+A indica groups were given intra-gastric instillations of B(a)P (40 mg/kg), twice a week for four weeks. Mice of A indica and B(a)P+A indica groups were orally administered with AAILE (100mg/kg), two weeks prior to B(a)P instillations till the end of the experiment. After 22 wk of the first B(a)P instillation, mice were sacrificed and the forestomachs were analyzed for development of tumors, scanning electron microscopy (SEM) and histopathology.RESULTS: Tumor incidence was observed to be 100%in mice that received only B(a)P. However, treatment with AAILE reduced the tumor incidence by 58.4%as observed in mice of B(a)P+A indica group when compared to that of B(a)P group. Similarly, the tumor burden and multiplicity were seen to decrease by 87.3% and 69.6% respectively in mice of B(a)P+A indica group when compared to those of B(a)P group.Scanning electron microscopy analysis showed that AAILE treatment itself did not cause any abnormalities on the surface architecture of forestomach epithelium.In tumorous forestomach, surface disruption was observed. Over the forestomach tumors of B(a)P group of mice certain rounded structures were seen in addition to closely placed tongue-shaped squamous cells. Interestingly, these rounded structures were not observed in B(a)P + A indica group of mice.Histopathalogically, the tumors were identical and diagnosed to be papillomas. Mice from control and A indica groups of mice did not develop any forestomach tumors and showed normal histo-architecture.CONCLUSION: The present data suggest that A indica exerts chemopreventive effects against B(a)P-induced forestomach tumors in

  11. BTB-Zinc Finger Oncogenes Are Required for Ras and Notch-Driven Tumorigenesis in Drosophila.

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    Karen Doggett

    Full Text Available During tumorigenesis, pathways that promote the epithelial-to-mesenchymal transition (EMT can both facilitate metastasis and endow tumor cells with cancer stem cell properties. To gain a greater understanding of how these properties are interlinked in cancers we used Drosophila epithelial tumor models, which are driven by orthologues of human oncogenes (activated alleles of Ras and Notch in cooperation with the loss of the cell polarity regulator, scribbled (scrib. Within these tumors, both invasive, mesenchymal-like cell morphology and continual tumor overgrowth, are dependent upon Jun N-terminal kinase (JNK activity. To identify JNK-dependent changes within the tumors we used a comparative microarray analysis to define a JNK gene signature common to both Ras and Notch-driven tumors. Amongst the JNK-dependent changes was a significant enrichment for BTB-Zinc Finger (ZF domain genes, including chronologically inappropriate morphogenesis (chinmo. chinmo was upregulated by JNK within the tumors, and overexpression of chinmo with either RasV12 or Nintra was sufficient to promote JNK-independent epithelial tumor formation in the eye/antennal disc, and, in cooperation with RasV12, promote tumor formation in the adult midgut epithelium. Chinmo primes cells for oncogene-mediated transformation through blocking differentiation in the eye disc, and promoting an escargot-expressing stem or enteroblast cell state in the adult midgut. BTB-ZF genes are also required for Ras and Notch-driven overgrowth of scrib mutant tissue, since, although loss of chinmo alone did not significantly impede tumor development, when loss of chinmo was combined with loss of a functionally related BTB-ZF gene, abrupt, tumor overgrowth was significantly reduced. abrupt is not a JNK-induced gene, however, Abrupt is present in JNK-positive tumor cells, consistent with a JNK-associated oncogenic role. As some mammalian BTB-ZF proteins are also highly oncogenic, our work suggests that

  12. The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

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    Bobrowska-Korczak Barbara

    2012-04-01

    Full Text Available Abstract Background The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca in tumors as compared with normal tissue of the mammary gland. Methods Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene, were treated with zinc ions (Zn or zinc ions + resveratrol (Zn + resveratrol or zinc ions + genistein (Zn + genistein via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. Results Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein, DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. Conclusions Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of

  13. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis

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    Thames Howard D

    2008-09-01

    -expressing cells of the murine mammary gland results in the development of squamous metaplastic lesions in nulliparous females, and in mammary tumors in biparous mice, suggesting that ATF3 acts as a mammary oncogene. A subset of human breast tumors expresses high levels of ATF3, suggesting that ATF3 may play an oncogenic role in human breast tumorigenesis, and therefore may be useful as either a biomarker or therapeutic target.

  14. Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway.

    Science.gov (United States)

    Park, Y-H; Kim, S-U; Kwon, T-H; Kim, J-M; Song, I-S; Shin, H-J; Lee, B-K; Bang, D-H; Lee, S-J; Lee, D-S; Chang, K-T; Kim, B-Y; Yu, D-Y

    2016-07-07

    The current study was carried out to define the involvement of Peroxiredoxin (Prx) II in progression of hepatocellular carcinoma (HCC) and the underlying molecular mechanism(s). Expression and function of Prx II in HCC was determined using H-ras(G12V)-transformed HCC cells (H-ras(G12V)-HCC cells) and the tumor livers from H-ras(G12V)-transgenic (Tg) mice and HCC patients. Prx II was upregulated in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg mouse tumor livers, the expression pattern of which highly similar to that of forkhead Box M1 (FoxM1). Moreover, either knockdown of FoxM1 or site-directed mutagenesis of FoxM1-binding site of Prx II promoter significantly reduced Prx II levels in H-ras(G12V)-HCC cells, indicating FoxM1 as a direct transcription factor of Prx II in HCC. Interestingly, the null mutation of Prx II markedly decreased the number and size of tumors in H-ras(G12V)-Tg livers. Consistent with this, knockdown of Prx II in H-ras(G12V)-HCC cells reduced the expression of cyclin D1, cell proliferation, anchorage-independent growth and tumor formation in athymic nude mice, whereas overexpression of Prx II increased or aggravated the tumor phenotypes. Importantly, the expression of Prx II was correlated with that of FoxM1 in HCC patients. The activation of extracellular signal-related kinase (ERK) pathway and the expression of FoxM1 and cyclin D1 were highly dependent on Prx II in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg livers. Prx II is FoxM1-dependently-expressed antioxidant in HCC and function as an enhancer of Ras(G12V) oncogenic potential in hepatic tumorigenesis through activation of ERK/FoxM1/cyclin D1 cascade.

  15. RORγt(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice.

    Science.gov (United States)

    Martin, Maria; Kesselring, Rebecca K; Saidou, Balam; Brunner, Stefan M; Schiechl, Gabriela; Mouris, Verena F; Wege, Anja K; Rümmele, Petra; Schlitt, Hans J; Geissler, Edward K; Fichtner-Feigl, Stefan

    2015-06-01

    Colorectal cancer (CRC) is one of the most common tumor entities. In patients with inflammatory bowel diseases, the development of colitis-associated colon cancer is considered a dangerous long-term complication. IL-17A and the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORγt-dependent CD4(+) IL17A(+) T helper (Th)17 cells in specimens of CRC, ulcerative colitis, and ulcerative colitis-associated colorectal cancer. However, the mechanistic role of RORγt(+) hematopoietic cells in colitis-associated tumorigenesis remains unclear. To investigate colitis-associated colon tumorigenesis, we conducted studies in the AOM+DSS mouse model that revealed the importance of RORγt for colon tumor progression. In the absence of RORγt-dependent Th17 lymphocytes, mice showed signs of intense chronic colitis, but developed significantly fewer macroscopic tumor nodules. The reduction of tumor development in RORγt(-/-) mice was not due to reduced colon tumor initiation. However, the proliferation rate of tumor cells was reduced in the absence of RORγt-dependent Th17 cells and tumor cells showed pronounced signs of senescence-associated epigenetic and lysosomal changes. These results indicate an important role for the immunological milieu in colitis-associated cancer, which is shaped in-part by RORγt-dependent Th17 lymphocytes that support CRC growth.

  16. Intracerebral Distribution of the Oncometabolite D-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Amanda Pickard

    2016-10-01

    Full Text Available The prevalence of mutant IDH1 brain tumors has generated significant efforts to understand the role of the mutated enzyme product D-2-hydroxyglutarate (D2HG, an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors who underwent two microdialysis – providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 µM awake and 117.6 ± 98.6 µM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis.

  17. Maslinic Acid-Enriched Diet Decreases Intestinal Tumorigenesis in ApcMin/+ Mice through Transcriptomic and Metabolomic Reprogramming

    Science.gov (United States)

    Sánchez-Tena, Susana; Reyes-Zurita, Fernando J.; Díaz-Moralli, Santiago; Vinardell, Maria Pilar; Reed, Michelle; García-García, Francisco; Dopazo, Joaquín; Lupiáñez, José A.; Günther, Ulrich; Cascante, Marta

    2013-01-01

    Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in ApcMin/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid–supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in ApcMin/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the ApcMin/+ mice model, suggesting its chemopreventive potential against colorectal cancer. PMID:23527181

  18. Cytochrome P450 1B1 expression in rat esophageal tumorigenesis promoted by gastric and duodenal reflux.

    Science.gov (United States)

    Devlin, Andrea H; McIlroy, Marie; McKeen, Hayley D; Bonde, Pramode; Menezes, A A Carlos; Swarbrick, Christine J; Robson, Tracy; Hirst, David G; Campbell, F Charles; McGuigan, James A; McKeown, Stephanie R

    2009-02-01

    Cytochrome P450 1B1 (CYP1B1) mRNA is constitutively expressed in most normal extra-hepatic tissues; however the protein is not detectable in these tissues but is expressed in a wide variety of tumors. CYP1B1 is responsible for the activation of a number of carcinogens present in tobacco smoke and food. A surgical model of rat esophageal tumorigenesis, promoted by gastric or duodenal reflux was used to determine CYP1B1 expression in premalignant esophageal tissue. Immunohistochemistry was performed using a modified amplified fluorescein tyramide protocol. CYP1B1 was not observed in normal esophageal mucosa, submucosa, or muscularis mucosa. Animals exposed to gastric reflux developed mild hyperplasia. Varying degrees of hyperplasia were observed in the duodenal reflux group. All regions of hyperplasia showed moderate or strong CYP1B1 immunoreactivity. Duodenal reflux induced a small number of premalignant changes: immunoreactivity was absent from the epithelium of squamous dysplasia (0/10), Barrett's esophagus (0/7), and majority of dysplastic Barrett's esophagus (1/4). Moderate or strong immunoreactivity was observed in the majority (7/8) of squamous cell carcinomas (SCCs) in situ. Immunoreactivity was also observed in the lamina propria and submucosa in association with inflammation, regardless of the severity of inflammation. The expression of CYP1B1 in hyperplasia, SCCs in situ, or in association with inflammation may increase the production of carcinogenic metabolites, which may promote esophageal tumorigenesis.

  19. Acetylation-dependent regulation of essential iPS-inducing factors: a regulatory crossroad for pluripotency and tumorigenesis.

    Science.gov (United States)

    Dai, Xiangpeng; Liu, Pengda; Lau, Alan W; Liu, Yueyong; Inuzuka, Hiroyuki

    2014-10-01

    Induced pluripotent stem (iPS) cells can be generated from somatic cells by coexpression of four transcription factors: Sox2, Oct4, Klf4, and c-Myc. However, the low efficiency in generating iPS cells and the tendency of tumorigenesis hinder the therapeutic applications for iPS cells in treatment of human diseases. To this end, it remains largely unknown how the iPS process is subjected to regulation by upstream signaling pathway(s). Here, we report that Akt regulates the iPS process by modulating posttranslational modifications of these iPS factors in both direct and indirect manners. Specifically, Akt directly phosphorylates Oct4 to modulate the Oct4/Sox2 heterodimer formation. Furthermore, Akt either facilitates the p300-mediated acetylation of Oct4, Sox2, and Klf4, or stabilizes Klf4 by inactivating GSK3, thus indirectly modulating stemness. As tumorigenesis shares possible common features and mechanisms with iPS, our study suggests that Akt inhibition might serve as a cancer therapeutic approach to target cancer stem cells.

  20. Association of pituitary tumor transforming gene expression with early oral tumorigenesis and malignant progression of precancerous lesions.

    Science.gov (United States)

    Liao, Li-Jen; Hsu, Yi-Hsin; Yu, Chuan-Hang; Chiang, Chun-Pin; Jhan, Jing-Ru; Chang, Lien-Cheng; Lin, Jing-Jer; Lou, Pei-Jen

    2011-05-01

    Pituitary tumor transforming gene (PTTG1) is overexpressed in many types of human cancers and is involved in late-stage tumor progression. The role of PTTG1 in initiating tumorigenesis is unclear. PTTG1 expression was assessed in precancerous lesions and squamous cell carcinomas of the oral cavity (OSCC). The association between the protein expression and clinicopathologic parameters was analyzed. The expression level of PTTG1 upon carcinogen treatment was also investigated. PTTG1 was overexpressed in both precancerous lesions and OSCC. The expression of PTTG1 was associated with carcinogen exposure in vivo and in vitro. PTTG1 overexpression was an independent factor for oral cancer development in precancerous lesions. This study provides the first evidence that PTTG1 is involved in the early stages of oral tumorigenesis. Carcinogen exposure may cause the initial induction of PTTG1 expression in oral precancerous lesions. PTTG1 overexpression is a potential prognosticator for malignant progression of oral precancerous lesions. Copyright © 2010 Wiley Periodicals, Inc.

  1. Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis.

    Science.gov (United States)

    Li, Xinjian; Jiang, Yuhui; Meisenhelder, Jill; Yang, Weiwei; Hawke, David H; Zheng, Yanhua; Xia, Yan; Aldape, Kenneth; He, Jie; Hunter, Tony; Wang, Liwei; Lu, Zhimin

    2016-03-01

    It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis.

  2. Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+ mice through transcriptomic and metabolomic reprogramming.

    Directory of Open Access Journals (Sweden)

    Susana Sánchez-Tena

    Full Text Available Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA, a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01. Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+ mice model, suggesting its chemopreventive potential against colorectal cancer.

  3. gga-miR-375 plays a key role in tumorigenesis post subgroup J avian leukosis virus infection.

    Science.gov (United States)

    Li, Hongxin; Shang, Huiqing; Shu, Dingming; Zhang, Huanmin; Ji, Jun; Sun, Baoli; Li, Hongmei; Xie, Qingmei

    2014-01-01

    Avian leukosis is a neoplastic disease caused in part by subgroup J avian leukosis virus J (ALV-J). Micro ribonucleic acids (miRNAs) play pivotal oncogenic and tumour-suppressor roles in tumour development and progression. However, little is known about the potential role of miRNAs in avian leukosis tumours. We have found a novel tumour-suppressor miRNA, gga-miR-375, associated with avian leukosis tumorigenesis by miRNA microarray in a previous report. We have also previously studied the biological function of gga-miR-375; Overexpression of gga-miR-375 significantly inhibited DF-1 cell proliferation, and significantly reduced the expression of yes-associated protein 1 (YAP1) by repressing the activity of a luciferase reporter carrying the 3'-untranslated region of YAP1. This indicates that gga-miR-375 is frequently downregulated in avian leukosis by inhibiting cell proliferation through YAP1 oncogene targeting. Overexpression of gga-miR-375 markedly promoted serum starvation induced apoptosis, and there may be the reason why the tumour cycle is so long in the infected chickens. In vivo assays, gga-miR-375 was significantly downregulated in chicken livers 20 days after infection with ALV-J, and YAP1 was significantly upregulated 20 days after ALV-J infection (Pleukosis tumorigenesis.

  4. Dark Aberrant Crypt Foci with activated Wnt pathway are related to tumorigenesis in the colon of AOM-treated rat

    Directory of Open Access Journals (Sweden)

    Lin Chen

    2008-08-01

    Full Text Available Abstract Background To evaluate the relationship between Aberrant Crypt Foci (ACF and tumorigenesis, we observed the sequential development from ACF to tumor in the colon of azoxymethane-exposed wistar rats. Methods Sixty wistar rats were sacrificed at different time points after exposure to azoxymethane and the colons were stained with methylene blue for stereomicroscopic analysis. Results We found two types of early lesions: classic ACF and dark ACF. Dark ACF were characterized by dark blue staining, mildly enlarged or small compressed crypts that are not elevated from the surrounding epithelium. Large dark ACF and nascent tumors displayed the same surface morphology. Furthermore, dark ACF grew significantly faster than classic ACF and showed dysplasia without hyperplasia. In contrast, classic ACF showed hyperplasia without dysplasia. Dark ACF has significant higher expression rate of β-catenin (100% and MMP-7 (81.82% compared with the expression of β-catenin and MMP-7 in classic ACF (4.84% and 7.87%, respectively. Conclusion Our data indicated that dark ACF is closely related to tumorigenesis while classic ACF is not. Furthermore, Wnt signal pathway was activated during the early period of dark ACF.

  5. MicroRNA-186 targets Yes-associated protein 1 to inhibit Hippo signaling and tumorigenesis in hepatocellular carcinoma.

    Science.gov (United States)

    Ruan, Tingyan; He, Xiaoting; Yu, Jun; Hang, Zhiqiang

    2016-04-01

    Liver cancer, particularly hepatocellular carcinoma (HCC), is one of leading causes of cancer-related mortality worldwide. Upregulation of the evolutionary conserved Hippo signaling pathway has been observed in HCC patients, and Yes-associated protein 1 (YAP1) has been reported to play a key role in HCC tumorigenesis. microRNAs (miRNAs) are a family of small non-coding RNAs, usually 21-25 nucleotides in length, and are essential in the regulation of gene expression. Abnormal miRNA expression has been implicated in the initiation and progression of numerous forms of cancers, including liver cancer. Here, we report the identification of a novel miRNA, miR-186, and its functions as an HCC tumor suppressor. We observed that miR-186 was downregulated in several HCC cell lines, and that it directly targets YAP1 mRNA. Overexpression of miR-186 in HCC cells significantly downregulates YAP1 mRNA and protein levels, leading to downregulation of the Hippo signaling pathway, which in turn severely inhibits HCC cell migration, invasion and proliferation. Our study is the first to report the direct involvement of miR-186 in downregulating YAP1 and, more significantly, inhibiting HCC tumorigenesis, and supports the role miR-186 as a potential therapeutic target in treating liver cancer.

  6. Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila.

    Science.gov (United States)

    Garcia, Ana Maria; Salomon, Robert N; Witsell, Alice; Liepkalns, Justine; Calder, R Brent; Lee, Moonsook; Lundell, Martha; Vijg, Jan; McVey, Mitch

    2011-12-19

    The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. To address this, we used a lacZ reporter system in wild-type and several mutant strains of Drosophila melanogaster to analyze mechanisms of mutagenesis throughout their lifespan. Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. Although in normal flies most genome rearrangements occur through DNA ligase 4-dependent classical end joining, most rearrangements that accumulate during aging in blm mutants do not require DNA ligase 4, suggesting the influence of an alternative end-joining mechanism. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues. These results suggest that Drosophila BLM suppresses error-prone alternative end-joining repair of DNA double-strand breaks that can result in genome instability and tumor formation during aging. In addition, since loss of BLM significantly affects lifespan and tumorigenesis, the data provide a link between error-prone end joining, genome rearrangements, and tumor formation in a model metazoan.

  7. Unravelling the connection between metabolism and tumorigenesis through studies of the liver kinase B1 tumour suppressor

    Directory of Open Access Journals (Sweden)

    David B Shackelford

    2013-01-01

    Full Text Available The liver kinase B1 (LKB1 tumour suppressor functions as a master regulator of growth, metabolism and survival in cells, which is frequently mutated in sporadic human non-small cell lung and cervical cancers. LKB1 functions as a key upstream activator of the AMP-activated protein kinase (AMPK, a central metabolic switch found in all eukaryotes that govern glucose and lipid metabolism and autophagy in response to alterations in nutrients and intracellular energy levels. The LKB1/AMPK signalling pathway suppresses mammalian target of rapamycin complex 1 (mTORC1, an essential regulator of cell growth in all eukaryotes that is deregulated in a majority of human cancers. LKB1 inactivation in cancer leads to both tumorigenesis and metabolic deregulation through the AMPK and mTORC1-signalling axis and there remain critical challenges to elucidate the direct role LKB1 inactivation plays in driving aberrant metabolism and tumour growth. This review addresses past and current efforts to delineate the molecular mechanisms fueling metabolic deregulation and tumorigenesis following LKB1 inactivation as well as translational promise of therapeutic strategies aimed at targeting LKB1-deficient tumors.

  8. Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer. | Office of Cancer Genomics

    Science.gov (United States)

    Body mass index (BMI) has been implicated as a primary factor influencing cancer development. However, understanding the relationship between these two complex traits has been confounded by both environmental and genetic heterogeneity. Analysis of QTL linked to tumorigenesis and BMI identified several loci associated with both phenotypes. Exploring these loci in greater detail revealed a novel relationship between the Pannexin 3 gene (Panx3) and both BMI and tumorigenesis. Panx3 is positively associated with BMI and is strongly tied to a lipid metabolism gene expression network.

  9. Prolonged sulforaphane treatment does not enhance tumorigenesis in oncogenic K-ras and xenograft mouse models of lung cancer

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    Ponvijay Kombairaju

    2012-01-01

    Full Text Available Background: Sulforaphane (SFN, an activator of nuclear factor erythroid-2 related factor 2 (Nrf2, is a promising chemopreventive agent which is undergoing clinical trial for several diseases. Studies have indicated that there is gain of Nrf2 function in lung cancer and other solid tumors because of mutations in the inhibitor Kelch-like ECH-associated protein 1 (Keap1. More recently, several oncogenes have been shown to activate Nrf2 signaling as the main prosurvival pathway mediating ROS detoxification, senescence evasion, and neoplastic transformation. Thus, it is important to determine if there is any risk of enhanced lung tumorigenesis associated with prolonged administration of SFN using mouse models of cancer. Materials and Methods: We evaluated the effect of prolonged SFN treatment on oncogenic K-ras (K-ras LSL-G12D -driven lung tumorigenesis. One week post mutant-K-ras expression, mice were treated with SFN (0.5 mg, 5 d/wk for 3 months by means of a nebulizer. Fourteen weeks after mutant K-ras expression (K-ras LSL-G12D , mice were sacrificed, and lung sections were screened for neoplastic foci. Expression of Nrf2-dependent genes was measured using real time RT-PCR. We also determined the effect of prolonged SFN treatment on the growth of preclinical xenograft models using human A549 (with mutant K-ras and Keap1 allele and H1975 [with mutant epidermal growth factor receptor (EGFR allele] nonsmall cell lung cancer cells. Results: Systemic SFN administration did not promote the growth of K-ras LSL-G12D -induced lung tumors and had no significant effect on the growth of A549 and H1975 established tumor xenografts in nude mice. Interestingly, localized delivery of SFN significantly attenuated the growth of A549 tumors in nude mice, suggesting an Nrf2-independent antitumorigenic activity of SFN. Conclusions: Our results demonstrate that prolonged SFN treatment does not promote lung tumorigenesis in various mouse models of lung cancer.

  10. Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC1638N/+ mice

    Science.gov (United States)

    Suman, Shubhankar; Kumar, Santosh; Moon, Bo-Hyun; Fornace, Albert J.; Datta, Kamal

    2017-05-01

    Ionizing radiation (IR) is a recognized risk factor for colorectal cancer (CRC) and astronauts undertaking long duration space missions are expected to receive IR doses in excess of permissible limits with implications for colorectal carcinogenesis. Exposure to IR in outer space occurs at low doses and dose rates, and energetic heavy ions due to their high linear energy transfer (high-LET) characteristics remain a major concern for CRC risk in astronauts. Previously, we have demonstrated that intestinal tumorigenesis in a mouse model (APC1638N/+) of human colorectal cancer was significantly higher after exposure to high dose rate energetic heavy ions relative to low-LET γ radiation. The purpose of the current study was to compare intestinal tumorigenesis in APC1638N/+ mice after exposure to energetic heavy ions at high (50 cGy/min) and relatively low (0.33 cGy/min) dose rate. Male and female mice (6-8 weeks old) were exposed to either 10 or 50 cGy of 28Si (energy: 300 MeV/n; LET: 70 keV/μm) or 56Fe (energy: 1000 MeV/n; LET: 148 keV/μm) ions at NASA Space Radiation Laboratory in Brookhaven National Laboratory. Mice (n = 20 mice/group) were euthanized and intestinal and colon tumor frequency and size were counted 150 days after radiation exposure. Intestinal tumorigenesis in male mice exposed to 56Fe was similar for high and low dose rate exposures. Although male mice showed a decreasing trend at low dose rate relative to high dose rate exposures, the differences in tumor frequency between the two types of exposures were not statistically significant after 28Si radiation. In female mice, intestinal tumor frequency was similar for both radiation type and dose rates tested. In both male and female mice intestinal tumor size was not different after high and low dose rate radiation exposures. Colon tumor frequency in male and female mice after high and low dose rate energetic heavy ions was also not significantly different. In conclusion, intestinal and colonic tumor

  11. Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC(1638N/+) mice.

    Science.gov (United States)

    Suman, Shubhankar; Kumar, Santosh; Moon, Bo-Hyun; Fornace, Albert J; Datta, Kamal

    2017-05-01

    Ionizing radiation (IR) is a recognized risk factor for colorectal cancer (CRC) and astronauts undertaking long duration space missions are expected to receive IR doses in excess of permissible limits with implications for colorectal carcinogenesis. Exposure to IR in outer space occurs at low doses and dose rates, and energetic heavy ions due to their high linear energy transfer (high-LET) characteristics remain a major concern for CRC risk in astronauts. Previously, we have demonstrated that intestinal tumorigenesis in a mouse model (APC(1638N/+)) of human colorectal cancer was significantly higher after exposure to high dose rate energetic heavy ions relative to low-LET γ radiation. The purpose of the current study was to compare intestinal tumorigenesis in APC(1638N/+) mice after exposure to energetic heavy ions at high (50cGy/min) and relatively low (0.33cGy/min) dose rate. Male and female mice (6-8 weeks old) were exposed to either 10 or 50cGy of (28)Si (energy: 300MeV/n; LET: 70keV/μm) or (56)Fe (energy: 1000MeV/n; LET: 148keV/μm) ions at NASA Space Radiation Laboratory in Brookhaven National Laboratory. Mice (n=20 mice/group) were euthanized and intestinal and colon tumor frequency and size were counted 150days after radiation exposure. Intestinal tumorigenesis in male mice exposed to (56)Fe was similar for high and low dose rate exposures. Although male mice showed a decreasing trend at low dose rate relative to high dose rate exposures, the differences in tumor frequency between the two types of exposures were not statistically significant after (28)Si radiation. In female mice, intestinal tumor frequency was similar for both radiation type and dose rates tested. In both male and female mice intestinal tumor size was not different after high and low dose rate radiation exposures. Colon tumor frequency in male and female mice after high and low dose rate energetic heavy ions was also not significantly different. In conclusion, intestinal and colonic

  12. Lycopene metabolite, apo-10'-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice

    Science.gov (United States)

    Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavag...

  13. WNT/β-Catenin signaling pathway regulates non-tumorigenesis of human embryonic stem cells co-cultured with human umbilical cord mesenchymal stem cells

    Science.gov (United States)

    Chang, Yu-Hsun; Chu, Tang-Yuan; Ding, Dah-Ching

    2017-01-01

    Human pluripotent stem cells harbor hope in regenerative medicine, but have limited application in treating clinical diseases due to teratoma formation. Our previous study has indicated that human umbilical cord mesenchymal stem cells (HUCMSC) can be adopted as non-teratogenenic feeders for human embryonic stem cells (hESC). This work describes the mechanism of non-tumorigenesis of that feeder system. In contrast with the mouse embryonic fibroblast (MEF) feeder, HUCMSC down-regulates the WNT/β-catenin/c-myc signaling in hESC. Thus, adding β-catenin antagonist (FH535 or DKK1) down-regulates β-catenin and c-myc expressions, and suppresses tumorigenesis (3/14 vs. 4/4, p = 0.01) in hESC fed with MEF, while adding the β-catenin enhancer (LiCl or 6-bromoindirubin-3′-oxime) up-regulates the expressions, and has a trend (p = 0.056) to promote tumorigenesis (2/7 vs. 0/21) in hESC fed with HUCMSC. Furthermore, FH535 supplement does not alter the pluripotency of hESC when fed with MEF, as indicated by the differentiation capabilities of the three germ layers. Taken together, this investigation concludes that WNT/β-catenin/c-myc pathway causes the tumorigenesis of hESC on MEF feeder, and β-catenin antagonist may be adopted as a tumor suppressor. PMID:28157212

  14. Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis.

    NARCIS (Netherlands)

    van Boxtel, R.; Toonen, P.W.; van Roekel, H.S.; Verheul, M.; Smits, B.M.; Korving, J.; de Bruin, A.; Cuppen, E.

    2008-01-01

    To understand genetic instability in relation to tumorigenesis, experimental animal models have proven very useful. The DNA mismatch repair (MMR) machinery safeguards genomic integrity by repairing mismatches, insertion or deletion loops and responding to genotoxic agents. Here, we describe the func

  15. High-fat diet enhances mammary tumorigenesis and pulmonary metastasis and alters inflammatory and angiogenic profiles in MMTV-PyMT mice

    Science.gov (United States)

    The MMTV-PyMT transgenic mouse model is commonly used to study luminal B breast cancer, which has a lower prevalence but a worse prognosis. The objective of the present study was to determine whether an obesogenic, high-fat diet enhances primary tumorigenesis and pulmonary metastasis in female MMTV...

  16. METCAM/MUC18 promoted tumorigenesis of human breast cancer SK-BR-3 cells in a dosage-specific manner

    Directory of Open Access Journals (Sweden)

    Chang-Yu Huang

    2016-04-01

    Conclusion: Transient suppression observed previously in the clone was caused by injection of a high cell number (2 × 106–5 × 106. METCAM/MUC18 positively promotes tumorigenesis of SK-BR-3 cells by increasing the survival and proliferation pathway.

  17. Roles of mitochondria in tumorigenesis%线粒体在肿瘤发生中的作用

    Institute of Scientific and Technical Information of China (English)

    张百红; 岳红云

    2013-01-01

    线粒体作为半自主的细胞器,容易受到外界因子的损伤.线粒体功能改变,如氧化磷酸化损伤、能量代谢异常、抑制凋亡、自噬障碍、促进免疫逃避和信号通路改变,可能影响肿瘤的发生.调节线粒体功能可以预防肿瘤的发生.%As semi-autonomous organelles,mitochondria are easily damaged by various factors.Mitochondrial dysfunction such as abnormal oxidative phosphorylation,metabolism alterations,apoptosis prevention,damaged mitophagy,immune escape and deregulated signaling pathway have been hypothesized to be involved in tumorigenesis.Modulated mitochondria may prevent the occurrence of tumors.

  18. JC virus and tumorigenesis%JC病毒与肿瘤的研究进展

    Institute of Scientific and Technical Information of China (English)

    郑玉双; 郑华川

    2012-01-01

    , agnoprotein. T antigen can bind to and inactivate such tumor suppressors as p53 and pRb, disrupt the Wnt and IGF signaling pathways and instablize the genome by inserting to result in tumorigenesis. Intravenous or intracranial inoculation of JCV into experimental animals or its transgenic models have been found to cause a variety of neurological tumors. In recent years, presence of JCV T antigen DNA has been suggested to correlate with malignancies of digestive and respiratory tracts and B cell lymphoma. CONCLUSIONS: JCV is closely linked to the carcinogenesis. It would be hot to establish transgenic animal of epithelial malignancies using JCV T antigen, which can provide an evidence for its oncogenic role in the carcinogenesis. Additionally, the animal model would become a tool to investigate the molecular mechanisms of JCV oncogenesis and the approach of gene therapy for the cancer.

  19. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.

    Science.gov (United States)

    Pieterman, C R C; Conemans, E B; Dreijerink, K M A; de Laat, J M; Timmers, H Th M; Vriens, M R; Valk, G D

    2014-06-01

    Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

  20. 炎症小体与肿瘤发生的研究进展%The inflammasome and tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    秦淼; 房静远

    2013-01-01

    炎症小体(inflammasome)是细胞内多聚体蛋白复合物,可调节白细胞介素1(interleukin-1,IL-1)家族促炎性细胞因子的成熟与释放,通过诱导caspase-1分子活化和细胞程序性死亡对外源性或内源性危险信号产生应答.作为炎性反应的中心环节,炎症小体不仅与各种炎性疾病有重要关联,而且对肿瘤的发生起着重要作用.本文就炎症小体的结构、活化信号、激活通路及其对肿瘤发生的作用等研究进展作一综述.%The inflammasome is an intracellular multimeric protein complex that regulates the maturation and release of proinflammatory cytokines of the interleukin-1 (IL-1) family in response to exogenous or endogenous danger signals by the induction of activating caspase-1 molecule and the programmed cell death.As the center of the inflammatory response,the inflammasomes not only have a significant association with some inflammatory diseases,but also play a key role in tumorigenesis.This review is focused on the current progress in the structure,triggers and activation pathways of inflamasomes,as well as,their function in tumorigenesis.

  1. Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner.

    Science.gov (United States)

    Liu, Jia; Wan, Lixin; Liu, Jing; Yuan, Zhu; Zhang, Jinfang; Guo, Jianfeng; Malumbres, Marcos; Liu, Jiankang; Zou, Weiguo; Wei, Wenyi

    2016-01-01

    Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers.

  2. The Cell Surface Estrogen Receptor, G Protein- Coupled Receptor 30 (GPR30, is Markedly Down Regulated During Breast Tumorigenesis

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    Indira Poola

    2008-01-01

    Full Text Available Background: GPR30 is a cell surface estrogen receptor that has been shown to mediate a number of non-genomic rapid effects of estrogen and appear to balance the signaling of estrogen and growth factors. In addition, progestins appear to use GPR30 for their actions. Therefore, GPR30 could play a critical role in hormonal regulation of breast epithelial cell integrity. Deregulation of the events mediated by GPR30 could contribute to tumorigenesis.Methods: To understand the role of GPR30 in the deregulation of estrogen signaling processes during breast carcinogenesis, we have undertaken this study to investigate its expression at mRNA levels in tumor tissues and their matched normal tissues. We compared its expression at mRNA levels by RT quantitative real-time PCR relative to GAPDH in ERα”—positive (n = 54 and ERα”—negative (n = 45 breast cancer tissues to their matched normal tissues.Results: We report here, for the first time, that GPR30 mRNA levels were significantly down-regulated in cancer tissues in comparison with their matched normal tissues (p 0.0001 by two sided paired t-test. The GPR30 expression levels were significantly lower in tumor tissues from patients (n = 29 who had lymph node metastasis in comparison with tumors from patients (n = 53 who were negative for lymph node metastasis (two sample t-test, p 0.02, but no association was found with ERα, PR and other tumor characteristics.Conclusions: Down-regulation of GPR30 could contribute to breast tumorigenesis and lymph node metastasis.

  3. Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1.

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    Hui Li

    Full Text Available Ovarian cancer G protein-coupled receptor 1 (OGR1 has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK activation and nitric oxide (NO production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.

  4. Prostate-derived ets factor represses tumorigenesis and modulates epithelial-to-mesenchymal transition in bladder carcinoma cells.

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    Tsui, Ke-Hung; Lin, Yu-Hsiang; Chung, Li-Chuan; Chuang, Sung-Ting; Feng, Tsui-Hsia; Chiang, Kun-Chun; Chang, Phei-Lang; Yeh, Chi-Ju; Juang, Horng-Heng

    2016-05-28

    Prostate-derived Ets (E-twenty six) factor (PDEF), an epithelium-specific member of the Ets family of transcription factors, has been shown to play a role in suppressing the development of many epithelium-derived cancers such as prostate and breast cancer. It is not clear, however, whether PDEF is involved in the development or progression of bladder cancer. In a comparison between normal urothelium and bladder tumor tissue, we identified significant decreases of PDEF in the tumor tissue. Further, the immunohistochemistry assays indicated a significantly higher immunostaining of PDEF in low-grade bladder tumors. Additionally, the highly differentiated transitional-cell bladder carcinoma RT-4 cells expressed significantly more PDEF levels than the bladder carcinoma HT1376 and the T24 cells. Ectopic overexpression of PDEF attenuated proliferation, invasion, and tumorigenesis of bladder carcinoma cells in vitro and in vivo. PDEF enhanced the expression levels of mammary serine protease inhibitor (MASPIN), N-myc downstream regulated gene 1 (NDRG1), KAI1, and B-cell translocation gene 2 (BTG2). PDEF modulated epithelial-mesenchymal-transition (EMT) by upregulating E-cadherin expression and downregulating the expression of N-cadherin, SNAIL, SLUG, and vimentin, leading to lower migration and invasion abilities of bladder carcinoma cells. Filamentous actin (F-actin) polarization and remodeling were observed in PDEF-knockdown RT-4 cells. Our results suggest that PDEF gene expression is associated with the extent of bladder neoplasia and PDEF modulated the expressions of EMT-related genes. The induction of BTG2, NDRG1, MASPIN, and KAI1 gene expressions by PDEF may explain the inhibitory functions of PDEF on the proliferation, invasion, and tumorigenesis in bladder carcinoma cells.

  5. gga-miR-375 plays a key role in tumorigenesis post subgroup J avian leukosis virus infection.

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    Hongxin Li

    Full Text Available Avian leukosis is a neoplastic disease caused in part by subgroup J avian leukosis virus J (ALV-J. Micro ribonucleic acids (miRNAs play pivotal oncogenic and tumour-suppressor roles in tumour development and progression. However, little is known about the potential role of miRNAs in avian leukosis tumours. We have found a novel tumour-suppressor miRNA, gga-miR-375, associated with avian leukosis tumorigenesis by miRNA microarray in a previous report. We have also previously studied the biological function of gga-miR-375; Overexpression of gga-miR-375 significantly inhibited DF-1 cell proliferation, and significantly reduced the expression of yes-associated protein 1 (YAP1 by repressing the activity of a luciferase reporter carrying the 3'-untranslated region of YAP1. This indicates that gga-miR-375 is frequently downregulated in avian leukosis by inhibiting cell proliferation through YAP1 oncogene targeting. Overexpression of gga-miR-375 markedly promoted serum starvation induced apoptosis, and there may be the reason why the tumour cycle is so long in the infected chickens. In vivo assays, gga-miR-375 was significantly downregulated in chicken livers 20 days after infection with ALV-J, and YAP1 was significantly upregulated 20 days after ALV-J infection (P<0.05. We also found that expression of cyclin E, an important regulator of cell cycle progression, was significantly upregulated (P<0.05. Drosophila inhibitor of apoptosis protein 1 (DIAP1, which is related to caspase-dependent apoptosis, was also significantly upregulated after infection. Our data suggests that gga-miR-375 may function as a tumour suppressor thereby regulating cancer cell proliferation and it plays a key role in avian leukosis tumorigenesis.

  6. Dysregulation of CDK8 and Cyclin C in tumorigenesis %Dysregulation of CDK8 and Cyclin C in tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Wu Xu; Jun-Yuan Ji

    2011-01-01

    Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms.In eukaryotes,the transcription of protein-coding mRNAs is dependent on RNA polymerase Ⅱ (Pol Ⅱ).The multi-subunit transcription cofactor Mediator complex is proposed to regulate most,if not all,of the Pol Ⅱ-dependent transcription.Here we focus our discussion on two subunits of the Mediator complex,cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC),because they are either mutated or amplified in a variety of human cancers.CDK8 functions as an oncoprotein in melanoma and colorectal cancers,thus there are considerable interests in developing drugs specifically targeting the CDK8 kinase activity.However,to evaluate the feasibility of targeting CDK8 for cancer therapy and to understand how their dysregulation contributes to tumorigenesis,it is essential to elucidate the in vivo function and regulation of CDK8-CycC,which are still poorly understood in multi-cellular organisms.We summarize the evidence linking their dysregulation to various cancers and present our bioinformatics and computational analyses on the structure and evolution of CDK8.We also discuss the implications of these observations in tumorigenesis.Because most of the Mediator subunits,including CDK8 and CycC,are highly conserved during eukaryotic evolution,we expect that investigations using model organisms such as Drosophila will provide important insights into the function and regulation of CDK8 and CycC in different cellular and developmental contexts.

  7. Effect of Dietary Fibers on Cecal Microbiota and Intestinal Tumorigenesis in Azoxymethane Treated A/J Min/+ Mice.

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    Birgitte Moen

    Full Text Available Foods naturally high in dietary fiber are generally considered to protect against development of colorectal cancer (CRC. However, the intrinsic effect of dietary fiber on intestinal carcinogenesis is unclear. We used azoxymethane (AOM treated A/J Min/+ mice, which developed a significantly higher tumor load in the colon than in the small intestine, to compare the effects of dietary inulin (IN, cellulose (CE or brewers spent grain (BSG on intestinal tumorigenesis and cecal microbiota. Each fiber was tested at two dose levels, 5% and 15% (w/w content of the AIN-93M diet. The microbiota was investigated by next-generation sequencing of the 16S rRNA gene (V4. We found that mice fed IN had approximately 50% lower colonic tumor load than mice fed CE or BSG (p<0.001. Surprisingly, all three types of fiber caused a dose dependent increase of colonic tumor load (p<0.001. The small intestinal tumor load was not affected by the dietary fiber interventions. Mice fed IN had a lower bacterial diversity than mice fed CE or BSG. The Bacteroidetes/Firmicutes ratio was significantly (p = 0.003 different between the three fiber diets with a higher mean value in IN fed mice compared with BSG and CE. We also found a relation between microbiota and the colonic tumor load, where many of the operational taxonomic units (OTUs related to low tumor load were significantly enriched in mice fed IN. Among the OTUs related to low tumor load were bacteria affiliated with the Bacteroides genus. These results suggest that type of dietary fiber may play a role in the development of CRC, and that the suppressive effect of IN on colonic tumorigenesis is associated with profound changes in the cecal microbiota profile.

  8. Co-treating with arecoline and 4-nitroquinoline 1-oxide to establish a mouse model mimicking oral tumorigenesis.

    Science.gov (United States)

    Chang, Nai-Wen; Pei, Ren-Jeng; Tseng, Hsien-Chang; Yeh, Kun-Tu; Chan, Hsu-Chin; Lee, Miau-Rong; Lin, Chingju; Hsieh, Wen-Tsong; Kao, Ming-Ching; Tsai, Ming-Hsui; Lin, Chin-Fen

    2010-01-05

    The aim of this study was to establish an effective mouse model of oral cancer and to use this model to identify potential markers of oral tumor progression. C57BL/6JNarl mice were treated with arecoline, 4-nitroquinoline 1-oxide (4-NQO), or both arecoline and 4-NQO in high and low doses for 8 weeks to induce oral tumor. The induced oral lesions were observed for 20 weeks to assess the efficiency of cancer induction and survival rate of the mice. In addition, two target proteins that are frequently overexpressed during tongue cancer tumorigenesis, alphaB-crystallin and Hsp27, were examined by immunohistochemical analysis. In mice exposed to 4-NQO (200 microg/mL) and arecoline (500 microg/mL), the tongue lesions showed evidence of hyperplasia, papilloma, dysplasia, and carcinoma, and the lesions were pathologically similar to those lesions in human oral cancer. The tongue tumor incidence rate was 100% in mice exposed to concomitant 4-NQO (200 microg/mL) and arecoline (500 microg/mL) treatment, 57% in mice exposed to 4-NQO only, and 0% in mice exposed to arecoline only. Immunohistochemical analysis demonstrated that, consistent with human studies, alphaB-crystallin and Hsp27 were upregulated in murine oral tumors. In conclusion, we have established a powerful animal model that enables the study of the promoting effects of arecoline on tongue tumorigenesis. Data subsequently attained from this mouse model support a role for alphaB-crystallin and Hsp27 as clinical markers for tumor progression.

  9. Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes.

    Science.gov (United States)

    Wei, Li; Su, Yu-Kai; Lin, Chien-Min; Chao, Tsu-Yi; Huang, Shang-Pen; Huynh, Thanh-Tuan; Jan, Hsun-Jin; Whang-Peng, Jacqueline; Chiou, Jeng-Fong; Wu, Alexander T H; Hsiao, Michael

    2016-10-25

    Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.

  10. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model.

    Science.gov (United States)

    Achiwa, Koichi; Ishigami, Masatoshi; Ishizu, Yoji; Kuzuya, Teiji; Honda, Takashi; Hayashi, Kazuhiko; Hirooka, Yoshiki; Katano, Yoshiaki; Goto, Hidemi

    2016-01-29

    Nonalcoholic steatohepatitis (NASH) patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Several lines of evidence indicate that accumulation of lipopolysaccharide (LPS) and disruption of gut microbiota play contributory roles in HCC. Moreover, in a dextran sodium sulfate (DSS)-induced colitis model in mice, a high-fat diet increases portal LPS level and promotes hepatic inflammation and fibrosis. However, this diet-induced NASH model requires at least 50 weeks for carcinogenesis. In this study, we sought to determine whether increased intestinal permeability would aggravate liver inflammation and fibrosis and accelerate tumorigenesis in a diet-induced NASH model. Mice were fed a choline-deficient high-fat (CDHF) diet for 4 or 12 weeks. The DSS group was fed CDHF and intermittently received 1% DSS in the drinking water. Exposure to DSS promoted mucosal changes such as crypt loss and increased the number of inflammatory cells in the colon. In the DSS group, portal LPS levels were elevated at 4 weeks, and the proportions of Clostridium cluster XI in the fecal microbiota were elevated. In addition, levels of serum transaminase, number of lobular inflammatory cells, F4/80 staining-positive area, and levels of inflammatory cytokines were all elevated in the DSS group. Liver histology in the DSS group revealed severe fibrosis at 12 weeks. Liver tumors were detected in the DSS group at 12 weeks, but not in the other groups. Thus, DSS administration promoted liver tumors in a CDHF diet-induced NASH mouse over the short term, suggesting that the induction of intestinal inflammation and gut disruption of microbiota in NASH promote hepatic tumorigenesis.

  11. Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis

    Science.gov (United States)

    Pickard, Amanda J.; Sohn, Albert S. W.; Bartenstein, Thomas F.; He, Shan; Zhang, Yi; Gallo, James M.

    2016-01-01

    The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis – providing D2HG interstitial fluid concentrations – sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 μM awake and 117.6 ± 98.6 μM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis. PMID:27781195

  12. Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model.

    Science.gov (United States)

    Cranford, Taryn L; Velázquez, Kandy T; Enos, Reilly T; Bader, Jackie E; Carson, Meredith S; Chatzistamou, Ioulia; Nagarkatti, Mitzi; Murphy, E Angela

    2017-02-01

    Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

  13. Protection against N-nitrosodiethylamine and benzo[a]pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea.

    Science.gov (United States)

    Katiyar, S K; Agarwal, R; Zaim, M T; Mukhtar, H

    1993-05-01

    In recent years we and others have shown the cancer chemopreventive effects of green tea in several animal tumor models. In this study we assessed the cancer chemopreventive effects of water extract of green tea (WEGT) and the polyphenolic fraction (GTP) isolated from WEGT against N-nitrosodiethylamine (DEN)- and benzo[a]pyrene (BP)-induced forestomach and lung tumorigenesis in A/J mice. The protective effects, both in forestomach and lungs, were evident by a decrease in number of tumors and the percentage of mice with tumors when WEGT and GTP were fed to animals during initiation, post-initiation and entire period of tumorigenesis protocols. Oral feeding of 0.2% GTP in drinking water to mice afforded 68-82 and 39-66% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of pulmonary tumor multiplicity caused by DEN and BP, the protective effects of GTP were between 38-43 and 25-46% respectively. Similarly, oral feeding of 2.5% WEGT to mice also afforded 80-85 and 61-71% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of lung tumorigenesis, the protective effects of WEGT were 43-62 and 25-51% respectively. Histological studies of forestomach tumors showed significantly lower squamous cell carcinoma counts in GTP- and WEGT-fed groups of mice compared to carcinogen alone treated control group of mice. When pulmonary tumors were examined histologically, no adenocarcinomas were observed in GTP- and WEGT-fed groups of mice compared to 20% mice with adenocarcinomas in carcinogen alone treated control group. Oral feeding of GTP and WEGT in drinking water also showed significant enhancement in the activities of glutathione S-transferase and NADP(H): quinone reductase in liver, small bowel, stomach and lung. The results of this study suggest that green tea possesses chemopreventive effects against carcinogen-induced tumorigenesis in internal body organs, and that the mechanism of such effects may

  14. Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

    Energy Technology Data Exchange (ETDEWEB)

    Arumugam, Aadithya; Weng, Zhiping; Chaudhary, Sandeep C.; Afaq, Farrukh [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Elmets, Craig A. [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2014-08-29

    Highlights: • Targeting ODC to hair follicle augments skin carcinogenesis and invasive SCCs. • Hair follicle ODC expands stem cell compartment carrying CD34{sup +}/K15{sup +}/p63{sup +} keratinocytes. • Negatively regulated Notch1 is associated with expansion of stem cell compartment. - Abstract: Over-expression of ornithine decarboxylase (ODC) is known to be involved in the epidermal carcinogenesis. However, the mechanism by which it enhances skin carcinogenesis remains undefined. Recently, role of stem cells localized in various epidermal compartments has been shown in the pathogenesis of skin cancer. To direct ODC expression in distinct epidermal compartments, we have developed keratin 6 (K6)-ODC/SKH-1 and keratin 14 (K14)-ODC/SKH-1 mice and employed them to investigate the role of ODC directed to these epidermal compartments on UVB-induced carcinogenesis. K6-driven ODC over-expression directed to outer root sheath (ORS) of hair follicle was more effective in augmenting tumorigenesis as compared to mice where K14-driven ODC expression was directed to inter-follicular epidermal keratinocytes. Chronically UVB-irradiated K6-ODC/SKH-1 developed 15 ± 2.5 tumors/mouse whereas K14-ODC/SKH-1 developed only 6.8 ± 1.5 tumors/mouse. K6-ODC/SKH-1 showed augmented UVB-induced proliferation and much higher pro-inflammatory responses than K14-ODC/SKH-1 mice. Tumors induced in K6-ODC/SKH-1 were rapidly growing, invasive and ulcerative squamous cell carcinoma (SCC) showing decreased expression of epidermal polarity marker E-cadherin and enhanced mesenchymal marker, fibronectin. Interestingly, the number of CD34/CK15/p63 positive stem-like cells was significantly higher in chronically UVB-irradiated K6-ODC/SKH-1 as compared to K14-ODC/SKH-1 mice. Reduced Notch1 expression was correlated with the expansion of stem cell compartment in these animals. However, other signaling pathways such as DNA damage response or mTOR signaling pathways were not significantly different in

  15. A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations

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    Michael Buchert

    2015-11-01

    Full Text Available Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great extent by the genetic make-up of individual tumors and the combination of oncogenic mutations. In order to express throughout the intestinal epithelium a degradation-resistant β-catenin (Ctnnb1, which lacks the first 131 amino acids, we inserted an epitope-tagged ΔN(1-131-β-catenin-encoding cDNA as a knock-in transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33ΔN-Bcat mice showed an increase in the constitutive Wnt/β-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33ΔN-Bcat mice spontaneously developed aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to those observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7  and Tenascin-C, which are most highly expressed in benign human adenomas and early tumor stages, were upregulated in pre-malignant tissue of gpA33ΔN-Bcat mice, but those Wnt target genes associated with excessive proliferation (i.e. Cdnn1, myc were not. We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33ΔN-Bcat mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of ΔN(1-131-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.

  16. U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3

    Directory of Open Access Journals (Sweden)

    Chan Wai-Yee

    2005-06-01

    Full Text Available Abstract Background Insensitivity of advanced-stage prostate cancer to androgen ablation therapy is a serious problem in clinical practice because it is associated with aggressive progression and poor prognosis. Targeted therapeutic drug discovery efforts are thwarted by lack of adequate knowledge of gene(s associated with prostate tumorigenesis. Therefore there is the need for studies to provide leads to targeted intervention measures. Here we propose that stable expression of U94, a tumor suppressor gene encoded by human herpesvirus 6A (HHV-6A, could alter gene expression and thereby inhibit the tumorigenicity of PC3 cell line. Microarray gene expression profiling on U94 recombinant PC3 cell line could reveal genes that would elucidate prostate cancer biology, and hopefully identify potential therapeutic targets. Results We have shown that stable expression of U94 gene in PC3 cell line inhibited its focus formation in culture, and tumorigenesis in nude mice. Moreover gene expression profiling revealed dramatic upregulation of FN 1 (fibronectin, 91 ± 16-fold, and profound downregulation of ANGPTL 4 (angiopoietin-like-4, 20 ± 4-fold in U94 recombinant PC3 cell line. Quantitative real-time polymerase chain reaction (QRT-PCR analysis showed that the pattern of expression of FN 1 and ANGPTL 4 mRNA were consistent with the microarray data. Based on previous reports, the findings in this study implicate upregulation of FN 1 and downregulation of ANGPTL 4 in the anti tumor activity of U94. Genes with cancer inhibitory activities that were also upregulated include SERPINE 2 (serine/cysteine protease inhibitor 2, 7 ± 1-fold increase and ADAMTS 1 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7 ± 2-fold increase. Additionally, SPUVE 23 (serine protease 23 that is pro-tumorigenic was significantly downregulated (10 ± 1-fold. Conclusion The dramatic upregulation of FN 1 and downregulation of ANGPTL 4 genes in PC3 cell line

  17. Scaling of titanium implants entrains inflammation-induced osteolysis

    Science.gov (United States)

    Eger, Michal; Sterer, Nir; Liron, Tamar; Kohavi, David; Gabet, Yankel

    2017-01-01

    With millions of new dental and orthopedic implants inserted annually, periprosthetic osteolysis becomes a major concern. In dentistry, peri-implantitis management includes cleaning using ultrasonic scaling. We examined whether ultrasonic scaling releases titanium particles and induces inflammation and osteolysis. Titanium discs with machined, sandblasted/acid-etched and sandblasted surfaces were subjected to ultrasonic scaling and we physically and chemically characterized the released particles. These particles induced a severe inflammatory response in macrophages and stimulated osteoclastogenesis. The number of released particles and their chemical composition and nanotopography had a significant effect on the inflammatory response. Sandblasted surfaces released the highest number of particles with the greatest nanoroughness properties. Particles from sandblasted/acid-etched discs induced a milder inflammatory response than those from sandblasted discs but a stronger inflammatory response than those from machined discs. Titanium particles were then embedded in fibrin membranes placed on mouse calvariae for 5 weeks. Using micro-CT, we observed that particles from sandblasted discs induced more osteolysis than those from sandblasted/acid-etched discs. In summary, ultrasonic scaling of titanium implants releases particles in a surface type-dependent manner and may aggravate peri-implantitis. Future studies should assess whether surface roughening affects the extent of released wear particles and aseptic loosening of orthopedic implants. PMID:28059080

  18. Local inflammation induces complement crosstalk which amplifies the antimicrobial response.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2009-01-01

    Full Text Available By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRPratioL-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRPratioL-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRPratioL-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection.

  19. Inflammation induced by perfluorocarbon liquid: intra- and postoperative use.

    Science.gov (United States)

    Figueroa, Marta S; Casas, Diego Ruiz

    2014-01-01

    Perfluorocarbon liquids (PFCLs) are useful and safe surgical tools in vitreoretinal surgery. The use of PFCL as a tamponade has been controversial due to the corneal toxicity, retinal infiltration, and inflammatory reaction in experimental studies. Several authors have studied in humans the anatomical and functional outcome and adverse effects of perfluorocarbon liquids used as short-, medium-, and long-term tamponade. PFCLs develop dispersion a few days after injection and droplets may move into the anterior chamber and cause corneal endothelial damage. When PFCLs are used as postoperative tamponades for more than one week, a foreign-body inflammatory reaction is observed in up to 30% of cases but such a reaction does not induce PVR, and it resolves after removal of PFCLs. Although most clinical studies have found no signs of retinal toxicity such as progressive visual acuity deterioration or macular anatomical changes, few performed ERG or retinal histological analysis.

  20. Inflammation Induced by Perfluorocarbon Liquid: Intra- and Postoperative Use

    Directory of Open Access Journals (Sweden)

    Marta S. Figueroa

    2014-01-01

    Full Text Available Perfluorocarbon liquids (PFCLs are useful and safe surgical tools in vitreoretinal surgery. The use of PFCL as a tamponade has been controversial due to the corneal toxicity, retinal infiltration, and inflammatory reaction in experimental studies. Several authors have studied in humans the anatomical and functional outcome and adverse effects of perfluorocarbon liquids used as short-, medium-, and long-term tamponade. PFCLs develop dispersion a few days after injection and droplets may move into the anterior chamber and cause corneal endothelial damage. When PFCLs are used as postoperative tamponades for more than one week, a foreign-body inflammatory reaction is observed in up to 30% of cases but such a reaction does not induce PVR, and it resolves after removal of PFCLs. Although most clinical studies have found no signs of retinal toxicity such as progressive visual acuity deterioration or macular anatomical changes, few performed ERG or retinal histological analysis.

  1. Sustained Inflammation Induces Degeneration of the Temporomandibular Joint

    Science.gov (United States)

    Wang, X.D.; Kou, X.X.; Mao, J.J.; Gan, Y.H.; Zhou, Y.H.

    2012-01-01

    The temporomandibular joint (TMJ) undergoes degenerative changes among patients who suffer from arthritis, and yet the pathogenesis of TMJ osteoarthritis and rheumatoid arthritis is poorly understood. We hypothesized that sustained inflammation in the TMJ induces structural abnormalities, and accordingly characterized the disc and synovium in a novel model with double injections of complete Freund’s adjuvant (CFA), using behavioral, morphological, cellular, and molecular assessments. Thirty-five days following double CFA injections in seven-week-old female Sprague-Dawley rats, the disc in the CFA-induced inflammation group demonstrated multiple degenerative changes, including marked thickening, opacity, and deformation. The discs in the CFA group further showed significantly greater wet and net weights, and elevated collagen, aggrecan, and total glycosaminoglycan contents. The synovium in the CFA-induced inflammation group showed marked infiltration of mononucleated cells and accumulated sub-synovial adipose tissue. Both the disc and synovium had significantly higher iNOS and IL-1β mRNA expression than controls (saline injections). These findings are consistent with our hypothesis that sustained TMJ inflammation, even within the presently observed 35 days, may be a predisposing factor for structural abnormalities. Insight into TMJ inflammation and degeneration is anticipated to improve our understanding of the pathogenesis of TMJ arthritis and help design clinically relevant strategies for tissue engineering. PMID:22427270

  2. Study on MCP-1 related to inflammation induced by biomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Ding Tingting [Ninth People' s Hospital, School of Medicine, Shanghai Jiao Tong University/Shanghai Biomaterials Research and Testing Center, Shanghai 200023 (China); Sun Jiao [Shanghai Key Laboratory of Stomatology, Shanghai 200023 (China); Zhang Ping, E-mail: jiaosun59@yahoo.co [School of Life Science, East China Normal University, Shanghai 200062 (China)

    2009-06-15

    The study of inflammation is important for understanding the reaction between biomaterials and the human body, in particular, the interaction between biomaterials and immune system. In the current study, rat macrophages were induced by multiple biomaterials with different biocompatibilities, including polyvinyl chloride (PVC) containing 8% of organic tin, a positive control material with cellular toxicity. Human umbilical vein endothelial cells (ECV-304), cultured with PRMI-1640, were detached from cells cultured with the supernatant of macrophages containing TNF-alpha and IL-1beta because of stimulation by biomaterials. The cells were then treated with different biomaterials. Then both TNF-alpha and IL-1beta in macrophages were detected by ELISA. Levels of monocyte chemoattractant protein-1 (MCP-1) were measured by RT-PCR. The results suggested that the expression of TNF-alpha and IL-1beta was elevated by polytetrafluoroethylene (PTFE), polylactic-co-glycolic acid (PLGA) and American NPG alloy (p < 0.001). The level of MCP-1 cultured in supernatant of macrophages was higher than in PRMI-1640 with the same biomaterials. And the exposure to PTFE, PLGA and NPG resulted in the high expression of MCP-1 (p < 0.001) following cytokine stimulation. MCP-1 was also significantly expressed in beta-tricalcium phosphate (beta-TCP) and calcium phosphate cement samples (CPC) (p < 0.01). Thus, TNF-alpha, IL-1beta and MCP-1 had played an important role in the immune reaction induced by biomaterials and there was a close relationship between the expression of cytokines and biomcompatibility of biomaterials. Furthermore, these data suggested that MCP-1 was regulated by TNF-alpha and IL-1beta, and activated by both cytokines and biomaterials. The data further suggested that the expression of MCP-1 could be used as a marker to indicate the degree of immune reaction induced by biomaterials.

  3. Periodontal inflammation induced by chronic ethanol consumption in ovariectomized rats

    OpenAIRE

    2016-01-01

    The immune system plays an important role in the pathogenesis of periodontal diseases. The host may modulate periodontal inflammatory reactions and it determines variances in the individual susceptibility and in the periodontal disease progression speed. Osteoporosis and alcoholism are described as risk indicators of periodontal disease among the systemic acquired factors. Objective: The current study aims to analyze chronic alcohol consumption influence on induced periodontitis in rats prese...

  4. The features of skin inflammation induced by lupus serum.

    Science.gov (United States)

    Liu, Lena; Xu, Guangqion; Dou, Hui; Deng, Guo-Min

    2016-04-01

    We recently developed a model of lupus serum-induced skin inflammation, which was used to study the pathogenesis of skin injury in systemic lupus erythematosus (SLE). We further characterized the features of lupus serum-induced skin inflammation. This skin inflammation was evident within 3h and lasted for at least two weeks. The skin inflammation was characterized by an influx of monocytic, CD11b+cells and by a scarcity of T and B lymphocytes. Depletion of IgG from the serum abrogated the skin inflammatory response. The skin inflammation was related to lupus patients' skin history but not to SLE disease activity and type of autoantibody. The expression of TNFR1, NF-kB and MCP-1 was increased locally in skin lesions. The TLR9 ligand and lupus serum act synergistically to trigger skin inflammation. These findings suggest that this novel model is valuable for the study of the pathogenesis and therapy of skin injury in SLE.

  5. Increased hypothalamic serotonin turnover in inflammation-induced anorexia

    OpenAIRE

    Dwarkasing, J.T.; Witkamp, R F; Boekschoten, M.V.; Laak, ter, H.J.; Heins, M.S.; Norren, van, K.

    2016-01-01

    Background Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS....

  6. Increased hypothalamic serotonin turnover in inflammation-induced anorexia

    NARCIS (Netherlands)

    Dwarkasing, J.T.; Witkamp, R.F.; Boekschoten, M.V.; Laak, ter M.C.; Heins, M.S.; Norren, van K.

    2016-01-01

    Background: Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections b

  7. Lycopene metabolite, apo-10'-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice.

    Science.gov (United States)

    Ip, Blanche C; Hu, Kang-Quan; Liu, Chun; Smith, Donald E; Obin, Martin S; Ausman, Lynne M; Wang, Xiang-Dong

    2013-12-01

    Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.

  8. Ras-Directed N-Glycoproteins Are Novel Early Biomarkers for Tumorigenesis and Malignant Transformation and Therapeutic Targets of Neurofibromatosis Type 1

    Science.gov (United States)

    2014-08-01

    phosphorylates Ser192 in MGAT5B in MPNST cells. Moreover, wild type MGAT5B protein locates in the Golgi apparatus whereas mutated MGAT5BS192A protein...to the Golgi apparatus to attenuate MGAT5B-mediated glycosylation and phosphorylation of kinase receptors. Targeting MGAT5-mediated glycosylation of...tumorigenesis in Nf1+/-;p53+/- mice (bottom). Because proteins travelling to the Golgi apparatus for the consequent steps of glycosylation must be

  9. Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE{sub 2} and IL-6

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Xinhua [Department of Liver, Biliary And Pancreatic Tumors, Hubei Cancer Hospital, Wuhan 430079 (China); Chen, Xuewei; Li, Ying; Ke, Zunqiong [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Guo, Austin M. [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Chen, Honglei, E-mail: hl-chen@whu.edu.cn [Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-09-15

    M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE{sub 2} and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE{sub 2}/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE{sub 2} or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE{sub 2} and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer. - Highlights: • Isoliquiritigenin (ISL) prevents colitis-associated tumorigenesis. • ISL inhibits M2 macrophage polarization in vivo and in vitro. • ISL inhibits PGE{sub 2} and IL-6 signaling in colitis-associated tumorigenesis. • ISL may be an attractive candidate agent for

  10. Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Shiaw-Wei Tyan

    Full Text Available It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer-associated fibroblasts (CAFs had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs isolated from the same patients. The expression level of hepatocyte growth factor (HGF in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these "educated" NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling.

  11. Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis

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    Michael I. Carr

    2016-09-01

    Full Text Available ATM phosphorylation of Mdm2-S394 is required for robust p53 stabilization and activation in DNA-damaged cells. We have now utilized Mdm2S394A knockin mice to determine that phosphorylation of Mdm2-S394 regulates p53 activity and the DNA damage response in lymphatic tissues in vivo by modulating Mdm2 stability. Mdm2-S394 phosphorylation delays lymphomagenesis in Eμ-myc transgenic mice, and preventing Mdm2-S394 phosphorylation obviates the need for p53 mutation in Myc-driven tumorigenesis. However, irradiated Mdm2S394A mice also have increased hematopoietic stem and progenitor cell functions, and we observed decreased lymphomagenesis in sub-lethally irradiated Mdm2S394A mice. These findings document contrasting effects of ATM-Mdm2 signaling on p53 tumor suppression and reveal that destabilizing Mdm2 by promoting its phosphorylation by ATM would be effective in treating oncogene-induced malignancies, while inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies.

  12. Efficacy of Polyphenon E, Red Ginseng, and Rapamycin on Benzo(apyrene-Induced Lung Tumorigenesis in A/J Mice

    Directory of Open Access Journals (Sweden)

    Ying Yan

    2006-01-01

    Full Text Available The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(apyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity × tumor volume in a dose-dependent fashion. Polyphenon E (2% wt/wt in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.

  13. Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways.

    Science.gov (United States)

    Sharov, Andrey A; Mardaryev, Andrei N; Sharova, Tatyana Y; Grachtchouk, Marina; Atoyan, Ruzanna; Byers, H Randolph; Seykora, John T; Overbeek, Paul; Dlugosz, Andrzej; Botchkarev, Vladimir A

    2009-09-01

    Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways.

  14. The FGFR4-G388R polymorphism promotes mitochondrial STAT3 serine phosphorylation to facilitate pituitary growth hormone cell tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Toru Tateno

    2011-12-01

    Full Text Available Pituitary tumors are common intracranial neoplasms, yet few germline abnormalities have been implicated in their pathogenesis. Here we show that a single nucleotide germline polymorphism (SNP substituting an arginine (R for glycine (G in the FGFR4 transmembrane domain can alter pituitary cell growth and hormone production. Compared with FGFR4-G388 mammosomatotroph cells that support prolactin (PRL production, FGFR4-R388 cells express predominantly growth hormone (GH. Growth promoting effects of FGFR4-R388 as evidenced by enhanced colony formation was ascribed to Src activation and mitochondrial serine phosphorylation of STAT3 (pS-STAT3. In contrast, diminished pY-STAT3 mediated by FGFR4-R388 relieved GH inhibition leading to hormone excess. Using a knock-in mouse model, we demonstrate the ability of FGFR4-R385 to promote GH pituitary tumorigenesis. In patients with acromegaly, pituitary tumor size correlated with hormone excess in the presence of the FGFR4-R388 but not the FGFR4-G388 allele. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders.

  15. The FGFR4-G388R polymorphism promotes mitochondrial STAT3 serine phosphorylation to facilitate pituitary growth hormone cell tumorigenesis.

    Science.gov (United States)

    Tateno, Toru; Asa, Sylvia L; Zheng, Lei; Mayr, Thomas; Ullrich, Axel; Ezzat, Shereen

    2011-12-01

    Pituitary tumors are common intracranial neoplasms, yet few germline abnormalities have been implicated in their pathogenesis. Here we show that a single nucleotide germline polymorphism (SNP) substituting an arginine (R) for glycine (G) in the FGFR4 transmembrane domain can alter pituitary cell growth and hormone production. Compared with FGFR4-G388 mammosomatotroph cells that support prolactin (PRL) production, FGFR4-R388 cells express predominantly growth hormone (GH). Growth promoting effects of FGFR4-R388 as evidenced by enhanced colony formation was ascribed to Src activation and mitochondrial serine phosphorylation of STAT3 (pS-STAT3). In contrast, diminished pY-STAT3 mediated by FGFR4-R388 relieved GH inhibition leading to hormone excess. Using a knock-in mouse model, we demonstrate the ability of FGFR4-R385 to promote GH pituitary tumorigenesis. In patients with acromegaly, pituitary tumor size correlated with hormone excess in the presence of the FGFR4-R388 but not the FGFR4-G388 allele. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders.

  16. Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells.

    Science.gov (United States)

    Zhou, Fuling; Li, Ming; Wei, Yongchang; Lin, Kevin; Lu, Yue; Shen, Jianjun; Johanning, Gary L; Wang-Johanning, Feng

    2016-12-20

    Human endogenous retrovirus type K (HERV-K) Env protein was previously demonstrated to be overexpressed in human breast cancer (BC) cells and tissues. However, the molecular pathways driving the specific alterations are unknown. We now show that knockdown of its expression with an shRNA (shRNAenv) blocked BC cell proliferation, migration, and invasion. shRNAenv transduction also attenuated the ability of BC cells to form tumors, and notably prevented metastasis. Mechanistically, downregulation of HERV-K blocked expression of tumor-associated genes that included Ras, p-RSK, and p-ERK. The major upstream regulators influenced by HERV-K knockdown were p53, TGF- β1, and MYC. Of interest, when the HERV-K env gene was overexpressed in shRNAenv-transduced BC cells using an HERV-K env expression vector, Ras/Raf/MEK/ERK pathway signaling was restored. CDK5, which alters p53 phosphorylation in some cancers, was upregulated and p53 was downregulated when HERV-K was overexpressed. CDK5 is also a mediator of TGF-β1-induced epithelial-mesenchymal transition and migration in cancer cells, and is involved in tumor formation. Importantly, reductions in migration, invasion, and transformation of BC cells stably transduced with shRNAenv was reversed after adding back a vector with a synonymous mutation of HERV-K env. Taken together, these results indicate that HERV-K Env protein plays an important role in tumorigenesis and metastasis of BC.

  17. Tumorigenesis of mammary gland by 7,12-dimethylbenz(a)anthracene during pregnancy: relationship with DNA synthesis.

    Science.gov (United States)

    Sinha, D K; Pazik, J E

    1981-06-15

    The relationship between mammary cell proliferation during pregnancy and susceptibility to 7,12-dimethylbenz(a)anthracene (DMBA) was examined. DMBA was administered intravenously to Sprague-Dawley rats on the 5th, 10th or 15th day of pregnancy. [3H]thymidine labelling index (LI) of the mammary cells at the time of treatment with the carcinogen was determined and found to be higher in the pregnant rats than in age-matched virgin controls. In spite of the high proliferative index of the mammary cells, significant inhibition of tumorigenesis occurred in the pregnancy rats allowed to complete pregnancy and parturition following treatment with DMBA. However, when pregnancy was terminated by cesarian section shortly after treatment with DMBA, there was a significantly higher tumor incidence as compared to the "full-term" rats. It was observed that the earlier the pregnancy was terminated, the greater was the incidence of mammary tumors. This would indicate that the inhibitory effect of pregnancy is related to changes occurring during the later half of gestation. The differentiation of mammary cells for milk synthesis as pregnancy progresses is postulated to be a major reason for the observed refractoriness of the mammary cells to DMBA at that time.

  18. Neutrophil infiltration favors colitis-associated tumorigenesis by activating the interleukin-1 (IL-1)/IL-6 axis.

    Science.gov (United States)

    Wang, Y; Wang, K; Han, G-C; Wang, R-X; Xiao, H; Hou, C-M; Guo, R-F; Dou, Y; Shen, B-F; Li, Y; Chen, G-J

    2014-09-01

    Neutrophil infiltration is a key event in chronic intestinal inflammation and associated colorectal cancer, but how these cells support cancer development is poorly understood. In this study, using a mouse model of colitis-associated cancer (CAC), we have demonstrated that infiltrated neutrophils produce large amounts of interleukin-1 (IL)-1β that is critical for the development of CAC. Depletion of neutrophil or blockade of IL-1β activity significantly reduced mucosal damage and tumor formation. This protumorigenic function of IL-1β was mainly attributed to increased IL-6 secretion by intestine-resident mononuclear phagocytes (MPs). Furthermore, commensal flora-derived lipopolysaccharide (LPS) was identified to trigger IL-1β expression in neutrophils. Importantly, accumulation of IL-1β-expressing neutrophils was seen in lesions of patients suffering from ulceratic CAC and these infiltrated neutrophils induced IL-6 production by intestinal MPs in an IL-1β-dependent manner. Overall, these findings reveal that in CAC milieu, infiltrating neutrophils secrete IL-1β that promotes tumorigenesis by inducing IL-6 production by intestinal MPs.

  19. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.

    Science.gov (United States)

    Kinross, Kathryn M; Montgomery, Karen G; Kleinschmidt, Margarete; Waring, Paul; Ivetac, Ivan; Tikoo, Anjali; Saad, Mirette; Hare, Lauren; Roh, Vincent; Mantamadiotis, Theo; Sheppard, Karen E; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L; Christensen, James G; Cullinane, Carleen; Hicks, Rodney J; Pearson, Richard B; Johnstone, Ricky W; McArthur, Grant A; Phillips, Wayne A

    2012-02-01

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.

  20. Tripartite interactions between Wnt signaling, Notch and Myb for stem/progenitor cell functions during intestinal tumorigenesis

    Directory of Open Access Journals (Sweden)

    Markus Germann

    2014-11-01

    Full Text Available Deletion studies confirm Wnt, Notch and Myb transcriptional pathway engagement in intestinal tumorigenesis. Nevertheless, their contrasting and combined roles when activated have not been elucidated. This is important as these pathways are not ablated but rather are aberrantly activated during carcinogenesis. Using ApcMin/+ mice as a source of organoids we documented their transition, on a clone-by-clone basis, to cyst-like spheres with constitutively activated Wnt pathway, increased self-renewal and growth and reduced differentiation. We then looked at this transition when Myb and/or Notch1 are activated. Activated Notch promoted cyst-like organoids. Conversely growth and propagation of cyst-like, but not normal organoids were Notch-independent. Activated Myb promoted normal, but not cyst-like organoids. Interestingly the Wnt, Notch and Myb pathways were all involved in regulating the expression of the intestinal stem cell (ISC gene Lgr5 in organoids, while ISC gene and Notch target Olfm4 was dominantly repressed by Wnt. These findings parallel mouse intestinal adenoma formation where Notch promoted the initiation, but not growth, of Wnt-driven Olfm4-repressed colon tumors. Also Myb was essential for colon tumor initiation and collateral mouse pathologies. These data reveal the complex interplay and hierarchy of transcriptional networks that operate in ISCs and uncover a shift in pathway-dependencies during tumor initiation.

  1. Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation.

    Science.gov (United States)

    Shukla, Pradeep K; Chaudhry, Kamaljit K; Mir, Hina; Gangwar, Ruchika; Yadav, Nikki; Manda, Bhargavi; Meena, Avtar S; Rao, RadhaKrishna

    2016-03-07

    Alcohol consumption is one of the major risk factors for colorectal cancer. However, the mechanism involved in this effect of alcohol is unknown. We evaluated the effect of chronic ethanol feeding on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in mouse colon. Inflammation in colonic mucosa was assessed at a precancerous stage by evaluating mucosal infiltration of neutrophils and macrophages, and analysis of cytokine and chemokine gene expression. Chronic ethanol feeding significantly increased the number and size of polyps in colon of AOM/DSS treated mice. Confocal microscopic and immunoblot analyses showed a significant elevation of phospho-Smad, VEGF and HIF1α in the colonic mucosa. RT-PCR analysis at a precancerous stage indicated that ethanol significantly increases the expression of cytokines IL-1α, IL-6 and TNFα, and the chemokines CCL5/RANTES, CXCL9/MIG and CXCL10/IP-10 in the colonic mucosa of AOM/DSS treated mice. Confocal microscopy showed that ethanol feeding induces a dramatic elevation of myeloperoxidase, Gr1 and CD68-positive cells in the colonic mucosa of AOM/DSS-treated mice. Ethanol feeding enhanced AOM/DSS-induced suppression of tight junction protein expression and elevated cell proliferation marker, Ki-67 in the colonic epithelium. This study demonstrates that chronic ethanol feeding promotes colonic tumorigenesis potentially by enhancing inflammation and elevation of proinflammatory cytokines and chemokines.

  2. P-Selectin-Mediated Adhesion between Platelets and Tumor Cells Promotes Intestinal Tumorigenesis in Apc(Min/+) Mice.

    Science.gov (United States)

    Qi, Cuiling; Li, Bin; Guo, Simei; Wei, Bo; Shao, Chunkui; Li, Jialin; Yang, Yang; Zhang, Qianqian; Li, Jiangchao; He, Xiaodong; Wang, Lijing; Zhang, Yajie

    2015-01-01

    Studies have indicated that platelets play an important role in tumorigenesis, and an abundance of platelets accumulate in the ovarian tumor microenvironment outside the vasculature. However, whether cancer cells recruit platelets within intestinal tumors and how they signal adherent platelets to enter intestinal tumor tissues remain unknown. Here, we unexpectedly found that large numbers of platelets were deposited within human colorectal tumor specimens using immunohistochemical staining, and these platelets were fully associated with tumor development. We further report the robust adhesion of platelet aggregates to tumor cells within intestinal tumors, which occurs via a mechanism that is dependent on P-selectin (CD62P), a cell adhesion molecule that is abundantly expressed on activated platelets. Using spontaneous intestinal tumor mouse models, we determined that the genetic deletion of P-selectin suppressed intestinal tumor growth, which was rescued by the infusion of wild-type platelets but not P-selectin(-/-) platelets. Mechanistically, platelet adhesion to tumor cells induced the secretion of vascular endothelial growth factor (VEGF) to promote angiogenesis and accelerate intestinal tumor cell proliferation. Our results indicate that the adherence of platelets to tumor cells could promote tumor growth and metastasis. By targeting this platelet-tumor cell interaction, recombinant soluble P-selectin may have therapeutic value for the treatment of intestinal tumors.

  3. Yes-associated protein in the liver: Regulation of hepatic development, repair, cell fate determination and tumorigenesis.

    Science.gov (United States)

    Nguyen, Quy; Anders, Robert A; Alpini, Gianfranco; Bai, Haibo

    2015-10-01

    The liver is a vital organ that plays a major role in many bodily functions from protein production and blood clotting to cholesterol, glucose and iron metabolism and nutrition storage. Maintenance of liver homeostasis is critical for these essential bodily functions and disruption of liver homeostasis causes various kinds of liver diseases, some of which have high mortality rate. Recent research advances of the Hippo signalling pathway have revealed its nuclear effector, Yes-associated protein, as an important regulator of liver development, repair, cell fate determination and tumorigenesis. Therefore, a precise control of Yes-associated protein activity is critical for the maintenance of liver homeostasis. This review is going to summarize the discoveries on how the manipulation of Yes-associated protein activity affects liver homeostasis and induces liver diseases and the regulatory mechanisms that determine the Yes-associated protein activity in the liver. Finally, we will discuss the potential of targeting Yes-associated protein as therapeutic strategies in liver diseases.

  4. Mesenchymal stem cells develop tumor tropism but do not accelerate breast cancer tumorigenesis in a somatic mouse breast cancer model.

    Directory of Open Access Journals (Sweden)

    Lydia Usha

    Full Text Available The role of mesenchymal stem cells (MSCs on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves.

  5. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.

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    Mark M Pomerantz

    2010-11-01

    Full Text Available Genome-wide association studies (GWAS have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.

  6. Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice.

    Science.gov (United States)

    Shao, Shujuan; Liu, Rong; Wang, Yang; Song, Yongmei; Zuo, Lihui; Xue, Liyan; Lu, Ning; Hou, Ning; Wang, Mingrong; Yang, Xiao; Zhan, Qimin

    2010-02-01

    Disruption of mitotic events contributes greatly to genomic instability and results in mutator phenotypes. Indeed, abnormalities of mitotic components are closely associated with malignant transformation and tumorigenesis. Here we show that ninein-like protein (Nlp), a recently identified BRCA1-associated centrosomal protein involved in microtubule nucleation and spindle formation, is an oncogenic protein. Nlp was found to be overexpressed in approximately 80% of human breast and lung carcinomas analyzed. In human lung cancers, this deregulated expression was associated with NLP gene amplification. Further analysis revealed that Nlp exhibited strong oncogenic properties; for example, it conferred to NIH3T3 rodent fibroblasts the capacity for anchorage-independent growth in vitro and tumor formation in nude mice. Consistent with these data, transgenic mice overexpressing Nlp displayed spontaneous tumorigenesis in the breast, ovary, and testicle within 60 weeks. In addition, Nlp overexpression induced more rapid onset of radiation-induced lymphoma. Furthermore, mouse embryonic fibroblasts (MEFs) derived from Nlp transgenic mice showed centrosome amplification, suggesting that Nlp overexpression mimics BRCA1 loss. These findings demonstrate that Nlp abnormalities may contribute to genomic instability and tumorigenesis and suggest that Nlp might serve as a potential biomarker for clinical diagnosis and therapeutic target.

  7. Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

    Science.gov (United States)

    Larive, Romain M.; Moriggi, Giulia; Menacho-Márquez, Mauricio; Cañamero, Marta; Álava, Enrique De; Alarcón, Balbino; Dosil, Mercedes; Bustelo, Xosé R.

    2014-05-01

    R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss- and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

  8. Intermittent hypoxia with or without hypercapnia is associated with tumorigenesis by decreasing the expression of brain derived neurotrophic factor and miR-34a in rats

    Institute of Scientific and Technical Information of China (English)

    Zhang Jing; Guo Xu; Shi Yanwei; Ma Jing; Wang Guangfa

    2014-01-01

    Background Very recent studies revealed that obstructive sleep apnoea (OSA) is a contributor of the increased incidence and mortality of cancer in humans,but mechanisms of how OSA promotes tumorigenesis remains largely unknown.We investigated whether intermittent hypoxia with and without hypercapnia plays a role in tumorigenesis.Methods First,Sprague-Dawley (SD) male rats (12 weeks old) were subjected to different hypoxia exposures:intermittent hypoxia and intermittent hypoxia with hypercapnia; continuous hypoxia and normal air.The systemic application of chronic fast rate hypoxia with or without hypercapnia mimicked severe OSA patients with apnoea/hypopnea index equivalent to 60 events per hour.Then routine blood tests were performed and the levels of brain derived neurotrophic factor (BDNF) and miR-34a were examined.Results In contrast to intermittent hypoxia with hypercapnia,both intermittent hypoxia and continuous hypoxia treatments caused significantly higher levels of haematology parameters than normoxia treatments.Compared to normoxia,intermittent hypoxia with hypercapnia exposure resulted in substantial decrease of serum BDNF and,miR-34a in the lower brainstem,while less pronounced results were found in intermittent hypoxia and continuous hypoxia exposure.Conclusions The exposure of intermittent hypoxia with or without hypercapnia,mimicking the situations in severe OSA patients,was associated with,or even promoted tumorigenesis.

  9. Characterization of newly established colorectal cancer cell lines: correlation between cytogenetic abnormalities and allelic deletions associated with multistep tumorigenesis

    Indian Academy of Sciences (India)

    Hans Gerdes; Abul Elahi; Quanguang Chen; Suresh C. Jhanwar

    2000-01-01

    We have established a series of 20 colorectal cancer cell lines and performed cytogenetic and RFLP analyses to show that the recurrent genetic abnormalities of chromosomes 1, 5, 17 and 18 associated with multistep tumorigenesis in colorectal cancer, and frequently detected as recurrent abnormalities in primary tumours, are also retained in long-term established cell lines. Earlier studies by us and other investigators showed that allelic losses of chromosomes 1 and 17 in primary colorectal cancers predicted poorer survival for the patients $(P = 0.03)$. We utilized the cell lines to identify specific chromosomal sites or gene(s) on chromosomes 1 and 17 which confer more aggressive phenotype. Cytogenetic deletions of chromosome 1p were detected in 14 out of the 20 (70%) cell lines, whereas allelic deletions for 1p using polymorphic markers were detected in 13 out of 18 (72%) informative cell lines for at least one polymorphic marker. We have performed Northern blotting, immunohistochemical staining (p53 mRNA, protein) and RFLP analysis using several probes including p53 and nm23. RFLP analysis using a total of seven polymorphic markers located on 17p and 17q arms showed allelic losses around the p53 locus in 16 out of the 20 cell lines (80%), four of which were losses of the p53 locus itself. In addition, seven cell lines (out of nine informative cases) also showed losses of the nm23 gene, four with concurrent losses of the p53 locus, while the remaining three were homozygous. In addition, five out of seven cell lines with nm23 deletions were derived from hepatic metastatic tumours, and one cell line was obtained from recurrent tumour. A comparison between allelic deletions of 1p and functional loss of nm23 gene revealed a close association between these two events in cell lines derived from hepatic metastasis. Following immunohistochemical staining, nine out of the twenty cell lines showed high levels (25–80%) of mutant p53, four showed intermediate levels (< 20

  10. Dietary administration of Nexrutine inhibits rat liver tumorigenesis and induces apoptotic cell death in human hepatocellular carcinoma cells

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    Shamshad Alam

    2015-01-01

    Full Text Available Epidemiological studies suggested that plant-based dietary supplements can reduce the risk of liver cancer. Nexrutine (NX, an herbal extract from Phellodendronamurense, has been shown to have anti-inflammatory, anti-microbial and anti-tumor activities. In the present study, we have shown the anti-tumor potential of NX against Solt-Farber model with elimination of PH, rat liver tumor induced by diethylnitrosoamine (DEN as carcinogen and 2-acetylaminofluorene (2-AAF as co-carcinogen. The elucidation of mechanistic pathways was explored in human liver cancer cells. Dietary intake of NX significantly decreased the cell proliferation and inflammation, as well as increased apoptosis in the liver sections of DEN/2-AAF-treated rats. Moreover, NX (2.5–10 μg/ml exposure significantly decreased the viability of liver cancer cells and modulated the levels of Bax and Bcl-2 proteins levels. NX treatment resulted in increased cytochrome-c release and cleavage of caspases 3 and 9. In addition, NX decreased the expression of CDK2, CDK4 and associated cyclins E1 and D1, while up-regulated the expression of p21, p27 and p53 expression. NX also enhanced phosphorylation of the mitogen-activated protein kinases (MAPKs ERK1/2, p38 and JNK1/2. Collectively, these findings suggested that NX-mediated protection against DEN/2-AAF-induced liver tumorigenesis involves decrease in cell proliferation and enhancement in apoptotic cell death of liver cancer cells.

  11. Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic Kras(G12D.).

    Science.gov (United States)

    Wang, I-C; Ustiyan, V; Zhang, Y; Cai, Y; Kalin, T V; Kalinichenko, V V

    2014-11-13

    Lung cancer is the leading cause of deaths in cancer patients in the United States. Identification of new molecular targets is clearly needed to improve therapeutic outcomes of this devastating human disease. Activating mutations in K-Ras oncogene and increased expression of FOXM1 protein are associated with poor prognosis in patients with non-small-cell lung cancer. Transgenic expression of activated Kras(G12D) in mouse respiratory epithelium is sufficient to induce lung adenocarcinomas; however, transcriptional mechanisms regulated by K-Ras during the initiation of lung cancer remain poorly understood. Foxm1 transcription factor, a downstream target of K-Ras, stimulates cellular proliferation during embryogenesis, organ repair and tumor growth, but its role in tumor initiation is unknown. In the present study, we used transgenic mice expressing Kras(G12D) under control of Sftpc promoter to demonstrate that Foxm1 was induced in type II epithelial cells before the formation of lung tumors. Conditional deletion of Foxm1 from Kras(G12D)-expressing respiratory epithelium prevented the initiation of lung tumors in vivo. The loss of Foxm1 inhibited expression of K-Ras target genes critical for the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, including Ikbkb, Nfkb1, Nfkb2, Rela, Jnk1, N-Myc, Pttg1 and Cdkn2a. Transgenic overexpression of activated FOXM1 mutant was sufficient to induce expression of these genes in alveolar type II cells. FOXM1 directly bound to promoter regions of Ikbkb, Nfkb2, N-Myc, Pttg1 and Cdkn2a, indicating that these genes are direct FOXM1 targets. FOXM1 is required for K-Ras-mediated lung tumorigenesis by activating genes critical for the NF-κB and JNK pathways.

  12. A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland

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    Hubert Pakula

    2017-01-01

    Full Text Available Prostate cancer (PCa is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR. Androgen deprivation therapy (ADT is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent.

  13. Circular RNA hsa_circ_0001564 facilitates tumorigenesis of osteosarcoma via sponging miR-29c-3p.

    Science.gov (United States)

    Li, Ji-Feng; Song, Yu-Ze

    2017-08-01

    Circular RNAs are a novel type of non-coding RNAs generated from back splicing, which has been verified to mediate multiple tumorigenesis. However, the role of circular RNA in osteosarcoma is still unclear. In this study, we preliminarily screened the circular RNAs expression profiles in osteosarcoma and investigated the potential regulation mechanism. The circular RNAs expression profiles in osteosarcoma were screened using circular RNA microarray analysis, and results showed that there were 1152 circular RNAs upregulated and 915 circular RNAs downregulated in tumor tissue compared to adjacent tissue. Hsa_circ_0001564, located at 5q35.3 and its associated gene symbol is CANX, was one of the significantly overexpressed circular RNAs in osteosarcoma tissue, as well as in osteosarcoma cell lines. In functional experiments, hsa_circ_001564 knockdown significantly suppressed the proliferation activity, induced cell-cycle arrest in G0/G1 phase, and promoted apoptosis in HOS and MG-63 cells. Subsequently, we explored the probable mechanism of hsa_circ_001564, and fortunately, bioinformatics analysis revealed that miR-29c-3p contained the complementary binding region with hsa_circ_0001564, which was confirmed by dual-luciferase reporter assay. Moreover, rescue experiments illustrated that miR-29c-3p could reverse the oncogenesis effect of hsa_circ_001564. Our study discovers that hsa_circ_0001564 acts as miR-29c-3p sponge to mediate the tumorigenicity, which could act as a potential biomarker for the osteosarcoma and provide a novel insight for competing endogenous RNA mechanism in osteosarcoma.

  14. A context-specific role for retinoblastoma protein-dependent negative growth control in suppressing mammary tumorigenesis.

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    Sarah M Francis

    Full Text Available BACKGROUND: The ability to respond to anti-growth signals is critical to maintain tissue homeostasis and loss of this negative growth control safeguard is considered a hallmark of cancer. Negative growth regulation generally occurs during the G0/G1 phase of the cell cycle, yet the redundancy and complexity among components of this regulatory network has made it difficult to discern how negative growth cues protect cells from aberrant proliferation. METHODOLOGY/PRINCIPAL FINDINGS: The retinoblastoma protein (pRB acts as the final barrier to prevent cells from entering into the cell cycle. By introducing subtle changes in the endogenous mouse Rb1 gene (Rb1(ΔL, we have previously shown that interactions at the LXCXE binding cleft are necessary for the proper response to anti-growth signals such as DNA damage and TGF-β, with minimal effects on overall development. This disrupts the balance of pro- and anti-growth signals in mammary epithelium of Rb1(ΔL/ΔL mice. Here we show that Rb1(ΔL/ΔL mice are more prone to mammary tumors in the Wap-p53(R172H transgenic background indicating that negative growth regulation is important for tumor suppression in these mice. In contrast, the same defect in anti-growth control has no impact on Neu-induced mammary tumorigenesis. CONCLUSIONS/SIGNIFICANCE: Our work demonstrates that negative growth control by pRB acts as a crucial barrier against oncogenic transformation. Strikingly, our data also reveals that this tumor suppressive effect is context-dependent.

  15. RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis.

    Science.gov (United States)

    Di Fiore, Riccardo; D'Anneo, Antonella; Tesoriere, Giovanni; Vento, Renza

    2013-08-01

    Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell type-specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer.

  16. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.

    Science.gov (United States)

    Pemov, A; Li, H; Patidar, R; Hansen, N F; Sindiri, S; Hartley, S W; Wei, J S; Elkahloun, A; Chandrasekharappa, S C; Boland, J F; Bass, S; Mullikin, J C; Khan, J; Widemann, B C; Wallace, M R; Stewart, D R

    2017-01-09

    Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDRNF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.Oncogene advance online publication, 9 January 2017; doi:10.1038/onc.2016.464.

  17. Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis.

    Science.gov (United States)

    Webb, Meghan; Emberley, Ethan D; Lizardo, Michael; Alowami, Salem; Qing, Gefei; Alfia'ar, Abdullah; Snell-Curtis, Linda J; Niu, Yulian; Civetta, Alberto; Myal, Yvonne; Shiu, Robert; Murphy, Leigh C; Watson, Peter H

    2005-02-17

    The human psoriasin (S100A7) gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization) with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression.

  18. Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis

    Directory of Open Access Journals (Sweden)

    Niu Yulian

    2005-02-01

    Full Text Available Abstract Background The human psoriasin (S100A7 gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. Methods On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. Results Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. Conclusion These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression.

  19. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats.

    Science.gov (United States)

    Bishayee, Anupam; Mandal, Animesh

    2014-10-01

    Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight and reversed intratumor histopathological alterations. TPE dose-dependently suppressed proliferating cell nuclear antigen and cyclin D1 expression, induced apoptosis, upregulated proapoptotic protein Bax, downregulated antiapoptotic protein Bcl-2 and diminished the expression of nuclear and cytosolic β-catenin in mammary tumors. Our results clearly provide the first experimental evidence that TPE exerts chemopreventive effect in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through alteration of Bax/Bcl-2 ratio. Mechanistically, TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during an early-stage breast cancer. These results may encourage further

  20. The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma.

    Science.gov (United States)

    Wang, J; Tang, X; Weng, W; Qiao, Y; Lin, J; Liu, W; Liu, R; Ma, L; Yu, W; Yu, Y; Pan, Q; Sun, F

    2015-11-19

    Yes-associated protein (YAP) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). However, whether membrane protein can serve not only as a tumor marker that reflects YAP function but also as a therapeutic target that stimulates tumorigenesis in HCC remains unknown. Here we report that the membrane protein melanoma cell adhesion molecule (MCAM) was under positive regulation by YAP and was highly elevated in HCC cells. Within the MCAM promoter, we found the presence of a cAMP Response Element (CRE; -32 to -25 nt), which is conserved among species and is essential for YAP- and CREB-dependent regulation. Moreover, the interaction between CREB and YAP at the CRE site was dependent on PTPIY-WW domain interactions. However, MCAM expression was low and could not be regulated by YAP in breast and colon cancer cells because of the low levels of the acetyltransferase p300. In HCC cells, high levels of p300 facilitated the binding of YAP to the MCAM promoter, which in turn enhanced histone acetylation and polymerase II recruitment through the dissociation of the deacetylase Sirt1. These results suggest that MCAM is an HCC-specific target of YAP. In clinical serum samples, we found that the serum levels of MCAM were highly elevated in patients with HCC compared with healthy controls and with patients with cirrhosis, hepatitis, colon cancer and breast cancer. MCAM levels were shown to be a slightly better indicator than serum alpha-fetoprotein for predicting HCC. We further demonstrated that MCAM is essential for the survival and transformation of HCC. Mechanistically, MCAM induced translation initiation and the transcriptional activities of c-Jun/c-Fos. In addition, AKT activation had an essential role in the MCAM-promoted binding of eukaryotic initiation factor 4E to c-Jun/c-Fos mRNA. In conclusion, we demonstrated that MCAM may be a potential tumor marker and therapeutic target for the diagnosis and treatment of HCC.

  1. miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting Sirt1.

    Science.gov (United States)

    Zhang, Xia; Li, Yuehua; Wang, Dan; Wei, Xiaoer

    2017-09-07

    miR-22 has been shown to be frequently downregulated and act as a tumor suppressor in multiple cancers including breast cancers. However, the role of miR-22 in regulating the radioresistance of breast cancer cells, as well as its underlying mechanism is still not well understood. The expressions of miR-22 and sirt1 at mRNA and protein levels were examined by qRT-PCR and Western Blot. The effects of miR-22 overexpression and sirt1 knockdown on cell viability, apoptosis, radiosensitivity, γ-H2AX foci formation were evaluated by CCK-8 assay, flow cytometry, colony formation assay, and γ-H2AX foci formation assay, respectively. Luciferase reporter assay and qRT-PCR analysis were performed to confirm the interaction between miR-22 and sirt1. miR-22 was downregulated and sirt1 was upregulated at both mRNA and protein levels in breast cancer cells. miR-22 overexpression or sirt1 knockdown significantly suppressed viability, induced apoptosis, reduced survival fraction, and increased the number of γ-H2AX foci in breast cancer cells. Sirt1 was identified as a target of miR-22 and miR-22 negatively regulated sirt1 expression. Ectopic expression of sirt1 dramatically reversed the inhibitory effect of miR-22 on cell viability and promotive effect on apoptotic rates and radiosensitivity in breast cancer cells. miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting sirt1, providing a promising therapeutic target for breast cancer.

  2. Weight loss following diet-induced obesity does not alter colon tumorigenesis in the AOM mouse model.

    Science.gov (United States)

    Velázquez, Kandy T; Enos, Reilly T; Carson, Meredith S; Cranford, Taryn L; Bader, Jackie E; Chatzistamou, Ioulia; Singh, Udai P; Nagarkatti, Prakash S; Nagarkatti, Mitzi; Davis, J Mark; Carson, James A; Murphy, E Angela

    2016-10-01

    Obesity presents a significant public health concern given its association with increased cancer incidence, unfavorable prognosis, and metastasis. However, there is very little literature on the effects of weight loss, following obesity, on risk for colon cancer or liver cancer. Therefore, we sought to study whether intentional weight loss through diet manipulation was capable of mitigating colon and liver cancer in mice. We fed mice with a high-fat diet (HFD) comprised of 47% carbohydrates, 40% fat, and 13% protein for 20 wk to mimic human obesity. Subsequently, azoxymethane (AOM) was used to promote colon and liver carcinogenesis. A subset of obese mice was then switched to a low-fat diet (LFD) containing 67.5% carbohydrate, 12.2% fat, and 20% protein to promote intentional weight loss. Body weight loss and excess fat reduction did not protect mice from colon cancer progression and liver dysplastic lesion in the AOM-chemical-cancer model even though these mice had improved blood glucose and leptin levels. Intentional weight loss in AOM-treated mice actually produced histological changes that resemble dysplastic alterations in the liver and presented a higher percentage of F4/80(+)CD206(+) macrophages and activated T cells (CD4(+)CD69(+)) in the spleen and lymph nodes, respectively. In addition, the liver of AOM-treated mice exposed to a HFD during the entire period of the experiment exhibited a marked increase in proliferation and pNF-κB activation. Altogether, these data suggest that intentional weight loss following chemical-induced carcinogenesis does not affect colon tumorigenesis but may in fact negatively impact liver repair mechanisms. Copyright © 2016 the American Physiological Society.

  3. ISL1在肿瘤发生中的作用%The Functions of ISL1 in Tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    宋卓伦; 赵珺; 王卫平

    2013-01-01

    ISL1 (insulin gene enhancer binding protein 1 ) is a LIM-homeodomain transcription factor. It is known to play important roles in the development and maturation of multiple organs, including heart, pancreas and nerve system. The Isl1 knockout mice have shown multi-defects of cardiac development, absence of 4 types of pancreatic endocrine cells, and abnormal differentiation and migration of motor neurons. ISL1 is able to promote cell proliferation and inhibit cell apoptosis in the heart, nerves and pancreas islets. Recently, the abnormal overexpression of ISL1 was found in various tumors, indicating that the pathologic function of ISL1 and the underlining mechanism in tumorigenesis is worthwhile to be investigated.%胰岛因子1(Islet1,ISL1),又称胰岛素增强子结合蛋白1,以多效转录因子的身份在多种组织器官的发育及成熟中发挥作用.ISL1在心、胰腺、神经系统等组织器官的胚胎发育过程中发挥重要作用.Isl1基因敲除可导致小鼠心发育不全,4种胰岛内分泌细胞缺失,以及运动神经元分化、迁移障碍等.ISL1具有促进增殖、抑制凋亡的重要功能.近年的研究表明,ISL1在多种肿瘤发生中存在异常高表达.然而,其在肿瘤发生中的具体作用与机制尚未被阐明,有待进一步探索.

  4. microRNA-328 inhibits cervical cancer cell proliferation and tumorigenesis by targeting TCF7L2

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xuan [Department of Gynaecology, Qilu Hospital, Shandong University, Jinan (China); Department of Gynaecology, Yantai Yuhuangding Hospital, Qingdao University School of Medicine, Yantai (China); Xia, Ying, E-mail: YingXia2006@qq.com [Department of Gynecology, Huadong Hospital, Fudan University, Shanghai, 200040 (China)

    2016-06-24

    microRNAs (miRNAs) play a vital role in tumor development and progression. In this study, we aimed to determine the expression and biological roles of miR-328 in cervical cancer and identify its direct target gene. Our data showed that miR-328 was significantly downregulated in human cervical cancer tissues and cells. Re-expression of miR-328 inhibited cervical cancer cell proliferation and colony formation in vitro and suppressed the growth of xenograft tumors in vivo. Bioinformatic analysis predicted TCF7L2 (an essential effector of canonical Wnt signaling) as a target gene of miR-328, which was confirmed by luciferase reporter assays. Enforced expression of miR-328 led to a decline in the expression of endogenous TCF7L2 in cervical cancer cells. In cervical cancer tissues, TCF7L2 protein levels were negatively correlated with miR-328 expression levels (r = −0.462, P = 0.017). Small interfering RNA-mediated knockdown of TCF7L2 significantly impaired the proliferation and colony formation of cervical cancer cells. Ectopic expression of a miRNA-resistant form of TCF7L2 significantly reversed the growth suppressive effects of miR-328 on cervical cancer cells, which was accompanied by induction of cyclin D1 expression. Taken together, our results provide first evidence for the growth suppressive activity of miR-328 in cervical cancer, which is largely ascribed to downregulation of TCF7L2. Restoration of miR-328 may have therapeutic potential in cervical cancer. -- Highlights: •miR-328 inhibits cervical cancer cell growth and tumorigenesis. •TCF7L2 is a direct target gene of miR-328 in cervical cancer. •Knockdown of TCF7L2 impairs the proliferation and colony formation of cervical cancer cells.

  5. Analysis of different components in the peritumoral tissue microenvironment of colorectal cancer: A potential prospect in tumorigenesis.

    Science.gov (United States)

    Huang, Chao; Liu, Hong; Gong, Xiuli; Wen, Bin; Chen, Dan; Liu, Jinyuan; Hu, Fengliang

    2016-09-01

    The present study aimed to observe the varying expression of biomarkers in the microenvironment adjacent to colorectal cancer lesions to provide additional insight into the functions of microenvironment components in carcinogenesis and present a novel or improved indicator for early diagnosis of cancer. A total of 144 human samples from three different locations in 48 patients were collected, these locations were 10, 5 and 2 cm from the colorectal cancer lesion, respectively. The biomarkers analyzed included E‑cadherin, cytokeratin 18 (CK18), hyaluronidase‑1 (Hyal‑1), collagen type I (Col‑I), Crumbs3 (CRB3), vimentin, proteinase activated receptor 3 (PAR‑3), α‑smooth muscle actin (α‑SMA), cyclin D1 (CD1) and cluster of differentiation (CD)133. In addition, crypt architecture was observed. Related functional analysis of proteins was performed using hierarchical index cluster analysis. More severe destroyed crypt architecture closer to the cancer lesions was observed compared with the 10 cm sites, with certain crypts degraded entirely. Expression levels of E‑cadherin, CK18, CRB3 and PAR‑3 were lower in 2 cm sites compared with the 10 cm sites (all P0.05 and P=0.0001, respectively), while the expression of vimentin, α‑SMA, CD1 and CD133 were not. Hyal‑1 and Col‑I may be independently important in cancer initiation in the tumor microenvironment. The results of the present study suggest that the biomarkers in the tissue microenvironment are associated with early tumorigenesis and may contribute to the development of carcinomas. These observations may be useful for early diagnosis of colorectal cancer.

  6. 益生菌与结直肠癌发病的关系%Probiotics and Colorectal Tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    杨静; 朱元民; 刘玉兰

    2012-01-01

    Gut microbiota impacts human health profoundly and it is demonstrated that a composition change in microbiota could be associated with various disorders such as inflammatory bowel disease and colorectal cancer. Intake of probiotic formulations is a popular approach to modulate the microbiome and its functions. In fact, there is growing evidence that probiotics supplement is a potential approach to prevent and treat colorectal neoplasms, and the antitumor effect might be attributed to multifactorial mechanisms, including modulation of intestinal mucosal immune responses and inflammation, inhibition of colonization and reproduction of pathogenic bacteria, restoration of intestinal epithelial barrier function, inhibition of tumor cell proliferation, repression of carcinogenic chemicals, increase of antioxidant potential, etc. We summarized the relationship between probiotics and colorectal tumorigenesis in this review article.%肠道菌群与人体健康有密切联系,炎症性肠病、结直肠癌等均与肠道菌群失调有关.摄人益生菌制剂是调节肠道菌群及其功能较为常用的方法.研究表明补充益生菌可能通过调节肠道黏膜免疫和炎症、抑制致病菌定植和繁殖、修复肠上皮屏障功能、抑制肿瘤细胞增殖、抑制致癌化学物活性以及抗氧化作用等,对结直肠肿瘤产生一定预防和治疗作用.本文就益生菌与结直肠癌发病的关系作一综述.

  7. Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium.

    Directory of Open Access Journals (Sweden)

    Ying Feng

    2015-11-01

    Full Text Available Adenomatous polyposis coli (APC inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in β-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key β-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for β-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for β-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active β-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected β-catenin levels and some β-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected β-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.

  8. A prognosis classifier for breast cancer based on conserved gene regulation between mammary gland development and tumorigenesis: a multiscale statistical model.

    Science.gov (United States)

    Tian, Yingpu; Chen, Baozhen; Guan, Pengfei; Kang, Yujia; Lu, Zhongxian

    2013-01-01

    Identification of novel cancer genes for molecular therapy and diagnosis is a current focus of breast cancer research. Although a few small gene sets were identified as prognosis classifiers, more powerful models are still needed for the definition of effective gene sets for the diagnosis and treatment guidance in breast cancer. In the present study, we have developed a novel statistical approach for systematic analysis of intrinsic correlations of gene expression between development and tumorigenesis in mammary gland. Based on this analysis, we constructed a predictive model for prognosis in breast cancer that may be useful for therapy decisions. We first defined developmentally associated genes from a mouse mammary gland epithelial gene expression database. Then, we found that the cancer modulated genes were enriched in this developmentally associated genes list. Furthermore, the developmentally associated genes had a specific expression profile, which associated with the molecular characteristics and histological grade of the tumor. These result suggested that the processes of mammary gland development and tumorigenesis share gene regulatory mechanisms. Then, the list of regulatory genes both on the developmental and tumorigenesis process was defined an 835-member prognosis classifier, which showed an exciting ability to predict clinical outcome of three groups of breast cancer patients (the predictive accuracy 64∼72%) with a robust prognosis prediction (hazard ratio 3.3∼3.8, higher than that of other clinical risk factors (around 2.0-2.8)). In conclusion, our results identified the conserved molecular mechanisms between mammary gland development and neoplasia, and provided a unique potential model for mining unknown cancer genes and predicting the clinical status of breast tumors. These findings also suggested that developmental roles of genes may be important criteria for selecting genes for prognosis prediction in breast cancer.

  9. The Relationship between EBV Gene Methylation and Tumorigenesis%EB病毒基因甲基化与肿瘤的关系

    Institute of Scientific and Technical Information of China (English)

    路素丽

    2011-01-01

    EB virus ( EBV ) DNA methylation leads to genomic instability and plays an important role in tumorigenesis.EBV promoter is inactivated mainly due to the methylation of promoter.EBV gene hypermethylation helps EBV to escape from immune monitoring and persist in host cells.The speculation that EBV controls viral gene promoter through epigenetic mechanisms,in particular through the methylation of EBV genes to regulate expression of viral genes, thus,leads to tumorigenesis.The occurrence of EBV methylation is closely related to the development of many cancers.This article reviews the relationship between EBV gene methylation and tumorigenesis.%EB病毒(EBV)中DNA甲基化导致了基因组的不稳定,对肿瘤发生起着重要作用.EBV启动子的失活主要是由于启动子被甲基化,EBV基因的高甲基化状态有助于其逃避免疫系统的监视作用,并长期存在于宿主细胞内.推测EBV可能通过表观遗传机制调控病毒基因启动子,尤其是通过EBV基因甲基化状态来调控病毒基因的表达,从而导致肿瘤的发生.EBV甲基化与多种肿瘤的发生发展密切相关,在此对EBV基因甲基化与肿瘤的关系进行简要综述.

  10. The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC)

    Science.gov (United States)

    Reichrath, Jörg; Reichrath, Sandra

    2013-01-01

    Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body’s requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53-mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin`s vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives. PMID:24494041

  11. The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC): Present concepts and future perspectives.

    Science.gov (United States)

    Reichrath, Jörg; Reichrath, Sandra

    2013-01-01

    Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body's requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53-mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin`s vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives.

  12. TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells

    Directory of Open Access Journals (Sweden)

    Chan Wai-Yee

    2006-06-01

    Full Text Available Abstract Background TSPY is a repeated gene mapped to the critical region harboring the gonadoblastoma locus on the Y chromosome (GBY, the only oncogenic locus on this male-specific chromosome. Elevated levels of TSPY have been observed in gonadoblastoma specimens and a variety of other tumor tissues, including testicular germ cell tumors, prostate cancer, melanoma, and liver cancer. TSPY contains a SET/NAP domain that is present in a family of cyclin B and/or histone binding proteins represented by the oncoprotein SET and the nucleosome assembly protein 1 (NAP1, involved in cell cycle regulation and replication. Methods To determine a possible cellular function for TSPY, we manipulated the TSPY expression in HeLa and NIH3T3 cells using the Tet-off system. Cell proliferation, colony formation assays and tumor growth in nude mice were utilized to determine the TSPY effects on cell growth and tumorigenesis. Cell cycle analysis and cell synchronization techniques were used to determine cell cycle profiles. Microarray and RT-PCR were used to investigate gene expression in TSPY expressing cells. Results Our findings suggest that TSPY expression increases cell proliferation in vitro and tumorigenesis in vivo. Ectopic expression of TSPY results in a smaller population of the host cells in the G2/M phase of the cell cycle. Using cell synchronization techniques, we show that TSPY is capable of mediating a rapid transition of the cells through the G2/M phase. Microarray analysis demonstrates that numerous genes involved in the cell cycle and apoptosis are affected by TSPY expression in the HeLa cells. Conclusion These data, taken together, have provided important insights on the probable functions of TSPY in cell cycle progression, cell proliferation, and tumorigenesis.

  13. New perspectives for radiosensitization in pancreatic carcinoma: A review of mechanisms involved in pancreatic tumorigenesis; Mecanismes de carcinogenese des cancers du pancreas: quelles pistes pour la radiosensibilisation?

    Energy Technology Data Exchange (ETDEWEB)

    Huguet, F. [Service d' oncologie-radiotherapie, hopital Tenon, Assistance publique-Hopitaux de Paris, 4, rue de la Chine, 75020 Paris (France); Universite Pierre-et-Marie-Curie Paris 6, 4, place Jussieu, 75005 Paris (France); Centre de recherche, institut Curie, campus universitaire, 91898 Orsay cedex (France); Inserm U612, campus universitaire, 91898 Orsay cedex (France); Fernet, M.; Favaudon, V. [Centre de recherche, institut Curie, campus universitaire, 91898 Orsay cedex (France); Inserm U612, campus universitaire, 91898 Orsay cedex (France); Monnier, L.; Touboul, E. [Service d' oncologie-radiotherapie, hopital Tenon, Assistance publique-Hopitaux de Paris, 4, rue de la Chine, 75020 Paris (France); Universite Pierre-et-Marie-Curie Paris 6, 4, place Jussieu, 75005 Paris (France)

    2011-08-15

    Pancreatic carcinoma is the fifth leading cause of cancer-related mortality. The 5-year overall survival is less than 5 %. This very poor prognosis can be explained both by late diagnosis and by treatment resistance, including resistance to radiation therapy. A better understanding of the pancreatic tumorigenesis and knowledge of the most frequent mutations in pancreatic adenocarcinoma (KRAS, p16, TP53, Smad4) open new perspectives for the development of more effective treatments. This review presents the major genetic and molecular alterations in pancreatic cancer that could be targeted to improve radiosensitization. (authors)

  14. Overexpression of PGC‑1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein.

    Science.gov (United States)

    Shin, Sung-Won; Yun, Seong-Hoon; Park, Eun-Seon; Jeong, Jin-Sook; Kwak, Jong-Young; Park, Joo-In

    2015-03-01

    Peroxisome proliferator-activated receptor γ coactivator-1α (PGC‑1α), a coactivator interacting with multiple transcription factors, regulates several metabolic processes. Although recent studies have focused on the role of PGC‑1α in cancer, the underlying molecular mechanism has not been clarified. Therefore, we evaluated the role of PGC‑1α in cell proliferation and tumorigenesis using human embryonic kidney (HEK)293 cells and colorectal cancer cells. We established stable HEK293 cell lines expressing PGC‑1α and examined cell proliferation, anchorage-independent growth, and oncogenic potential compared to parental HEK293 cells. To identify the molecular PGC‑1α targets for increased cell proliferation and tumorigenesis, the GeneFishing™ DEG (differentially expressed genes) screening system was used. Western blot analysis and immunofluorescence staining were performed for a regulated gene product to confirm the results. Forced expression of PGC‑1α in HEK293 cells promoted cell proliferation and anchorage-independent growth in soft agar. In addition, HEK293 cells that highly expressed PGC‑1α showed enhanced tumor formation when subcutaneously injected into the bilateral flanks of immunodeficient mice. The results of the GeneFishing DEG screening system identified one upregulated gene (Acyl-CoA binding protein; ACBP). Real-time RT-PCR, western blot analysis, and immunofluorescence staining showed that ACBP was markedly increased in HEK293 cells stably overexpressing PGC‑1α (PGC‑1α-HEK293 cells) compared to those expressing an empty vector. In PGC‑1α, ACBP, and specificity protein 1 (Sp1) siRNA knockdown experiments in PGC‑1α-HEK293 and SNU-C4 cells, we also observed inhibition of cell proliferation, reduced expression of antioxidant enzymes, and increased H2O2-induced reactive oxygen species production and apoptosis. These findings suggest that PGC‑1α may promote cell proliferation and tumorigenesis through upregulation of ACBP

  15. HIV-1 Tat promotes Kaposi's sarcoma-associated herpesvirus (KSHV vIL-6-induced angiogenesis and tumorigenesis by regulating PI3K/PTEN/AKT/GSK-3β signaling pathway.

    Directory of Open Access Journals (Sweden)

    Feng Zhou

    Full Text Available Kaposi's sarcoma (KS-associated herpesvirus (KSHV is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. LY294002, a specific inhibitor of PI3K, effectively impaired Tat's promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients.

  16. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Bishayee, Anupam, E-mail: abishayee@auhs.edu [Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755 (United States); Mandal, Animesh [Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272 (United States)

    2014-10-15

    Highlights: • Dietary administration of an ethanolic extract of aerial parts of T. portulacastrum (TPE) exhibits a striking chemopreventive effect in an experimentally induced classical animal model of breast cancer. • The mammary tumor-inhibitory effect of TPE could be achieved, at least in part, though intervention of key hallmark capabilities of tumor cells, such as abnormal cell proliferation and evasion of apoptosis. • TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during this early-stage mammary carcinoma. • These results coupled with a safety profile of T. portulacastrum may encourage further studies to understand the full potential of this dietary plant for chemoprevention of breast cancer. - Abstract: Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight

  17. Regulation of tumorigenesis and metastasis of hepatocellular carcinoma tumor endothelial cells by microRNA-3178 and underlying mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Li, Wei; Shen, Shiqiang, E-mail: shenshiqiang2014@hotmail.com; Wu, Shanmin; Chen, Zubing; Hu, Chao; Yan, Ruichen

    2015-08-28

    This study explored the effects of microRNA-3178 (miR-3178) on hepatocellular carcinoma (HCC) tumor endothelial cells (TECs) and on the target mRNA. Real-time polymerase chain reaction (PCR) was performed to detect the differential expression of miR-3178 in hepatic sinusoidal endothelial cells (HSECs) and HCC TECs. Furthermore, HCC TECs were transfected with miR-3178 mimic/inhibitor or their respective negative controls. The expression of miR-3178 before and after transfection was confirmed through RT-PCR. The effects of miR-3178 on the proliferation, apoptosis, cell cycle, invasion, migration, and angiogenesis of HCC TECs were also investigated through methyl thiazol tetrazolium assay, flow cytometry, matrigel invasion assay, transwell migration assay, and tube formation assay. Early growth responsive gene 3 (EGR3), as the putative target of miR-3178, was detected through RT-PCR and Western blot. Compared with HSECs, HCC TECs had lower miR-3178 expression levels (P < 0.001). MiR-3178 mimic inhibited proliferation, arrested cell cycle in G1 phase, and increased apoptosis. The numbers of migrated and invaded cells and capillary-like structures were significantly less in the mimic group than in the other groups. MiR-3178 mimic significantly decreased the mRNA and protein expression levels of EGR3. By contrast, miR-3178 inhibitor induced opposite effects. We conclude that miR-3178 was lowly expressed in HCC TECs, and miR-3178 mimic specifically inhibited the proliferation, migration, invasion, and angiogenesis and promoted the apoptosis and G1 phase arrest of HCC TECs in vitro through the inhibition of EGR3 expression. Thus, miR-3178 might be a critical target in HCC therapy. - Highlights: • MiR-3178 is significantly low-expression in HCC TECs. • MiR-3178 acts as a tumor suppressor to inhibit tumorigenesis and metastasis. • MiR-3178 inhibit angiogenesis of HCC TECs. • EGR3 may be a target gene of miR-3178. • MiR-3178 may have therapeutic application for

  18. Sickle Cells Abolish Melanoma Tumorigenesis in Hemoglobin SS Knockin Mice and Augment the Tumoricidal Effect of Oncolytic Virus In Vivo.

    Science.gov (United States)

    Sun, Chiang Wang; Willmon, Candice; Wu, Li-Chen; Knopick, Peter; Thoerner, Jutta; Vile, Richard; Townes, Tim M; Terman, David S

    2016-01-01

    toxicity. Collectively, these data unveil two hitherto unrecognized findings: hemoglobin SS knockin mice appear to present a natural barrier to melanoma tumorigenesis while SSRBCs demonstrate therapeutic function as a vehicle for enhancing the oncolytic effect of free reovirus against established melanoma.

  19. Mixed Beam Murine Harderian Gland Tumorigenesis: Predicted Dose-Effect Relationships if neither Synergism nor Antagonism Occurs

    Energy Technology Data Exchange (ETDEWEB)

    Siranart, Nopphon; Blakely, Eleanor A.; Cheng, Alden; Handa, Naval; Sachs, Rainer K.

    2016-12-01

    Complex mixed radiation fields exist in interplanetary space, and not much is known about their latent effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology. However, for more than a century pharmacologists interested in mixtures of therapeutic drugs have analyzed conceptual, mathematical and practical questions similar to those that arise when analyzing mixed radiation fields, and have shown that simple effect additivity often gives unreasonable predictions when the IDER are curvilinear. Various alternatives to simple effect additivity proposed in radiobiology, pharmacometrics, toxicology and other fields are also known to have important limitations. In this work, we analyze upcoming murine Harderian gland (HG) tumor prevalence mixed-beam experiments, using customized open-source software and published IDER from past single-ion experiments. The upcoming experiments will use acute irradiation and the mixed beam will include components of high atomic number and energy (HZE). We introduce a new alternative to simple effect additivity, "incremental effect additivity", which is more suitable for the HG analysis and perhaps for other end points. We use incremental effect additivity to calculate default predictions for mixture dose-effect relationships, including 95% confidence intervals. We have drawn three main conclusions from this work. 1. It is important to supplement mixed-beam experiments with single-ion experiments, with matching end point(s), shielding and dose timing. 2. For HG tumorigenesis due to a mixed beam, simple effect additivity and incremental effect additivity sometimes give

  20. Human RNA polymerase II associated factor 1 complex promotes tumorigenesis by activating c-MYC transcription in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhi, Xiuyi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 (China); Giroux-Leprieur, Etienne [ER2 GRC UPMC04 Theranoscan, Pierre et Marie Curie University, Tenon Hospital, 4 Rue de La Chine, 75020, Paris (France); Respiratory Diseases and Thoracic Oncology Department, Ambroise Pare Hospital – APHP, Versailles Saint Quentin en Yvelines University, 9 Avenue Charles de Gaulle, 92100, Boulogne-Billancourt (France); Wislez, Marie [ER2 GRC UPMC04 Theranoscan, Pierre et Marie Curie University, Tenon Hospital, 4 Rue de La Chine, 75020, Paris (France); Hu, Mu; Zhang, Yi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 (China); Shi, Huaiyin [Department of Pathology, Chinese PLA General Hospital, Fu-xing Road #28, Beijing, 100853 (China); Du, Kaiqi, E-mail: kaiqidu_zhejiang@163.com [Department of Cardiothoracic Surgery, Chinese People' s Armed Police Force, Zhejiang Corps Hospital, Jiaxing, Zhejiang Province (China); Wang, Lei, E-mail: leiwang_hebei@163.com [Department of Human Anatomy, Hebei Medical University, Hebei Province (China)

    2015-10-02

    Human RNA polymerase II (RNAPII)-associated factor 1 complex (hPAF1C) plays a crucial role in protein-coding gene transcription. Overexpression of hPAF1C has been implicated in the initiation and progression of various human cancers. However, the molecular pathways involved in tumorigenesis through hPAF1C remain to be elucidated. The current study suggested hPAF1C expression as a prognostic biomarker for early stage non-small cell lung cancer (NSCLC) and patients with low hPAF1C expression levels had significantly better overall survival. Furthermore, the expression of hPAF1C was found to be positively correlated with c-MYC expression in patient tumor samples and in cancer cell lines. Mechanistic studies indicated that hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription. These results demonstrated the prognostic value of hPAF1C in early-stage NSCLC and the role of hPAF1C in the transcriptional regulation of c-MYC oncogene during NSCLC tumorigenesis. - Highlights: • hPAF1C expression is a prognostic biomarker for early stage non-small cell lung cancer. • The expression of hPAF1C was positively correlated with c-MYC in tumor samples of patients and in several NSCLC cell lines. • hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription.

  1. Roles of Slit/Robo Pathway in Gynecological Tumorigenesis%Slit/Robo信号通路在妇科肿瘤发生中的作用

    Institute of Scientific and Technical Information of China (English)

    袁蕾

    2013-01-01

    Slit/Robo信号作为神经导向因子在神经系统发育中具有导向轴突生长和排斥神经细胞迁移的重要作用.目前研究发现,Slit/Robo信号也可能参与了肿瘤发生发展中某些关键步骤,如细胞迁移和肿瘤新生血管的形成,但其在妇科肿瘤中的作用尚不清楚.从Slit/Robo信号在女性生殖系统生理、病理状态下的表达情况,以及参与妇科肿瘤发生的机制等方面做一综述.%As important axon guidance molecules,the Slit family of secreted proteins acts through the Roundabout (Robo) receptors to direct axonal growth and repel axonal migration during central nervous system development. Recent research has revealed that the Slit/Robo pathway might play roles in some pivotal processes in tumorigenesis, such as cell migration and tumor angiogenesis. However, the role of Slit/Robo in gynecological tumorigenesis remains largely unknown. This review will examine the roles of this pathway in the physiology and pathology of the reproductive system and highlight areas for future research.

  2. Human RNA polymerase II associated factor 1 complex promotes tumorigenesis by activating c-MYC transcription in non-small cell lung cancer.

    Science.gov (United States)

    Zhi, Xiuyi; Giroux-Leprieur, Etienne; Wislez, Marie; Hu, Mu; Zhang, Yi; Shi, Huaiyin; Du, Kaiqi; Wang, Lei

    2015-10-02

    Human RNA polymerase II (RNAPII)-associated factor 1 complex (hPAF1C) plays a crucial role in protein-coding gene transcription. Overexpression of hPAF1C has been implicated in the initiation and progression of various human cancers. However, the molecular pathways involved in tumorigenesis through hPAF1C remain to be elucidated. The current study suggested hPAF1C expression as a prognostic biomarker for early stage non-small cell lung cancer (NSCLC) and patients with low hPAF1C expression levels had significantly better overall survival. Furthermore, the expression of hPAF1C was found to be positively correlated with c-MYC expression in patient tumor samples and in cancer cell lines. Mechanistic studies indicated that hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription. These results demonstrated the prognostic value of hPAF1C in early-stage NSCLC and the role of hPAF1C in the transcriptional regulation of c-MYC oncogene during NSCLC tumorigenesis. Copyright © 2015. Published by Elsevier Inc.