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  1. Liver damage and senescence increases in patients developing hepatocellular carcinoma.

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    Rey, Silvia; Quintavalle, Cristina; Burmeister, Katharina; Calabrese, Diego; Schlageter, Manuel; Quagliata, Luca; Cathomas, Gieri; Diebold, Joachim; Molinolo, Alfredo; Heim, Markus H; Terracciano, Luigi M; Matter, Matthias S

    2017-08-01

    Most patients with a hepatocellular carcinoma (HCC) have an underlying chronic liver inflammation, which causes a continuous damage leading to liver cirrhosis and eventually HCC. However, only a minority of cirrhotic patients develop HCC. To assess a possible differential impact of liver inflammation in patients developing HCC versus patients remaining tumor-free, we designed a longitudinal study and analysed liver tissue of the same patients (n = 33) at two points in time: once when no HCC was present and once several years later when an HCC was present. As a control group, we followed cirrhotic patients (n = 37) remaining tumor-free over a similar time frame. We analysed cell damage and senescence of hepatocytes by measuring γ-H2AX positivity, p16 INK4 and p21 WAF/Cip1 expression, nuclear size, and telomere length. γ-H2AX positivity, p16 INK4 and p21 WAF/Cip1 expression, in the first liver biopsy was similar in patients developing HCC later on and cirrhotic patients remaining tumor free. In contrast, γ-H2AX positivity, p16 INK4 and p21 WAF/Cip1 expression, was significantly higher in the second non-tumoral liver biopsy of HCC patients than in the control patients. Consequently, the individual increase in γ-H2AX positivity, p16 INK4 and p21 WAF/Cip1 expression, from the first biopsy to the second biopsy was significantly higher in patients developing HCC than in patients remaining tumor free. In addition, changes in nuclear size and telomere length revealed a more pronounced cell aging in patients developing HCC than in patients remaining tumor free. Hepatocytes from patients developing HCC go through more pronounced cell damage and senescence in contrast to cirrhotic patients remaining tumor free. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  2. THE ROLE OF CYTOKINE NETWORK IN HEPATOCELLULAR DAMAGE CAUSED BY СHRONIC HEPATITIS C

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    L. Ph. Skljar

    2006-01-01

    Full Text Available Abstract. Hepatitis C virus (HCV is the leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Liver damage in chronic viral hepatitis C is caused by both direct cytopathic viral effects, and indirect immune-mediated mechanisms. The cytokines locally produced in the liver, as well as those circulating in the blood circulation, play an important role in the control of viral replication and sufficiently contribute to hepatocellular damage. The goal of present study was to investigate the contents of some cytokines in blood serum and their local levels, being in interrelation with indices of necrotic inflammatory changes in the liver tissue. Correlations established between systemic and local contents of studied cytokines, and morphological indices indicate that, among immunological tests checked, the contents of IL-4, IL-10, IL-12p70, and TNFα in blood serum and supernatants of liver biopsies were of the greatest significance for determining the stage of fibrosis. Quantitative assays of abovementioned cytokines in blood serum represent, therefore, an alternative approach in order to perform noninvasive screening of liver fibrosis.

  3. Dehydroepiandrosterone restores hepatocellular function and prevents liver damage in estrogen-deficient females following trauma and hemorrhage.

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    Kuebler, J F; Jarrar, D; Wang, P; Bland, K I; Chaudry, I H

    2001-05-15

    Recent studies have shown that administration of the sex steroid dehydroepiandrosterone (DHEA) in males following trauma-hemorrhagic shock has salutary effects on the depressed cardiovascular and immunological functions under those conditions. Since the effects of sex steroids are gender specific, we examined whether administration of DHEA has any beneficial effects on hepatocellular function in female rats with low estrogen levels following trauma-hemorrhage. Ovariectomy was performed in female Sprague-Dawley rats 14 days prior to the experiments. The animals then underwent a 5-cm midline laparotomy and were subjected to hemorrhagic shock (40 mm Hg for 90 min). This was followed by fluid resuscitation (Ringer's lactate over 60 min) and administration of DHEA (30 mg/kg BW) or vehicle subcutaneously at the end of resuscitation. At 24 h after resuscitation hepatocellular function, i.e., clearance of indocyanine green (ICG), and hepatocyte damage (serum alanine aminotransferase) were measured. Plasma levels of DHEA and 17beta-estradiol were also assayed. Vehicle-treated rats had significantly reduced hepatocellular function, increased ALT activity, and decreased levels of 17beta-estradiol following trauma-hemorrhage compared to sham-operated animals (P trauma-hemorrhage, hepatocellular function and ALT activity were similar to those of shams. However, administration of DHEA did not influence the plasma levels of 17beta-estradiol. Administration of DHEA following trauma-hemorrhage restored hepatocellular function and reduced hepatic damage that was observed in ovariectomized female rats under such conditions. This salutary effect of DHEA did not appear to be due to elevated levels of plasma 17beta-estradiol. We therefore propose that DHEA should be considered a novel, safe, and useful adjunct in the treatment of trauma-induced hepatocellular dysfunction in ovariectomized and postmenopausal females. Copyright 2001 Academic Press.

  4. Usage of adenovirus expressing thymidine kinase mediated hepatocellular damage for enabling mouse liver repopulation with allogenic or xenogenic hepatocytes.

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    Daniel Moreno

    Full Text Available It has been shown that the liver of immunodeficient mice can be efficiently repopulated with human hepatocytes when subjected to chronic hepatocellular damage. Mice with such chimeric livers represent useful reagents for medical and clinical studies. However all previously reported models of humanized livers are difficult to implement as they involve cross-breeding of immunodeficient mice with mice exhibiting genetic alterations causing sustained hepatic injury. In this paper we attempted to create chimeric livers by inducing persistent hepatocellular damage in immunodeficient Rag2(-/- γc(-/- mice using an adenovirus encoding herpes virus thymidine kinase (AdTk and two consecutive doses of ganciclovir (GCV. We found that this treatment resulted in hepatocellular damage persisting for at least 10 weeks and enabled efficient engraftment and proliferation within the liver of either human or allogenic hepatocytes. Interestingly, while the nodules generated from the transplanted mouse hepatocytes were well vascularized, the human hepatocytes experienced progressive depolarization and exhibited reduced numbers of murine endothelial cells inside the nodules. In conclusion, AdTk/GCV-induced liver damage licenses the liver of immunodeficient mice for allogenic and xenogenic hepatocyte repopulation. This approach represents a simple alternative strategy for chimeric liver generation using immunodeficient mice without additional genetic manipulation of the germ line.

  5. Linc-POU3F3 is overexpressed in hepatocellular carcinoma and regulates cell proliferation, migration and invasion.

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    Li, Yichun; Li, Yannan; Wang, Dan; Meng, Qingdong

    2018-06-12

    Linc-POU3F3 showed an up-regulated tendency and functioned as tumor promoter in glioma, esophageal cancer and colorectal cancer. There was no report about the expression pattern and clinical value of linc-POU3F3 in hepatocellular carcinoma. Thus, the purpose of our study is to explore the clinical significance and biological role of linc-POU3F3 in hepatocellular carcinoma. Our results suggested that levels of linc-POU3F3 were dramatically increased in hepatocellular carcinoma tissues and cell lines compared with paired normal hepatic tissues and normal hepatic cell line, respectively. Levels of linc-POU3F3 were positively correlated with clinical stage, tumor size, vascular invasion and metastasis. Moreover, high-expression of linc-POU3F3 was an independent prognostic factor for hepatocellular carcinoma patients. The gain- and loss-of-function experiments showed that linc-POU3F3 expression significantly promoted tumor cell proliferation, migration and invasion. In addition, linc-POU3F3 expression was negatively correlated with POU3F3 mRNA and protein expressions in hepatocellular carcinoma tissues, and negatively regulated POU3F3 mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, our study supports the first evidence that linc-POU3F3 plays an oncogenic role in hepatocellular carcinoma, and represents a potential therapeutic strategy for hepatocellular carcinoma patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

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    Stefanou Nikolaos

    2010-08-01

    Full Text Available Abstract Background Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC. The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT, a known mediator of cellular immortalization. Methods We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3 and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. Results We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. Conclusions We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

  7. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells

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    Li Fan

    2010-04-01

    Full Text Available Abstract Background In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells. Methods We constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7. Results CXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo

  8. Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism

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    Ma, Xiao-Ni; Liu, Xiao-Yun; Yang, Yue-Feng; Xiao, Feng-Jun; Li, Qing-Fang; Yan, Jun; Zhang, Qun-Wei; Wang, Li-Sheng; Li, Xue-Yan; Wang, Hua

    2011-01-01

    Highlights: → Hepatocellular carcinoma is inhibited by Spred2 through as yet unclear mechanisms. → We studied the overexpression of Spred2 in cell line and murine tumor models of HCC. → Spred2 inhibited cell proliferation and migration via attenuating ERK signaling. → Spred2 overexpression induced apoptosis via caspase-3 and downregulated Mcl-1. → A Spred2 knockdown markedly induced tumor growth in vivo. -- Abstract: Members of the Spred gene family are negative regulators of the Ras/Raf-1/ERK pathway, which has been associated with several features of the tumor malignancy. However, the effect of Spred genes on hepatocellular carcinoma (HCC) remains uninvestigated. In the present work, we analyzed the in vitro and in vivo effects of Spred2 expression on the hepatic carcinoma cell line, SMMC-7721. In addition to attenuated ERK activation, which inhibited the proliferation and migration of unstimulated and HGF-stimulated SMMC-7721 cells. Adenovirus-mediated Spred2 overexpression induced the activation of caspase-3 and apoptosis, as well as reduced the expression level of Mcl-1. Most importantly, the knockdown of Spred2 markedly enhanced tumor growth in vivo. In conclusion, these results suggest that Spred2 could qualify as a potential therapeutic target in HCC.

  9. MicroRNA-regulated non-viral vectors with improved tumor specificity in an orthotopic rat model of hepatocellular carcinoma

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    Ronald, J A; Katzenberg, R; Nielsen, Carsten Haagen

    2013-01-01

    In hepatocellular carcinoma (HCC), tumor specificity of gene therapy is of utmost importance to preserve liver function. MicroRNAs (miRNAs) are powerful negative regulators of gene expression and many are downregulated in human HCC. We identified seven miRNAs that are also downregulated in tumors...

  10. miR-367 promotes proliferation and invasion of hepatocellular carcinoma cells by negatively regulating PTEN

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    Meng, Xiangrui, E-mail: mengxiangruibb2008@163.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

    2016-01-29

    MicroRNAs play important roles in the carcinogenesis of many types of cancers by inhibiting gene expression at posttranscriptional level. However, the roles of microRNAs in hepatocellular carcinoma, are still unclear. Here, we identified that miR-367 promotes hepatocellular carcinoma (HCC) cell proliferation by negatively regulates its target gene PTEN. The expression of miR-367 and PTEN are significantly inverse correlated in 35 HCC patients. In HCC cell line, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-367, while miR-367 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-367 mimics significantly promoted the migration and invasion of HCC cells, whereas miR-367 inhibitors significantly reduced cell migration and invasion. Luciferase assays confirmed that miR-367 directly bound to the 3'untranslated region of PTEN, and western blotting showed that miR-367 suppressed the expression of PTEN at the protein levels. This study indicated that miR-367 negatively regulates PTEN and promotes proliferation and invasion of HCC cells. Thus, miR-367 may represent a potential therapeutic target for HCC intervention. - Highlights: • miR-367 mimics promote the proliferation and invasion of HCC cells. • miR-367 inhibitors inhibit the proliferation and invasion of HCC cells. • miR-367 targets 3′UTR of PTEN in HCC cells. • miR-367 negatively regulates PTEN in HCC cells.

  11. Gene regulation is governed by a core network in hepatocellular carcinoma.

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    Gu, Zuguang; Zhang, Chenyu; Wang, Jin

    2012-05-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and the mechanisms that lead to the disease are still relatively unclear. However, with the development of high-throughput technologies it is possible to gain a systematic view of biological systems to enhance the understanding of the roles of genes associated with HCC. Thus, analysis of the mechanism of molecule interactions in the context of gene regulatory networks can reveal specific sub-networks that lead to the development of HCC. In this study, we aimed to identify the most important gene regulations that are dysfunctional in HCC generation. Our method for constructing gene regulatory network is based on predicted target interactions, experimentally-supported interactions, and co-expression model. Regulators in the network included both transcription factors and microRNAs to provide a complete view of gene regulation. Analysis of gene regulatory network revealed that gene regulation in HCC is highly modular, in which different sets of regulators take charge of specific biological processes. We found that microRNAs mainly control biological functions related to mitochondria and oxidative reduction, while transcription factors control immune responses, extracellular activity and the cell cycle. On the higher level of gene regulation, there exists a core network that organizes regulations between different modules and maintains the robustness of the whole network. There is direct experimental evidence for most of the regulators in the core gene regulatory network relating to HCC. We infer it is the central controller of gene regulation. Finally, we explored the influence of the core gene regulatory network on biological pathways. Our analysis provides insights into the mechanism of transcriptional and post-transcriptional control in HCC. In particular, we highlight the importance of the core gene regulatory network; we propose that it is highly related to HCC and we believe further

  12. NDRG2 inhibits hepatocellular carcinoma adhesion, migration and invasion by regulating CD24 expression

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    Zheng, Jin; Guo, Hang; Tao, Yurong; Xue, Yan; Jiang, Ning; Yao, Libo; Liu, Wenchao; Li, Yan; Yang, Jiandong; Liu, Qiang; Shi, Ming; Zhang, Rui; Shi, Hengjun; Ren, Qinyou; Ma, Ji

    2011-01-01

    The prognosis of most hepatocellular carcinoma (HCC) patients is poor due to the high metastatic rate of the disease. Understanding the molecular mechanisms underlying HCC metastasis is extremely urgent. The role of CD24 and NDRG2 (N-myc downstream-regulated gene 2), a candidate tumor suppressor gene, has not yet been explored in HCC. The mRNA and protein expression of CD24 and NDRG2 was analyzed in MHCC97H, Huh7 and L-02 cells. Changes in cell adhesion, migration and invasion were detected by up- or down-regulating NDRG2 by adenovirus or siRNA. The expression pattern of NDRG2 and CD24 in HCC tissues and the relationship between NDRG2 and HCC clinical features was analyzed by immunohistochemical and western blotting analysis. NDRG2 expression was negatively correlated with malignancy in HCC. NDRG2 exerted anti-tumor activity by regulating CD24, a molecule that mediates cell-cell interaction, tumor proliferation and adhesion. NDRG2 up-regulation decreased CD24 expression and cell adhesion, migration and invasion. By contrast, NDRG2 down-regulation enhanced CD24 expression and cell adhesion, migration and invasion. Immunohistochemical analysis of 50 human HCC clinical specimens showed a strong correlation between NDRG2 down-regulation and CD24 overexpression (P = 0.04). In addition, increased frequency of NDRG2 down-regulation was observed in patients with elevated AFP serum level (P = 0.006), late TNM stage (P = 0.009), poor differentiation grade (P = 0.002), tumor invasion (P = 0.004) and recurrence (P = 0.024). Our findings indicate that NDRG2 and CD24 regulate HCC adhesion, migration and invasion. The expression level of NDRG2 is closely related to the clinical features of HCC. Thus, NDRG2 plays an important physiological role in HCC metastasis

  13. Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.

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    Kim, Juhyun; Won, Ranhui; Ban, Guyee; Ju, Mi Ha; Cho, Kyung Sook; Young Han, Sang; Jeong, Jin-Sook; Lee, Seong-Wook

    2015-07-20

    Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

  14. Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma.

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    Lin, Yang-Hsiang; Wu, Meng-Han; Huang, Ya-Hui; Yeh, Chau-Ting; Cheng, Mei-Ling; Chi, Hsiang-Cheng; Tsai, Chung-Ying; Chung, I-Hsiao; Chen, Ching-Ying; Lin, Kwang-Huei

    2018-01-01

    Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203). © 2017 by the American Association for the Study of Liver Diseases.

  15. BAG3 regulates epithelial-mesenchymal transition and angiogenesis in human hepatocellular carcinoma.

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    Xiao, Heng; Cheng, Shaobing; Tong, Rongliang; Lv, Zheng; Ding, Chaofeng; Du, Chengli; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

    2014-03-01

    Bcl2-associated athanogene 3 (BAG3) protein is a co-chaperone of heat-shock protein (Hsp) 70 and may regulate major physiological and pathophysiological processes. However, few reports have examined the role of BAG3 in human hepatocellular carcinoma (HCC). In this study, we show that BAG3 regulates epithelial-mesenchymal transition (EMT) and angiogenesis in HCC. BAG3 was overexpressed in HCC tissues and cell lines. BAG3 knockdown resulted in reduction in migration and invasion of HCC cells, which was linked to reversion of EMT by increasing E-cadherin expression and decreasing N-cadherin, vimentin and slug expression, as well as suppressing matrix metalloproteinase 2 (MMP-2) expression. In a xenograft tumorigenicity model, BAG3 knockdown effectively inhibited tumor growth and metastasis through reduction in CD34 and VEGF expression and reversal of the EMT pathway. In conclusion, BAG3 is associated with the invasiveness and angiogenesis in HCC, and the BAG3 gene may be a novel therapeutic approach against HCC.

  16. The miR-383-LDHA axis regulates cell proliferation, invasion and glycolysis in hepatocellular cancer

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    Zhixiong Fang

    2017-02-01

    Full Text Available Objective(s: To explore the correlation between expression patterns and functions of miR-383 and LDHA in hepatocellular cancer (HCC. Materials and Methods: We detected the expression of miR-383 and LDHA in 30 HCC tissues and their matched adjacent normal tissues using qRT-PCR. Then we performed MTT assay, foci formation assay, transwell migration assay, glucose uptake assay and lactate production assay to explore the function of miR-383 in cell proliferation, invasion and glycolysis in HCC cell lines. Luciferase reporter assay was used to explore whether LDHA was a target gene of miR-383. Western blot and qRT-PCR were used to further confirm LDHA was targeted by miR-383. Then the above functional experiments were repeated to see whether the function of LDHA could be inhibited by miR-383. Results: The results of qRT-PCR showed that miR-383 was down-regulated in HCC tissues compared with their matched adjacent normal tissues. Functional experiments showed that overexpression of miR-383 significantly suppressed cell proliferation, invasion and glycolysis. Luciferase reporter assay showed LDHA was a target gene of miR-383 and expression of LDHA was inversely correlated with that of miR-383 in HCC. Besides, increased cell proliferation, invasion and glycolysis triggered by LDHA could be inhibited by overexpression of miR-383 in HCC cell lines. Conclusion: Our study proved that miR-383 is down-regulated in HCC and acts as a tumor suppressor through targeting LDHA. Targeting the miR-383-LDHA axis might be a promising strategy in HCC treatment.

  17. Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites

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    Boll, M.; Weber, L.W.D.; Becker, E.; Stampfl, A. [Inst. of Toxicology, GSF - National Research Center for Environment and Health, Muenchen, Neuherberg (Germany)

    2001-08-01

    CCl{sub 4}-induced liver damage was modeled in monolayer cultures of rat primary hepatocytes with a focus on involvement of covalent binding of CCl{sub 4} metabolites to cell components and/or peroxidative damage as the cause of injury. (1) Covalent binding of {sup 14}C-labeled metabolites was detected in hepatocytes immediately after exposure to CCl{sub 4}. (2) Low oxygen partial pressure increased the reductive metabolism of CCl{sub 4} and thus covalent binding. (3) [{sup 14}C]-CCl{sub 4} was bound to lipids and to proteins throughout subcellular fractions. Binding occurred preferentially to triacylglycerols and phospholipids, with phosphatidylcholine containing the highest amount of label. (4) The lipid peroxidation potency of CCl{sub 4} revealed subtle differences compared to other peroxidative substances, viz., ADP-Fe{sup 3+} and cumol hydroperoxide, respectively. (5) CCl{sub 4}, but not the other peroxidative substances, decreased the rate of triacylglycerol secretion as very low density lipoproteins. (6) The anti-oxidant vitamin E ({alpha}-tocopherol) blocked lipid peroxidation, but not covalent binding, and secretion of lipoproteins remained inhibited. (7) The radical scavenger piperonyl butoxide prevented CCl{sub 4}-induced lipid peroxidation as well as covalent binding of CCl{sub 4} metabolites to cell components, and also restored lipoprotein metabolism. The results confirm that covalent binding of the CCl{sub 3}{sup *} radical to cell components initiates the inhibition of lipoprotein secretion and thus steatosis, whereas the reaction with oxygen, to form CCl{sub 3}-OO{sup *}, initiates lipid peroxidation. The two processes are independent of each other, and the extent to which either process occurs depends on partial oxygen pressure. The former process may result in adduct formation and, ultimately, cancer initiation, whereas the latter results in loss of calcium homeostasis and, ultimately, apoptosis and cell death. (orig.)

  18. Liver and biliary damages following transarterial chemoembolization of hepatocellular carcinoma: comparison between drug-eluting beads and lipiodol emulsion

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    Monier, Arnaud; Duran, Rafael; Bize, Pierre; Dunet, Vincent; Denys, Alban [Lausanne University Hospital, Department of Diagnostic and Interventional Radiology, Lausanne (Switzerland); Guiu, Boris [Lausanne University Hospital, Department of Diagnostic and Interventional Radiology, Lausanne (Switzerland); Montpellier University Hospital, Department of Diagnostic and Interventional Radiology, Montpellier (France); Aho, Serge [University Hospital, Department of Epidemiology, Dijon (France); Deltenre, Pierre [Lausanne University Hospital, Department of Gastroenterology, Lausanne (Switzerland)

    2017-04-15

    To compare transarterial chemoembolization (TACE)-related hepatic toxicities of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with intermediate-stage hepatocellular carcinoma. In this retrospective study, 151 consecutive patients undergoing cTACE or DEB-TACE and MRI 3-6 weeks before and after therapy were included. Toxicity was assessed on imaging (global hepatic damages (GHD), overall biliary injuries, biliary cast, bile duct dilatation, intrahepatic biloma, portal thrombosis), and clinico-biological follow-ups. Tumour response, time to progression (TTP), and overall survival were assessed. Factors influencing complication rate were identified by generalized equation logistic regression model. Biliary injuries and intrahepatic biloma incidence were significantly higher following DEB-TACE (p < 0.001). DEB-TACE showed a significant increased risk of GHD (OR: 3.13 [1.74-5.63], p < 0.001) and biliary injuries (OR: 4.53 [2.37-8.67], p < 0.001). A significant relationship was found between baseline prothrombin value and GHD, biliary injuries and intrahepatic biloma (all p < 0.01), and between the dose of chemotherapy and intrahepatic biloma (p = 0.001). Only TTP was significantly shorter following DEB-TACE compared to cTACE (p = 0.025). DEB-TACE was associated with increased hepatic toxicities compared to cTACE. GHD, biliary injuries, and intrahepatic biloma were more frequently observed with high baseline prothrombin value, suggesting that cTACE might be more appropriate than DEB-TACE in patients with less advanced cirrhosis. (orig.)

  19. Extract of Stellerachamaejasme L(ESC) inhibits growth and metastasis of human hepatocellular carcinoma via regulating microRNA expression.

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    Liu, Xiaoni; Wang, Shuang; Xu, Jianji; Kou, Buxin; Chen, Dexi; Wang, Yajie; Zhu, Xiaoxin

    2018-03-20

    MicroRNAs(miRNAs)are involved in the initiation and progression of hepatocellular carcinoma. ESC, an extract of Stellerachamaejasme L, had been confirmed as a potential anti-tumor extract of Traditional Chinese Medicine. In light of the important role of miRNAs in hepatocellular carcinoma, we questioned whether the inhibitory effects of ESC on hepatocellular carcinoma (HCC) were associated with miRNAs. The proliferation inhibition of ESC on HCC cells was measured with MTT assay. The migration inhibition of ESC on HCC cells was measured with transwell assay. The influences of ESC on growth and metastasis inhibition were evaluated with xenograft tumor model of HCC. Protein expressions were measured with western blot and immunofluorescence methods and miRNA profiles were detected with miRNA array. Differential miRNA and target mRNAs were verified with real-time PCR. The results showed that ESC could inhibit proliferation and epithelial mesenchymal transition (EMT) in HCC cells in vitro and tumor growth and metastasis in xenograft models in vivo. miRNA array results showed that 69 differential miRNAs in total of 429 ones were obtained in MHCC97H cells treated by ESC. hsa-miR-107, hsa-miR-638, hsa-miR-106b-5p were selected to be validated with real-time PCR method in HepG2 and MHCC97H cells. Expressions of hsa-miR-107 and hsa-miR-638 increased obviously in HCC cells treated by ESC. Target genes of three miRNAs were also validated with real-time PCR. Interestingly, only target genes of hsa-miR-107 changed greatly. ESC downregulated the MCL1, SALL4 and BCL2 gene expressions significantly but did not influence the expression of CACNA2D1. The findings suggested ESC regressed growth and metastasis of human hepatocellular carcinoma via regulating microRNAs expression and their corresponding target genes.

  20. Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

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    Lee, Hong-Jen; Lan, Li; Peng, Guang; Chang, Wei-Chao; Hsu, Ming-Chuan; Wang, Ying-Nai; Cheng, Chien-Chia; Wei, Leizhen; Nakajima, Satoshi; Chang, Shih-Shin; Liao, Hsin-Wei; Chen, Chung-Hsuan; Lavin, Martin; Ang, K Kian; Lin, Shiaw-Yih; Hung, Mien-Chie

    2015-01-01

    Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition. PMID:25601159

  1. Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities.

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    Soll, Jennifer M; Sobol, Robert W; Mosammaparast, Nima

    2017-03-01

    Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so-called 'epigenetic' adducts. Here, we discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Investigation of Pokemon-regulated proteins in hepatocellular carcinoma using mass spectrometry-based multiplex quantitative proteomics.

    Science.gov (United States)

    Bi, Xin; Jin, Yibao; Gao, Xiang; Liu, Feng; Gao, Dan; Jiang, Yuyang; Liu, Hongxia

    2013-01-01

    Pokemon is a transcription regulator involved in embryonic development, cellular differentiation and oncogenesis. It is aberrantly overexpressed in multiple human cancers including Hepatocellular carcinoma (HCC) and is considered as a promising biomarker for HCC. In this work, the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics strategy was used to investigate the proteomic profile associated with Pokemon in human HCC cell line QGY7703 and human hepatocyte line HL7702. Samples were labeled with four-plex iTRAQ reagents followed by two-dimensional liquid chromatography coupled with tandem mass spectrometry analysis. A total of 24 differentially expressed proteins were selected as significant. Nine proteins were potentially up-regulated by Pokemon while 15 proteins were potentially down-regulated and many proteins were previously identified as potential biomarkers for HCC. Gene ontology (GO) term enrichment revealed that the listed proteins were mainly involved in DNA metabolism and biosynthesis process. The changes of glucose-6-phosphate 1-dehydrogenase (G6PD, up-regulated) and ribonucleoside-diphosphate reductase large sub-unit (RIM1, down-regulated) were validated by Western blotting analysis and denoted as Pokemon's function of oncogenesis. We also found that Pokemon potentially repressed the expression of highly clustered proteins (MCM3, MCM5, MCM6, MCM7) which played key roles in promoting DNA replication. Altogether, our results may help better understand the role of Pokemon in HCC and promote the clinical applications.

  3. Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression

    Directory of Open Access Journals (Sweden)

    Carlos R. Morales

    2014-01-01

    Full Text Available Heterozygous mutations in the UBIAD1 gene cause Schnyder corneal dystrophy characterized by abnormal cholesterol and phospholipid deposits in the cornea. Ubiad1 protein was recently identified as Golgi prenyltransferase responsible for biosynthesis of vitamin K2 and CoQ10, a key protein in the mitochondrial electron transport chain. Our study shows that silencing UBIAD1 in cultured human hepatocellular carcinoma cells causes dramatic morphological changes and cholesterol storage in the mitochondria, emphasizing an important role of UBIAD1 in mitochondrial function.

  4. Epigenetic Regulators Modulate Muscle Damage in Duchenne Muscular Dystrophy Model.

    Science.gov (United States)

    Bajanca, Fernanda; Vandel, Laurence

    2017-12-21

    Histone acetyl transferases (HATs) and histone deacetylases (HDAC) control transcription during myogenesis. HDACs promote chromatin condensation, inhibiting gene transcription in muscle progenitor cells until myoblast differentiation is triggered and HDACs are released. HATs, namely CBP/p300, activate myogenic regulatory and elongation factors promoting myogenesis. HDAC inhibitors are known to improve regeneration in dystrophic muscles through follistatin upregulation. However, the potential of directly modulating HATs remains unexplored. We tested this possibility in a well-known zebrafish model of Duchenne muscular dystrophy. Interestingly, CBP/p300 transcripts were found downregulated in the absence of Dystrophin. While investigating CBP rescuing potential we observed that dystrophin-null embryos overexpressing CBP actually never show significant muscle damage, even before a first regeneration cycle could occur. We found that the pan-HDAC inhibitor trichostatin A (TSA) also prevents early muscle damage, however the single HAT CBP is as efficient even in low doses. The HAT domain of CBP is required for its full rescuing ability. Importantly, both CBP and TSA prevent early muscle damage without restoring endogenous CBP/p300 neither increasing follistatin transcripts. This suggests a new mechanism of action of epigenetic regulators protecting dystrophin-null muscle fibres from detaching, independent from the known improvement of regeneration upon damage of HDACs inhibitors. This study builds supporting evidence that epigenetic modulators may play a role in determining the severity of muscle dystrophy, controlling the ability to resist muscle damage. Determining the mode of action leading to muscle protection can potentially lead to new treatment options for muscular dystrophies in the future.

  5. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Mota, Alba, E-mail: amota@iib.uam.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Jiménez-Garcia, Lidia, E-mail: ljimenez@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Herránz, Sandra, E-mail: sherranz@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Heras, Beatriz de las, E-mail: lasheras@ucm.es [Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid (Spain); Hortelano, Sonsoles, E-mail: shortelano@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain)

    2015-08-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  6. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    International Nuclear Information System (INIS)

    Mota, Alba; Jiménez-Garcia, Lidia; Herránz, Sandra; Heras, Beatriz de las; Hortelano, Sonsoles

    2015-01-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  7. Knockdown of long noncoding RNA linc-ITGB1 suppresses migration, invasion of hepatocellular carcinoma via regulating ZEB1.

    Science.gov (United States)

    Yu, W-W; Wang, K; Liao, G-J

    2017-11-01

    This research focuses on the influence of linc-ITGB1 on the metastasis of hepatocellular carcinoma and further explores its underlying mechanism. A total of 70 hepatocellular carcinoma patients were chosen for our study. RT-qPCR was used for detecting the expression level of linc-ITGB1 in their cancer tissues. Moreover, the expression level of linc-ITGB1 was also detected in hepatocellular carcinoma cell lines. Furthermore, whether linc-ITGB1 could affect the migrated and invaded ability of hepatocellular carcinoma cells was determined by wound healing assay and transwell assay. We further explored the potential mechanism by RT-qPCR and Western blot assay. Linc-ITGB1 expression level in hepatocellular carcinoma tissues was remarkably higher than that in adjacent tissues. Moreover, migrated and invaded ability of hepatocellular carcinoma cells was inhibited through knockdown of linc-ITGB1. Further study revealed that silenced linc-ITGB1 inhibited the expression of ZEB1 and then suppressed epithelial to mesenchymal transition (EMT), which was important during the metastasis of hepatocellular carcinoma. Moreover, the inhibition of cell invasion by silenced linc-ITGB1 could be rescued through overexpression of ZEB1 in hepatocellular carcinoma. The results indicate that linc-ITGB1, a novel oncogene in tumorigenesis, could promote the metastasis and EMT via ZEB1, which may offer a possible therapeutic target in hepatocellular carcinoma.

  8. Nanocurcumin-Mediated Down-Regulation of Telomerase Via Stimulating TGFβ1 Signaling Pathway in Hepatocellular Carcinoma Cells

    Science.gov (United States)

    Shariati, Molood; Hajigholami, Samira; Veisi Malekshahi, Ziba; Entezari, Maliheh; Bodaghabadi, Narges; Sadeghizadeh, Majid

    2017-10-10

    Curcumin, extracted from turmeric, represents enormous potential to serve as an anticancer agent. Telomerase is viewed as a prominent molecular target of curcumin, and Transforming growth factor-β1 (TGFβ1) has proven to be a major inhibitory signaling pathway for telomerase activity. In the current study, we aimed to explore suppressive effects of nanocurcumin on telomerase expression through TGFβ1 pathway in a hepatocellular carcinoma cell line (Huh7). MTT assay was used to determine the effect of nonocurcumin on viability of Huh7 cells. RT-PCR was used to analyze the gene expression patterns. MTT assay revealed that nanocurcumin acts in a dose- and time-dependent manner to diminish the cell viability. RT-PCR analysis indicated that nanocurcumin results in augmentation of TGFβ1 72 hours post treatment and leads to the reduction of telomerase expression 48 and 72 hours post exposure. Also, up-regulation of Smad3 and E2F1 and down-regulation of Smad7 confirmed the effect of nanocurcumin on intermediate components of TGFβ1 pathway. Furthermore, transfection of the proximal promoter of telomerase triggered a significant reduction in luciferase activity. The data from the present study lead us to develop a deeper understanding of the mechanisms underlying nanocurcumin-mediated regulation of telomerase expression, thereby presenting a new perspective to the landscape of using nanocurcumin as a cancer-oriented therapeutic agent.

  9. A 4-Phenoxyphenol Derivative Exerts Inhibitory Effects on Human Hepatocellular Carcinoma Cells through Regulating Autophagy and Apoptosis Accompanied by Downregulating α-Tubulin Expression

    Directory of Open Access Journals (Sweden)

    Wen-Tsan Chang

    2017-05-01

    Full Text Available Hepatocellular carcinoma (HCC is a leading cancer worldwide. Advanced HCCs are usually resistant to anticancer drugs, causing unsatisfactory chemotherapy outcomes. In this study, we showed that a 4-phenoxyphenol derivative, 4-[4-(4-hydroxyphenoxyphenoxy]phenol (4-HPPP, exerts an inhibitory activity against two HCC cell lines, Huh7 and Ha22T. We further investigated the anti-HCC activities of 4-HPPP, including anti-proliferation and induction of apoptosis. Our results showed that higher dosage of 4-HPPP downregulates the expression of α-tubulin and causes nuclear enlargement in both the Huh-7 and Ha22T cell lines. Interestingly, the colony formation results showed a discrepancy in the inhibitory effect of 4-HPPP on HCC and rat liver epithelial Clone 9 cells, suggesting the selective cytotoxicity of 4-HPPP toward HCC cells. Furthermore, the cell proliferation and apoptosis assay results illustrated the differences between the two HCC cell lines. The results of cellular proliferation assays, including trypan blue exclusion and colony formation, revealed that 4-HPPP inhibits the growth of Huh7 cells, but exerts less cytotoxicity in Ha22T cells. Furthermore, the annexin V assay performed for detecting the apoptosis showed similar results. Western blotting results showed 4-HPPP caused the increase of pro-apoptotic factors including cleaved caspase-3, Bid and Bax in HCC cells, especially in Huh-7. Furthermore, an increase of autophagy-associated protein microtubule-associated protein-1 light chain-3B (LC3B-II and the decrease of Beclin-1 and p62/SQSTM1 were observed following 4-HPPP treatment. Additionally, the level of γH2A histone family, member X (γH2AX, an endogenous DNA damage biomarker, was dramatically increased in Huh7 cells after 4-HPPP treatment, suggesting the involvement of DNA damage pathway in 4-HPPP-induced apoptosis. On the contrary, the western blotting results showed that treatment up-regulates pro-survival proteins, including the

  10. miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Peng; Wu, Dingguo; You, Yu; Sun, Jing; Lu, Lele; Tan, Jiaxing; Bie, Ping, E-mail: bieping2010@163.com

    2015-08-15

    MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at post-transcriptional level. miRNA dysregulation plays a causal role in cancer progression. In this study, miR-208-3p was highly expressed and directly repressed ARID2 expression. As a result, ARID2 expression in hepatocellular carcinoma (HCC) was decreased. In vitro, miR-208-3p down-regulation and ARID2 over-expression elicited similar inhibitory effects on HCC cell proliferation and invasion. In vivo test results revealed that miR-208-3p down-regulation inhibited HCC tumorigenesis in Hep3B cells. Moreover, ARID2 was possibly a downstream element of transforming growth factor beta1 (TGFβ1)/miR-208-3p/ARID2 regulatory pathway. These findings suggested that miR-208-3p up-regulation is associated with HCC cell progression and may provide a new target for liver cancer treatment. - Highlights: • miR-208-3p was highly expressed and directly repressed the expression of ARID2 in HCC. • miR-208-3p contributed to HCC cell progression both in vitro and in vivo. • Over-expression of ARID2 inhibited the HCC cell proliferation and invasion. • Restoration of ARID2 partly reversed the the effect of miR-208-3p down-regulation on HCC cells. • Newly regulatory pathway: miR-208-3p mediated the repression of ARID2 by TGFβ1 in HCC cells.

  11. NLRC5 promotes cell proliferation via regulating the AKT/VEGF-A signaling pathway in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    He, Ying-hua; Li, Ming-fang; Zhang, Xing-yan; Meng, Xiao-ming; Huang, Cheng; Li, Jun

    2016-01-01

    NLRC5, a newly found member of the NLR family and the largest member of nucleotide-binding, has been reported to regulate immune responses and is associated with hepatocellular carcinoma (HCC). We investigated the mechanisms and signaling pathways of NLRC5 in HCC progression. Increased expression of NLRC5, vascular endothelial growth factor-A (VEGF-A) were found in human HCC tissue. There was a positive correlation between NLRC5 and VEGF-A expression and cell proliferation were enhanced in NLRC5-overexpressing HepG2 cells, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that up-regulation of NLRC5 also coordinated the activation of PI3K/AKT signaling pathway. An AKT inhibitor LY294002 blocked VEGF-A expression and AKT phosphorylation in HepG2 cells and NLRC5-overexpressing HepG2 cells. These results demonstrate that NLRC5 promotes HCC progression via the AKT/VEGF-A signaling pathway.

  12. The rs391957 variant cis-regulating oncogene GRP78 expression contributes to the risk of hepatocellular carcinoma.

    Science.gov (United States)

    Zhu, Xiao; Zhang, Jinfang; Fan, Wenguo; Wang, Fang; Yao, Hong; Wang, Zifeng; Hou, Shengping; Tian, Yinghong; Fu, Weiming; Xie, Dan; Zhu, Wei; Long, Jun; Wu, Leijie; Zheng, Xuebao; Kung, Hsiangfu; Zhou, Keyuan; Lin, Marie C M; Luo, Hui; Li, Dongpei

    2013-06-01

    Glucose-regulated protein 78 (GRP78) is one of the most important responders to disease-related stress. We assessed the association of the promoter polymorphisms of GRP78 with risk of hepatocellular carcinoma (HCC) and GRP78 expression in a Chinese population. We examined 1007 patients undergoing diagnostic HCC and 810 unrelated healthy controls. Mechanisms by which the GRP78 promoter polymorphism modulates HCC risk and GRP78 levels were analyzed. The promoter haplotype and diplotype carrying rs391957 (-415bp) allele G and genotype GG was strongly associated with HCC risk. Luciferase reporter assays indicated that the promoter carrying rs391957 allele G (haplotype GCCd) showed increased activity in HepG2 cells and Hela cells. rs391957 was also shown to increase the affinity of the transcriptional activator Ets-2, the resistance to apoptosis, as well as cell instability in stressful microenvironment. Furthermore, compared with allele A, rs391957 allele G was associated with higher levels of GRP78 mRNA and protein in HCC tissues. These findings provided new insights into the pathogenesis of HCC and an unexpected effect of the interaction between rs391957 and Ets-2 on hepatocarcinogenesis, and especially supported the hypothesis that stress-related and evolutionarily conserved genetic variant(s) influencing transcriptional regulation could predict susceptibilities.

  13. Hepatitis B virus X protein suppresses caveolin-1 expression in hepatocellular carcinoma by regulating DNA methylation

    International Nuclear Information System (INIS)

    Yan, Jun; Lu, Qian; Dong, Jiahong; Li, Xiaowu; Ma, Kuansheng; Cai, Lei

    2012-01-01

    To understand the molecular mechanisms of caveolin-1 downregulation by hepatitis B virus X protein (HBx). The DNA methylation status of the caveolin-1 promoter was examined by nested methylation-specific PCR of 33 hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) samples. The SMMC-7721 hepatoma cell line was transfected with a recombinant HBx adenoviral vector, and the effects of HBx protein on caveolin-1 expression and promoter methylation were examined and confirmed by sequencing. A reporter gene containing the caveolin-1 promoter region was constructed, and the effects of HBx on the transcriptional activity of the promoter were also studied. Methylation of the caveolin-1 promoter was detected in 84.8% (28/33) of HBV-infected HCC samples. Expression of caveolin-1 was significantly downregulated (P = 0.022), and multiple CpG sites in the promoter region of caveolin-1 were methylated in SMMC-7721 cells after HBx transfection. Transfected HBx significantly suppressed caveolin-1 promoter activity (P = 0.001). HBx protein induces methylation of the caveolin-1 promoter region and suppresses its expression

  14. SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma.

    Science.gov (United States)

    Tai, Wei-Tien; Hung, Man-Hsin; Chu, Pei-Yi; Chen, Yao-Li; Chen, Li-Ju; Tsai, Ming-Hsien; Chen, Min-Husan; Shiau, Chung-Wai; Boo, Yin-Pin; Chen, Kuen-Feng

    2016-04-19

    Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP-1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC.

  15. The Brussels I Regulation and Liability for Nuclear Damage

    International Nuclear Information System (INIS)

    Handrlica, J.

    2010-01-01

    Prior to 2004, the map of the European Union seemed to be basically identical to the map of the contracting parties to the Paris Convention on Third Party Liability in the Field of Nuclear Energy of 1960 ('the Paris Convention'). The 2004 and 2007 enlargements were mainly composed of the contracting parties to the Vienna Convention on Civil Liability for Nuclear Damage of 1963 ('the Vienna Convention'). In various discussions, the term 'nuclear liability patchwork' is used to describe this existing situation. One of the problems arising from this 'patchwork' is that, while a uniform legal framework was established for matters of jurisdiction and the enforcement of decisions under the authority given to the European Union ('EU') by the Council Regulation on jurisdiction and the recognition and enforcement of judgements in civil and commercial matters ('Brussels Regulation'), this overall framework does not apply to particular matters governed by the special conventions to which member states may be contracting parties, see Article 71 of the Brussels Regulation. This paper aims to outline the 'patchwork' of these rules that are applicable to nuclear third party liability cases in the EU and to point out the main consequences arising from this legal framework difficult to comprehend.5 Its scope, however, is limited to the legal issues arising from a nuclear incident occurring in a nuclear installation situated within the territory of the European Union

  16. Vesicular (liposomal and nanoparticulated delivery of curcumin: a comparative study on carbon tetrachloride–mediated oxidative hepatocellular damage in rat model

    Directory of Open Access Journals (Sweden)

    Choudhury ST

    2016-05-01

    -induced oxidative stress–mediated hepatocellular damage and thereby can be considered as an effective therapeutic strategy. Keywords: reactive oxygen species, mitochondria, apoptosis, antioxidants, histopathology, Western blot

  17. Up-regulation and subcellular localization of hnRNP A2/B1 in the development of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Cui, Huaqing; Wu, Feng; Sun, Yanling; Fan, Guocai; Wang, Qingming

    2010-01-01

    Hepatocellular carcinoma (HCC) is one of the world's leading causes of death among cancer patients. It is important to find a new biomarker that diagnoses HCC and monitors its treatment. In our previous work, we screened a single-chain antibody (scFv) N14, which could specifically recognize human HepG2 HCC cells but not human non-cancerous liver LO2 cells. However, the antigen it recognized in the cells remained unknown. Recombinant scFv N14 antibody was expressed as an active antibody. Using this antibody with a combination of immunological and proteomic approaches, we identified the antigen of scFv N14 antibody as the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). The expression of hnRNP A2/B1 in HCC cells was then investigated by semi-quantitative RT-PCR and immunohistochemistry. We found that the up-regulation of hnRNP A2/B1 was measured at both transcriptional and translational levels in rat HCC cells but not in rat hepatic cells. We also found that in various human hepatic tissues, hnRNP A2/B1 was highly expressed in both human hepatitis virus positive liver tissues and human HCC tissues but not in normal liver tissues. Interestingly, we observed that the localization of hnRNP A2/B1 in HCC cells was altered during the development of HCC. In human hepatitis virus infected tissues hnRNP A2/B1 resides exclusively in the nuclei of hepatocytes. However, when the HCC progressed from a well differentiated to a poorly differentiated stage, hnRNP A2/B1 was increasingly localized in the cytoplasm. In contrast, the HCC tissues with hnRNP A2/B1 highly expressed in the nucleus decreased. This work is the first to show that hnRNP A2/B1 is the antigen specifically recognized by the scFv N14 antibody in HCC cells. The over-expression of hnRNP A2/B1 was confirmed in cultured human and rat HCC cell lines, human virus related hepatitis liver tissues and human HCC tissues. The increased localization of hnRNP A2/B1 in the cytoplasm of HCC cells was revealed

  18. DNA methylation-dependent regulation of TrkA, TrkB, and TrkC genes in human hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Wook [Laboratory of Molecular Disease and Cell Regulation, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon (Korea, Republic of); Lee, Jong-Joo [Department of Environmental Medical Biology, Institute of Tropical Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Kim, Min Soo [Laboratory of Molecular Disease and Cell Regulation, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon (Korea, Republic of); Son, Byung Ho [Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746 (Korea, Republic of); Cho, Yong Kyun, E-mail: choyk2004@hanmail.net [Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746 (Korea, Republic of); Kim, Hyoung-Pyo, E-mail: kimhp@yuhs.ac [Department of Environmental Medical Biology, Institute of Tropical Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

    2011-03-04

    Research highlights: {yields} Expression of TrkA, TrkB, and TrkC is significantly elevated in human hepatocellular carcinoma. {yields} Downregulation of Trks is correlated with their promoter hypermethylation. {yields} Inhibiting DNA methylation restored expression of Trks in normal liver cell lines. {yields} Trks promote the proliferation of hepatocellular carcinoma. {yields} Trks induce expression of the metastatic regulator, Twist. -- Abstract: The tropomyosin-related kinase (Trk) family of neurotrophin receptors, TrkA, TrkB and TrkC, has been implicated in the growth and survival of human cancers. Here we report that Trks are frequently overexpressed in hepatocellular carcinoma (HCC) from patients and human liver cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of CpG islands in TrkA, TrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkA, TrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines. Furthermore, Trks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These results suggest that Trks may contribute to growth and metastasis of liver cancer.

  19. DNA methylation-dependent regulation of TrkA, TrkB, and TrkC genes in human hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Jin, Wook; Lee, Jong-Joo; Kim, Min Soo; Son, Byung Ho; Cho, Yong Kyun; Kim, Hyoung-Pyo

    2011-01-01

    Research highlights: → Expression of TrkA, TrkB, and TrkC is significantly elevated in human hepatocellular carcinoma. → Downregulation of Trks is correlated with their promoter hypermethylation. → Inhibiting DNA methylation restored expression of Trks in normal liver cell lines. → Trks promote the proliferation of hepatocellular carcinoma. → Trks induce expression of the metastatic regulator, Twist. -- Abstract: The tropomyosin-related kinase (Trk) family of neurotrophin receptors, TrkA, TrkB and TrkC, has been implicated in the growth and survival of human cancers. Here we report that Trks are frequently overexpressed in hepatocellular carcinoma (HCC) from patients and human liver cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of CpG islands in TrkA, TrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkA, TrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines. Furthermore, Trks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These results suggest that Trks may contribute to growth and metastasis of liver cancer.

  20. Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development.

    Science.gov (United States)

    Pu, Wenchen; Li, Jiao; Zheng, Yuanyuan; Shen, Xianyan; Fan, Xin; Zhou, Jian-Kang; He, Juan; Deng, Yulan; Liu, Xuesha; Wang, Chun; Yang, Shengyong; Chen, Qiang; Liu, Lunxu; Zhang, Guolin; Wei, Yu-Quan; Peng, Yong

    2018-01-30

    Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with the Pin1 inhibitor (API-1), a specific small molecule targeting Pin1 peptidyl-prolyl isomerase domain and inhibiting Pin1 cis-trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API-1-induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low exportin-5 (XPO5) phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated serine-proline motif of phosphorylated XPO5 and passivates phosphorylated XPO5. Pin1 inhibition by API-1 maintains the active conformation of phosphorylated XPO5 and restores XPO5-driven precursor miRNA nuclear-to-cytoplasm export, activating anticancer miRNA biogenesis and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Experimental evidence suggests that Pin1 inhibition by API-1 up-regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supporting API-1 as a drug candidate for HCC therapy, especially for Pin1-overexpressing, extracellular signal-regulated kinase-activated HCC. (Hepatology 2018). © 2018 by the American Association for the Study of Liver Diseases.

  1. Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Huang, Jian; Zhang, Yun-Li; Teng, Xiao-Mei; Lin, Yun; Zheng, Da-Li; Yang, Peng-Yuan; Han, Ze-Guang

    2007-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. SFRP1 (the secreted frizzled-related protein 1), a putative tumor suppressor gene mapped onto chromosome 8p12-p11.1, the frequent loss of heterozygosity (LOH) region in human HCC, encodes a Wingless-type (Wnt) signaling antagonist and is frequently inactivated by promoter methylation in many human cancers. However, whether the down-regulation of SFRP1 can contribute to hepatocarcinogenesis still remains unclear. We investigated the expression of SFRP1 through real time RT-PCR and immunohistochemistry staining. The cell growth and colony formation were observed as the overexpression and knockdown of SFRP1. The DNA methylation status within SFRP1 promoter was analyzed through methylation-specific PCR or bisulphate-treated DNA sequencing assays. Loss of heterozygosity was here detected with microsatellite markers. SFRP1 was significantly down-regulated in 76.1% (35/46) HCC specimens at mRNA level and in 30% (30/100) HCCs indicated by immunohistochemistry staining, as compared to adjacent non-cancerous livers. The overexpression of SFRP1 can significantly inhibit the cell growth and colony formation of YY-8103, SMMC7721, and Hep3B cells. The RNA interference against the constitutional SFRP1 in the offspring SMMC7721 cells, which were stably transfected by ectopic SFRP1, can markedly promote cell growth of these cells. LOH of both microsatellite markers D8S532 and D8SAC016868 flanking the gene locus was found in 13% (6 of 46 HCCs) and 6.5% (3 of 46 HCCs) of the informative cases, respectively, where 5 of 8 HCC specimens with LOH showed the down-regulation of SFRP1. DNA hypermethylation within SFRP1 promoter was identified in two of three HCC specimens without SFRP1 expression. Moreover, the DNA methylation of SFRP1 promoter was significantly reduced, along with the re-expression of the gene, in those HCC cell lines, Bel7404, QGY7701, and MHCC-H, as treated by DAC. Our data suggested that the

  2. JS-K, a nitric oxide prodrug, induces DNA damage and apoptosis in HBV-positive hepatocellular carcinoma HepG2.2.15 cell.

    Science.gov (United States)

    Liu, Zhengyun; Li, Guangmin; Gou, Ying; Xiao, Dongyan; Luo, Guo; Saavedra, Joseph E; Liu, Jie; Wang, Huan

    2017-08-01

    Hepatocellular carcinoma (HCC) is the most important cause of cancer-related death, and 85% of HCC is caused by chronic HBV infection, the prognosis of patients and the reduction of HBV DNA levels remain unsatisfactory. JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors, but little is known on its effects on HBV positive HCC. We found that JS-K reduced the expression of HBsAg and HBeAg in HBV-positive HepG2.2.15 cells. This study aimed to further examine anti-tumor effects of JS-K on HepG2.2.15 cells. The MTT assay and colony forming assay were used to study the cell growth inhibition of JS-K; scratch assay and transwell assay were performed to detect cell migration. The cell cycle was detected by flow cytometry. The immunofluorescence, flow cytometry analysis, and western blot were used to study DNA damage and cell apoptosis. JS-K inhibited HepG2.2.15 cell growth in a dose-dependent manner, suppressed cell colony formation and migration, arrested cells gather in the G2 phase. JS-K (1-20μM) increased the expression of DNA damage-associated protein phosphorylation H 2 AX (γH 2 AX), phosphorylation of checkpoint kinase 1 (p-Chk1), phosphorylation of checkpoint kinase 2 (p-Chk2), ataxia-telangiectasia mutated (ATM), phosphorylation of ataxia-telangiectasia mutated rad3-related (p-ATR) and apoptotic-associated proteins cleaved caspase-3, cleaved caspase-7, cleaved poly ADP-ribose polymerase (cleaved PARP). The study demonstrated JS-K is effective against HBV-positive HepG2.2.15 cells, the mechanisms are not only related to inhibition of HBsAg and HBeAg secretion, but also related with induction of DNA damage and apoptosis. JS-K is a promising anti-cancer candidate against HBV-positive HCC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Regulation of annexins following infection like tissue damage – investigated by 2-dimensional gel electrophoresis

    DEFF Research Database (Denmark)

    Wulff, Tune; Nielsen, Michael Engelbrecht

    are regulated after tissue damaged on the protein level. These proteins have been assign to functions like regulation of coagulation, apoptosis, and exocytosis, indicating their importance following infection and subsequent repair in fish. In addition the regulation observed in this study are supported...... an established model. In the model infection is mimicked by a well-defined tissue damage allowing each fish to be equally affected. Samples were taken 7 days after tissue damage and included samples from the damaged tissue, internal control and an external control. Changes in protein expression between the wound...... by previous findings on the mRNA level, where both proteins are regulated following infection. In conclusion this study show regulation on the protein level of two members of the annexin protein family after infection like tissue damage....

  4. Alteration of hepatocellular antioxidant gene expression pattern and biomarkers of oxidative damage in diazinon-induced acute toxicity in Wistar rat: A time-course mechanistic study.

    Science.gov (United States)

    Hassani, Shokoufeh; Maqbool, Faheem; Salek-Maghsoudi, Armin; Rahmani, Soheila; Shadboorestan, Amir; Nili-Ahmadabadi, Amir; Amini, Mohsen; Norouzi, Parviz; Abdollahi, Mohammad

    2018-01-01

    In the present survey, the plasma level of diazinon after acute exposure was measured by HPLC method at a time-course manner. In addition, the impact of diazinon on the expression of the key genes responsible for hepatocellular antioxidative defense, including PON1, GPx and CAT were investigated. The increase in oxidative damages in treated rats was determined by measuring LPO, protein carbonyl content and total antioxidant power in plasma. After administration of 85 mg/kg diazinon in ten groups of male Wistar rats at different time points between 0-24 hours, the activity of AChE enzyme was inhibited to about 77.94 %. Significant increases in carbonyl groups and LPO after 0.75 and 1 hours were also observed while the plasma antioxidant power was significantly decreased. Despite the dramatic reduction of GP X and PON1 gene expression, CAT gene was significantly upregulated in mRNA level by 1.1 fold after 4 hours and 1.5-fold after 24 hours due to diazinon exposure, compared to control group. Furthermore, no significant changes in diazinon plasma levels were found after 4 hours in the treated rats. The limits of detection and quantification were 137.42 and 416.52 ng/mL, respectively. The average percentage recoveries from plasma were between 90.62 % and 95.72 %. In conclusion, acute exposure to diazinon increased oxidative stress markers in a time-dependent manner and the changes were consistent with effects on hepatic antioxidant gene expression pattern. The effect of diazinon even as a non-lethal dose was induced on the gene expression of antioxidant enzymes. The change in antioxidant defense system occurs prior to diazinon plasma peak time. These results provide biochemical and molecular evidence supporting potential acute toxicity of diazinon and is beneficial in the evaluation of acute toxicity of other organophosphorus pesticides as well.

  5. Melittin induces PTCH1 expression by down-regulating MeCP2 in human hepatocellular carcinoma SMMC-7721 cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Xiaoqin; Zhao, Bin; Cheng, Yahui; Yang, Yang; Huang, Cheng; Meng, Xiaoming; Wu, Baoming; Zhang, Lei; Lv, Xiongwen; Li, Jun, E-mail: xqwu01@foxmail.com

    2015-10-01

    Hepatocellular carcinoma (HCC) has a high mortality rate worldwide and still remains to be a noticeable public health problem. Therefore, new remedies are urgently needed. Melittin, a major component of bee venom, is known to suppress cell growth in various cancers including HCC. However, the mechanism of the anticancer effect of melittin on HCC has not been fully elucidated. It has been reported that Methyl-CpG binding protein 2 (MeCP2) plays a key role in tumor proliferation, apoptosis, migration and invasion. In the present study, we found the high expression of MeCP2 in human HCC tissues and in the SMMC-7721 cell line. MeCP2 silencing inhibited cell proliferation, while over-expression of MeCP2 promoted cell growth in SMMC-7721 cells. It indicates that MeCP2 may be an attractive target for human HCC. We further found that melittin could inhibit cell proliferation by reducing MeCP2 expression in vitro. Interestingly, the inhibitory effect of melittin on cell proliferation was due to a delay in G{sub 0}/G{sub 1} cell cycle progression, without influencing cell apoptosis. Next, we investigated the potential molecular mechanisms and found that MeCP2 could modulate Shh signaling in SMMC-7721 cells. Further study indicates that melittin may induce the demethylation of PTCH1 promoter, resulting in the increased expression of PTCH1. Furthermore, the expression of Shh and GLI1 was significantly lowered upon treatment of melittin. These results suggest that melittin can block Shh signaling in vitro. In short, these results indicate that melittin inhibits cell proliferation by down-regulating MeCP2 through Shh signaling in SMMC-7721 cells. - Highlights: • MeCP2 plays a key role in the proliferation of human HCC cells. • Melittin reduces MeCP2 expression in vitro. • Melittin induces G{sub 0}/G{sub 1} cell cycle arrest in SMMC-7721 cells. • MeCP2 modulates the Shh signaling pathway in SMMC-7721 cells. • Melittin blocks the Shh signaling pathway in SMMC-7721 cells.

  6. Melittin induces PTCH1 expression by down-regulating MeCP2 in human hepatocellular carcinoma SMMC-7721 cells

    International Nuclear Information System (INIS)

    Wu, Xiaoqin; Zhao, Bin; Cheng, Yahui; Yang, Yang; Huang, Cheng; Meng, Xiaoming; Wu, Baoming; Zhang, Lei; Lv, Xiongwen; Li, Jun

    2015-01-01

    Hepatocellular carcinoma (HCC) has a high mortality rate worldwide and still remains to be a noticeable public health problem. Therefore, new remedies are urgently needed. Melittin, a major component of bee venom, is known to suppress cell growth in various cancers including HCC. However, the mechanism of the anticancer effect of melittin on HCC has not been fully elucidated. It has been reported that Methyl-CpG binding protein 2 (MeCP2) plays a key role in tumor proliferation, apoptosis, migration and invasion. In the present study, we found the high expression of MeCP2 in human HCC tissues and in the SMMC-7721 cell line. MeCP2 silencing inhibited cell proliferation, while over-expression of MeCP2 promoted cell growth in SMMC-7721 cells. It indicates that MeCP2 may be an attractive target for human HCC. We further found that melittin could inhibit cell proliferation by reducing MeCP2 expression in vitro. Interestingly, the inhibitory effect of melittin on cell proliferation was due to a delay in G 0 /G 1 cell cycle progression, without influencing cell apoptosis. Next, we investigated the potential molecular mechanisms and found that MeCP2 could modulate Shh signaling in SMMC-7721 cells. Further study indicates that melittin may induce the demethylation of PTCH1 promoter, resulting in the increased expression of PTCH1. Furthermore, the expression of Shh and GLI1 was significantly lowered upon treatment of melittin. These results suggest that melittin can block Shh signaling in vitro. In short, these results indicate that melittin inhibits cell proliferation by down-regulating MeCP2 through Shh signaling in SMMC-7721 cells. - Highlights: • MeCP2 plays a key role in the proliferation of human HCC cells. • Melittin reduces MeCP2 expression in vitro. • Melittin induces G 0 /G 1 cell cycle arrest in SMMC-7721 cells. • MeCP2 modulates the Shh signaling pathway in SMMC-7721 cells. • Melittin blocks the Shh signaling pathway in SMMC-7721 cells.

  7. Hepatocellular calcification

    DEFF Research Database (Denmark)

    Ladefoged, Claus; Frifelt, J J

    1987-01-01

    Autopsy of a twenty year old girl dying from complications of renal and cardiac failure demonstrated severe hepatocellular calcification, a rare finding. The pathogenesis is thought to be a combination of dystrophic calcification caused by severe centrilobular necrosis and metastatic calcificatio...

  8. Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma.

    Science.gov (United States)

    Lai, Kun-Goung; Chen, Chi-Fen; Ho, Chun-Te; Liu, Jun-Jen; Liu, Tsan-Zon; Chern, Chi-Liang

    2017-06-01

    We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose-regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including γ-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process.

  9. Glucose-regulated protein 78 regulates the expression of mitochondrial genesis proteins in HBV-related hepatocellular carcinoma: a clinical analysis

    Directory of Open Access Journals (Sweden)

    LI Yaping

    2017-10-01

    Full Text Available ObjectiveTo investigate the expression of glucose-regulated protein 78 (GRP78 in HBV-related hepatocellular carcinoma (HBV-HCC and its association with clinicopathological features, as well as its regulatory effect on mitochondrial genesis proteins in hepatoma cells, and to provide a basis for new strategies for the prevention and treatment of HCC. MethodsTissue samples were collected from 54 patients with HBV-HCC, and immunohistochemistry and Western blot were used to measure the expression of GRP78, Lon, TFAM, and cytochrome C oxidase Ⅳ (COXⅣ. The expression of GRP78 in hepatoma cells was interfered by siRNA, and then the expression of GRP78, Lon, mitochondrial transcription factor A (TFAM, and COX Ⅳ was measured. Quantitative real-time PCR was used to measure the level of mitochondrial DNA (mtDNA in clinical specimens and HCC cells after GRP78 expression was interfered with. A statistical analysis was performed for clinical and experimental data. The t-test was used for comparison of continuous data between groups, the Fisher′s exact test was used for comparison of categorical data between groups, and the Kaplan-Meier method was used for survival analysis. Results Compared with the adjacent tissues, HBV-HCC tissues had significantly higher expression of GRP78 and Lon (t=9.135 and 5523, both P<0.0001 and significantly lower expression of the mitochondrial genesis proteins TFAM and COX Ⅳ and mtDNA level (t=2.765, 4260, and 12.280, P=0.011, <0.001, and <0.001. There were significant increases in the expression of the mitochondrial genesis proteins TFAM and COX Ⅳ and mtDNA level after the interference with GRP78 expression in hepatoma cells (all P<0.05. There were significant differences in the expression of GRP78 between patients with different numbers of tumors, patients with and without portal vein tumor thrombus, and patients with different tumor stages (P=0.016, 0.003, and 0.045. The patients with low GRP78

  10. Overexpression of Zwint predicts poor prognosis and promotes the proliferation of hepatocellular carcinoma by regulating cell-cycle-related proteins

    Directory of Open Access Journals (Sweden)

    Ying H

    2018-02-01

    Full Text Available Hanning Ying,1,2 Zhiyao Xu,3 Mingming Chen,1,2 Senjun Zhou,1,2 Xiao Liang,1,2 Xiujun Cai1,2 1Department of General Surgery, 2Key Laboratory of Endoscopic Technique Research of Zhejiang Province, 3Central Lab of Biomedical Research Center, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China Introduction: Zwint, a centromere-complex component required for the mitotic spindle checkpoint, has been reported to be overexpressed in different human cancers, but it has not been studied in human hepatocellular carcinoma (HCC.Materials and methods: The role of Zwint in hepatocellular carcinoma cell proliferation capacities was evaluated by using cell counting kit-8 (CCK8, flow cytometry, clone formation and tumor formation assay in nude mice. Western blot analysis and qPCR assay were performed to assess Zwint interacting with cell-cycle-related proteins.Results: We report that ZWINT mRNA and protein expression were upregulated in HCC samples and cell lines. An independent set of 106 HCC-tissue pairs and corresponding noncancerous tissues was evaluated for Zwint expression using immunohistochemistry, and elevated Zwint expression in HCC tissues was significantly correlated with clinicopathological features, such as tumor size and number. Kaplan–Meier survival and Cox regression analysis revealed that high expression of Zwint was correlated with poor overall survival and a greater tendency for tumor recurrence. Ectopic expression of Zwint promoted HCC-cell proliferation, and Zwint expression affected the expression of several cell-cycle proteins, including PCNA, cyclin B1, Cdc25C and CDK1.Conclusion: Our findings suggest that upregulation of Zwint may contribute to the progression of HCC and may be a prognostic biomarker and potential therapeutic target for treating HCC. Keywords: Zwint, hepatocellular carcinoma, HCC, prognosis, cell proliferation, cell cycle

  11. Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating Snail2-mediated epithelial–mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Xu Y

    2017-02-01

    Full Text Available Yongfu Xu,* Binfeng Wang,* Fabiao Zhang, Aidong Wang, Xuefeng Du, Peng Hu, Yu Zhu, Zheping Fang Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Increasing evidence has demonstrated that aberrant expressions of long non-coding RNAs (lncRNAs are involved in various malignancies, including hepatocellular carcinoma (HCC. This study aimed to investigate the role of lncRNA colon cancer-associated transcript 2 (CCAT2 in the progression of HCC. Quantitative real-time polymerase chain reaction analysis confirmed that CCAT2 was upregulated in HCC cell lines and cancerous tissues compared with normal liver cell line and adjacent normal tissue samples. The level of CCAT2 was positively associated with tumor–node–metastasis stages and vessel invasion. Survival analyses revealed that high CCAT2 expression predicted poor prognostic outcomes, serving as an independent prognostic factor for HCC patients. Patients with high CCAT2 expression had a 1.849-fold increased risk of death compared with those with low CCAT2 expression. Moreover, we also found that knockdown of CCAT2 expression reduced cell migration and invasion in vitro. We further demonstrated that CCAT2 played a key role in enhancing the epithelial–mesenchymal transition (EMT through the regulation of vimentin, E-cadherin and transcription factor snail2 expression. Taken together, our findings showed that high CCAT2 expression is associated with poor survival in HCC patients. CCAT2 promotes HCC progression by regulating Snail2-induced EMT. CCAT2 may be a prognostic biomarker and therapeutic target for HCC. Keywords: long non-coding RNA, CCAT2, hepatocellular carcinoma, epithelial–mesenchymal transition, survival

  12. Annexin A2 promotes the migration and invasion of human hepatocellular carcinoma cells in vitro by regulating the shedding of CD147-harboring microvesicles from tumor cells.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    Full Text Available It has been reported that Annexin A2 (ANXA2 is up-regulated in hepatocellular carcinoma (HCC, but the roles of ANXA2 in the migration and invasion of HCC cells have not been determined. In this study, we found that ANXA2-specific siRNA (si-ANXA2 significantly inhibited the migration and invasion of HCC cells co-cultured with fibroblasts in vitro. In addition, the production of MMP-2 by fibroblasts cultured in supernatant collected from si-ANXA2-transfected HCC cells was notably down-regulated. ANXA2 was also found to be co-localized and co-immunoprecipitated with CD147. Further investigation revealed that the expression of ANXA2 in HCC cells affected the shedding of CD147-harboring membrane microvesicles, acting as a vehicle for CD147 in tumor-stromal interactions and thereby regulating the production of MMP-2 by fibroblasts. Together, these results suggest that ANXA2 enhances the migration and invasion potential of HCC cells in vitro by regulating the trafficking of CD147-harboring membrane microvesicles.

  13. Down-regulation of Transducin-Like Enhancer of Split protein 4 in hepatocellular carcinoma promotes cell proliferation and epithelial-Mesenchymal-Transition

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Xiao-cai; Xiao, Cui-cui; Li, Hua [Department of Hepatic Surgery, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou (China); Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou (China); Tai, Yan; Zhang, Qi [Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou (China); Yang, Yang, E-mail: yysysu2@163.com [Department of Hepatic Surgery, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou (China)

    2016-08-19

    Background: Transducin-Like Enhancer of Split protein 4 (TLE4) has been reported to be involved in some subsets of acute myeloid leukemia and colorectal cancer. In the present study, we aimed to explore the role of TLE4 in tumorigenesis and cancer progression in hepatocellular carcinoma (HCC). Methods: The expression pattern of TLE4 in HCC was determined by Western-blot and qRT-PCR, gain-of-function and loss-of-function was used to explore the biological role of TLE4 in HCC cells. A xenograft model was established to confirm its effects on proliferation. Results: The protein expression levels of TLE4 were significantly down-regulated in HCC tissues compared to matched adjacent normal liver tissues. In vitro, down-regulation of TLE4 in Huh7 or SMMC-7721 promoted cell proliferation and ectopical expression of TLE4 in Hep3B or Bel-7404 suppressed cell proliferation. In addition, the cell colony formation ability was enhanced after down-regulation of TLE4 expression in Huh-7 but suppressed after over-expression in Hep3B. Furthermore, down-regulation of TLE4 increased the cell invasion ability, as well as increased the expression level of Vimentin and decreased that of E-cadherin, indicating a phenotype of epithelial-mesenchymal transition (EMT) in HCC cells. On the contrary, ectopical expression of TLE4 in HCC cells decreased the cell invasion ability and inhibited EMT. In vivo, compared to control group, xenograft tumor volumes were significantly decreased in TLE4 overexpression group. Conclusions: These results demonstrated that TLE4 might play important regulatory roles in cellular proliferation and EMT process in HCC. - Highlights: • TLE4 is significantly down-regulated in HCC samples. • Down regulated of TLE4 in HCC cells promotes cell proliferation. • Down regulated of TLE4 in HCC cells promotes epithelial-to-mesenchymal transition.

  14. Hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Farooqi, J.I.; Farooqi, R.J.

    2001-01-01

    Hepatocellular carcinoma (HCC) is a common cause of cancer mortality. Hepatitis B and C viruses, aflatoxin and alga toxin in the contaminated drinking water are the major etiological factors. Rapidly progressing medical imaging has resulted in the improved treatment results. Surgical resection has a major role for influencing prognosis of HCC. Local cancer therapies based on the advances in early diagnosis are progressing rapidly. Multimodality combination and sequential treatment has proved effective, unfortunately systemic chemotherapy for HCC remains disappointed. All of these have resulted in the improved prognosis of HCC. (author)

  15. Down-regulated expression of the protein-tyrosine phosphatase 1B (PTP1B) is associated with aggressive clinicopathologic features and poor prognosis in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Zheng, Long-Yi; Zhou, Dong-Xun; Lu, Jin; Zhang, Wen-Jun; Zou, Da-Jin

    2012-01-01

    Highlights: ► PTP1B protein showed decreased expression in 67.79% of the HCC patients. ► Low PTP1B expression predicts poor prognosis of HCC. ► Low PTP1B expression is correlated with expansion of OV6 + tumor-initiating cells. ► Down-regulation of PTP1B is associated with activation of Wnt/β-Catenin signaling. -- Abstract: The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In this study, PTP1B expression was detected by immunohistochemistry in normal liver tissue (n = 16) and hepatocellular carcinoma (n = 169). The correlations between PTP1B expression level and clinicopathologic features and patient survival were also analyzed. One hundred and eleven of 169 HCC patients (65.7%) had negative or low PTP1B expression in tumorous tissues, whereas normal tissues always expressed strong PTP1B. Decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Immunohistochemistry also showed that low PTP1B expression level was correlated with high percentage of OV6 + tumor-initiating cells (T-ICs) and high frequency of nuclear β-Catenin expression in HCC specimens. Our findings demonstrate for the first time that the loss of inhibitory effect of PTP1B may contribute to progression and invasion of HCC through activation of Wnt/β-Catenin signaling and expansion of liver T-ICs. PTP1B may serve as a valuable prognostic biomarker and potential therapeutic target in HCC.

  16. Down-regulated expression of the protein-tyrosine phosphatase 1B (PTP1B) is associated with aggressive clinicopathologic features and poor prognosis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Long-Yi [Department of Endocrinology, Changhai Hospital, 168 Changhai Road, Shanghai 200433 (China); Zhou, Dong-Xun [Department of Comprehensive Treatment II, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438 (China); Lu, Jin [Department of Endocrinology, Changhai Hospital, 168 Changhai Road, Shanghai 200433 (China); Zhang, Wen-Jun [Department of Emergency, Changhai Hospital, 168 Changhai Road, Shanghai 200433 (China); Zou, Da-Jin, E-mail: dajinzou@hotmail.com [Department of Endocrinology, Changhai Hospital, 168 Changhai Road, Shanghai 200433 (China)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer PTP1B protein showed decreased expression in 67.79% of the HCC patients. Black-Right-Pointing-Pointer Low PTP1B expression predicts poor prognosis of HCC. Black-Right-Pointing-Pointer Low PTP1B expression is correlated with expansion of OV6{sup +} tumor-initiating cells. Black-Right-Pointing-Pointer Down-regulation of PTP1B is associated with activation of Wnt/{beta}-Catenin signaling. -- Abstract: The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In this study, PTP1B expression was detected by immunohistochemistry in normal liver tissue (n = 16) and hepatocellular carcinoma (n = 169). The correlations between PTP1B expression level and clinicopathologic features and patient survival were also analyzed. One hundred and eleven of 169 HCC patients (65.7%) had negative or low PTP1B expression in tumorous tissues, whereas normal tissues always expressed strong PTP1B. Decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Immunohistochemistry also showed that low PTP1B expression level was correlated with high percentage of OV6{sup +} tumor-initiating cells (T-ICs) and high frequency of nuclear {beta}-Catenin expression in HCC specimens. Our findings demonstrate for the first time that the loss of inhibitory effect of PTP1B may contribute to progression and invasion of HCC through activation of Wnt/{beta}-Catenin signaling and expansion of liver T-ICs. PTP1B may serve as a valuable prognostic biomarker and potential therapeutic target in HCC.

  17. Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2.

    Science.gov (United States)

    Huang, Ming-De; Chen, Wen-Ming; Qi, Fu-Zhen; Sun, Ming; Xu, Tong-Peng; Ma, Pei; Shu, Yong-Qian

    2015-09-04

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including HCC. Taurine Up-regulated Gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is found to be disregulated in non-small cell lung carcinoma (NSCLC) and esophageal squamous cell carcinoma (ESCC). However, its clinical significance and potential role in HCC remain unclear. In this study, expression of TUG1 was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qPCR). TUG1 expression was up-regulated in HCC tissues and the higher expression of TUG1 was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, silencing of TUG1 expression inhibited HCC cell proliferation, colony formation, tumorigenicity and induced apoptosis in HCC cell lines. We also found that TUG1 overexpression was induced by nuclear transcription factor SP1 and TUG1 could epigeneticly repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region. Our results suggest that lncRNA TUG1, as a growth regulator, may serve as a new diagnostic biomarker and therapy target for HCC.

  18. Long noncoding RNA NEAT1 promotes cell proliferation and invasion by regulating hnRNP A2 expression in hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Mang YY

    2017-02-01

    Full Text Available Yuanyi Mang, Li Li, Jianghua Ran, Shengning Zhang, Jing Liu, Laibang Li, Yiming Chen, Jian Liu, Yang Gao, Gang Ren Department of Hepato-Biliary-Pancreatic Surgery, The Calmette Affiliated Hospital of Kunming Medical University, The First Hospital of Kunming, Kunming, Yunnan, People’s Republic of China Abstract: Growing evidence demonstrates that long noncoding RNAs (lncRNAs are involved in the progression of various cancers, including hepatocellular carcinoma (HCC. The role of nuclear-enriched abundant transcript 1 (NEAT1, an essential lncRNA for the formation of nuclear body paraspeckles, has not been fully explored in HCC. We aimed to determine the expression, roles and functional mechanisms of NEAT1 in the proliferation and invasion of HCC. Based on real-time polymerase chain reaction data, we suggest that NEAT1 is upregulated in HCC tissues compared with noncancerous liver tissues. The knockdown of NEAT1 altered global gene expression patterns and reduced HCC cell proliferation, invasion and migration. RNA immunoprecipitation and RNA pull-down assays confirmed that U2AF65 binds to NEAT1. Furthermore, the study indicated that NEAT1 regulated hnRNP A2 expression and that this regulation may be associated with the NEAT1–U2AF65 protein complex. Thus, the NEAT1-hnRNP A2 regulation mechanism promotes HCC pathogenesis and may provide a potential target for the prognosis and treatment of HCC. Keywords: long noncoding RNA, NEAT1, RNA-binding protein, HCC

  19. 15 CFR 990.20 - Relationship to the CERCLA natural resource damage assessment regulations.

    Science.gov (United States)

    2010-01-01

    ...., and the Federal Water Pollution Control Act (Clean Water Act), 33 U.S.C. 1321 et seq., are codified at... Relating to Commerce and Foreign Trade (Continued) NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE OIL POLLUTION ACT REGULATIONS NATURAL RESOURCE DAMAGE ASSESSMENTS Authorities § 990.20...

  20. Transforming Growth Factor β1 Promotes Migration and Invasion of Human Hepatocellular Carcinoma Cells Via Up-Regulation of Connective Tissue Growth Factor.

    Science.gov (United States)

    Liu, Haizhou; Wang, Shaoyang; Ma, Weimin; Lu, Youguang

    2015-12-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a poor patient survival. Expression of TGF-β1 is up-regulated in HCC and is thought to play a crucial role in the occurrence and development of HCC. However, the mechanism of TGF-β1-mediated facilitation of malignant growth and invasion remains unclear, although some previous studies highlighted a potential involvement of the connective tissue growth factor (CTGF). Here we demonstrate that the in vitro migration of the HCC cell line SMMC-7721 is increased in the presence of recombinant TGF-β1, and that this effect is reversed by the specific inhibitor SB431542. Furthermore, TGF-β1 treatment up-regulated the expression of its own mRNA as well as the expression of CTGF mRNA. The TGF-β1-stimulated migration of SMMC-7721 cells was diminished by siRNA silencing of CTGF. These in vitro observations were validated in a murine xenograft model. In particular, silencing of CTFG diminished the TGF-β1-induced tumorigenesis in experimental animals. In conclusion, TGF-β1 plays a critical role in HCC migration and invasion, and this effect is dependent on CTGF.

  1. RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

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    Toshinori Ozaki

    2013-01-01

    Full Text Available A proper DNA damage response (DDR, which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such as p21WAF1, BAX, and PUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

  2. Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Screening (PDQ®)–Patient Version What is ... These are called diagnostic tests . General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  3. Up-Regulation of MicroRNA-190b Plays a Role for Decreased IGF-1 That Induces Insulin Resistance in Human Hepatocellular Carcinoma

    Science.gov (United States)

    Hung, Tzu-Min; Ho, Cheng-Maw; Liu, Yen-Chun; Lee, Jia-Ling; Liao, Yow-Rong; Wu, Yao-Ming; Ho, Ming-Chih; Chen, Chien-Hung; Lai, Hong-Shiee; Lee, Po-Huang

    2014-01-01

    Background & Aims Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally. Methods The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells. Results Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients. Conclusions Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC. PMID:24586785

  4. LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR-24-3p.

    Science.gov (United States)

    Zeng, Fei; Le, Yi-Guan; Fan, Ji-Chang; Xin, Lin

    2017-11-01

    Background Cancer susceptibility candidate 2 (CASC2), a recently discovered long non-coding RNA (lncRNA), was confirmed to play numerous roles in several human cancers. However, the involvement and concrete mechanism of CASC2 in hepatocellular carcinoma (HCC) still need to be further elucidated. Methods The relative expressions of CASC2 and miR-24-3p in HCC tissue and cell lines were determined by quantitative real-time PCR (qRT-PCR). The effects of CASC2 and miR-24-3p on HCC cells were further assessed via cell viability and apoptosis. In vivo tumorigenesis assay was performed to verify the inhibition effect of CASC2 on the tumor growth and further clarify the important role of miR-24-3p in this mechanism. Results Compared with the paired normal tissues, the relative expression of CASC2 significantly reduced in the HCC tissues, while miR-24-3p as determined by qRT-PCR obviously increased in the HCC tissues. This observation was also found in HCC cell lines. Meanwhile, the expression of CASC2 was negatively related to miR-24-3p expression in the HCC tissues (r = -0.804, p cells, but the up-regulation of miR-24-3p greatly eliminated the CASC2-induced effects. The tumorigenesis of HCC cells was restrained significantly by CASC2 overexpression as shown by decreased tumor volume and growth rate. However, miR-24-3p up-regulation rescued the inhibition of CASC2 on the tumor growth in tumor-bearing mice. Conclusion LncRNA CASC2 inhibited the viability and induced the apoptosis of HCC cells through regulating miR-24-3p. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. HAb18G/CD147 regulates vinculin-mediated focal adhesion and cytoskeleton organization in cultured human hepatocellular carcinoma cells.

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    Qiang Liang

    Full Text Available Focal adhesions (FAs, integrin-mediated macromolecular complexes located at the cell membrane extracellular interface, have been shown to regulate cell adhesion and migration. Our previous studies have indicated that HAb18G/CD147 (CD147 is involved in cytoskeleton reorganization and FA formation in human hepatocellular carcinoma (HCC cells. However, the precise mechanisms underlying these processes remain unclear. In the current study, we determined that CD147 was involved in vinculin-mediated FA focal adhesion formation in HCC cells. We also found that deletion of CD147 led to reduced vinculin-mediated FA areas (P<0.0001, length/width ratios (P<0.0001, and mean intensities (P<0.0001. CD147 promoted lamellipodia formation by localizing Arp2/3 to the leading edge of the cell. Deletion of CD147 significantly reduced the fluorescence (t1/2 recovery times (22.7±3.3 s of vinculin-mediated focal adhesions (P<0.0001. In cell-spreading assays, CD147 was found to be essential for dynamic focal adhesion enlargement and disassembly. Furthermore, the current data showed that CD147 reduced tyrosine phosphorylation in vinculin-mediated focal adhesions, and enhanced the accumulation of the acidic phospholipid phosphatidylinositol-4, 5-bisphosphate (PIP2. Together, these results revealed that CD147 is involved in vinculin-mediated focal adhesion formation, which subsequently promotes cytoskeleton reorganization to facilitate invasion and migration of human HCC cells.

  6. Protective Effects of Total Glucosides of Paeony on N-nitrosodiethylamine-induced Hepatocellular Carcinoma in Rats via Down-regulation of Regulatory B Cells.

    Science.gov (United States)

    Song, S S; Yuan, P F; Li, P P; Wu, H X; Ni, W J; Lu, J T; Wei, W

    2015-01-01

    Total glucoside of paeony (TGP), extracted from the root of Paeonia Lactiflora, has been known to show anti-inflammatory, anti-oxidative, hepato-protective and immuno-regulatory activities. The aim of this present study was to determine the anti-tumor effect of TGP against N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) in rats, and to find the related mechanisms. Rat HCC model was established by intragastrically administrating with DEN (8 mg/kg). We found the number of tumor nodules and the index of liver and spleen were increased in the model group compared with the normal group, and was significantly decreased by TGP. Additionally, TGP obviously improved the hepatic pathological lesions induced by DEN, and decreased the elevated levels of serum alanine aminotransferase (ALT), glutamic oxalacetic transaminase (AST), alkaline phosphatase (ALP) and alpha fetoprotein (AFP) by DEN. Moreover, TGP decreased the level of B cell-activating factor (BAFF) and the proportion of IL-10-producing regulatory B cells (Bregs), and the decrease of BAFF by TGP is positively correlated to the decrease of IL-10-producing Bregs by TGP. These results suggest that TGP had a good therapeutic action on DEN-induced HCC rats, which might be due to its down-regulation of Bregs through reducing the level of BAFF.

  7. 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

  8. Mycobacterium smegmatis PafBC is involved in regulation of DNA damage response.

    Science.gov (United States)

    Fudrini Olivencia, Begonia; Müller, Andreas U; Roschitzki, Bernd; Burger, Sibylle; Weber-Ban, Eilika; Imkamp, Frank

    2017-10-25

    Two genes, pafB and pafC, are organized in an operon with the Pup-ligase gene pafA, which is part of the Pup-proteasome system (PPS) present in mycobacteria and other actinobacteria. The PPS is crucial for Mycobacterium tuberculosis resistance towards reactive nitrogen intermediates (RNI). However, pafB and pafC apparently play only a minor role in RNI resistance. To characterize their function, we generated a pafBC deletion in Mycobacterium smegmatis (Msm). Proteome analysis of the mutant strain revealed decreased cellular levels of various proteins involved in DNA damage repair, including recombinase A (RecA). In agreement with this finding, Msm ΔpafBC displayed increased sensitivity to DNA damaging agents. In mycobacteria two pathways regulate DNA repair genes: the LexA/RecA-dependent SOS response and a predominant pathway that controls gene expression via a LexA/RecA-independent promoter, termed P1. PafB and PafC feature winged helix-turn-helix DNA binding motifs and we demonstrate that together they form a stable heterodimer in vitro, implying a function as a heterodimeric transcriptional regulator. Indeed, P1-driven transcription of recA was decreased in Msm ΔpafBC under standard conditions and induction of recA expression upon DNA damage was strongly impaired. Taken together, our data indicate an important regulatory function of PafBC in the mycobacterial DNA damage response.

  9. Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?

    Directory of Open Access Journals (Sweden)

    Gerhard Fritz

    2015-09-01

    Full Text Available The Ras-related C3 botulinum toxin substrate 1 (Rac1 belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR that are related to DNA repair, survival and cell death.

  10. On the development of the new harmonised damage stability regulations for dry cargo and passenger ships

    International Nuclear Information System (INIS)

    Papanikolaou, Apostolos; Eliopoulou, Eleftheria

    2008-01-01

    This paper outlines the methodological background and presents a summary of the main results of a series of undertaken international, IMO-led studies, on the harmonisation of the new probabilistic, risk-based regulations with the currently in-force regulatory provisions for assessing the damage stability of dry cargo and passenger ships. It reviews the historical development of the new regulations, to be applied to all new buildings on January 1, 2009, and the anticipated impact of the new rules on the design and indirect operation of various subcategories of dry cargo and passenger ships. It identifies certain loopholes in the existing regulations that appear cured by the new ones, though certain compromises adopted in the development of the new regulations, particularly those related to large passenger ships' survivability, have left some open issues to be addressed in the near future

  11. Research on garlic capsule and selenium-vitamin A, vitamin B, vitamin C applied in therapy of acute hepatocellular damage in a rat model

    Directory of Open Access Journals (Sweden)

    Jacob Kehinde Akintunde

    2015-10-01

    Conclusions: Collectively, the results suggest that therapeutic dose of lisinopril elicits toxicity in male rats through induction of oxidative damage and depletion of cellular adenosine triphosphate. The reversal effects of GAR and SACE during lisinopril treatment suggest that these antioxidants may find clinical application in cellular damage involving ROS and adenosine triphosphate.

  12. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Ming-De Yan

    2015-09-01

    Full Text Available Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC. Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1, a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9, by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

  13. Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells.

    Science.gov (United States)

    Wu, J; Lu, M; Li, Y; Shang, Y-K; Wang, S-J; Meng, Y; Wang, Z; Li, Z-S; Chen, H; Chen, Z-N; Bian, H

    2016-10-20

    Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-β1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-β1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-β1 by activating β-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-β1. The activated TGF-β1 signaling subsequently repressed the HNF4α expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-β1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-β1 and negatively correlated with HNF4α in human HCC tissues. Positive CD147 staining and lower HNF4α levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4α and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-β1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-β1 and CD147.

  14. BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma.

    Science.gov (United States)

    Huang, Chen-Song; Zhai, Jing-Ming; Zhu, Xiao-Xu; Cai, Jian-Peng; Chen, Wei; Li, Jian-Hui; Yin, Xiao-Yu

    2017-12-01

    Our previous study found that B cell translocation gene 2 (BTG2) was hyper-methylated and down-regulated in side population (SP) cells of hepatocellular carcinoma (HCC) cell line. However, its clinical significances and biological impacts on HCC SP cells remained unclear. To investigate the prognostic value of BTG2 gene in HCC and its influences on cancer stem cells (CSCs)-like traits of HCC cell line SP cells. BTG2 expression in human HCC and adjacent non-cancerous tissues was detected by immunohistochemical staining and quantitative real-time PCR, and also obtained from GEO and TCGA data. Its prognostic values were assessed. Its biological influences on HCC cell line SP cells were evaluated using cell viability, cell cycle, plate clone-forming assay, and chemoresistance in vitro and tumorigenicity in vivo. BTG2 expression was significantly suppressed in human HCC compared to adjacent non-cancerous tissues. BTG2 expression was correlated with TNM stage, tumor size and vascular invasion. Lower expression of BTG2 was associated with poorer overall survival and disease-free survival. In vitro, overexpression of BTG2 substantially suppressed cell proliferation and accumulation of HCC cell line SP cells in G0/G1 phase. Colony formation ability was markedly suppressed by BTG2 overexpression. Moreover, sensitivity of HCC cell line SP cells to 5-fluorouracil was substantially increased by overexpression of BTG2. Furthermore, tumorigenicity of HCC cell line SP cells transfected with BTG2 plasmids was significantly reduced in vivo. BTG2 gene could regulate the CSC-like traits of HCC cell line SP cells, and it represented as a molecular prognostic marker for HCC.

  15. Up-regulated MicroRNA-181a induces carcinogenesis in Hepatitis B virus-related hepatocellular carcinoma by targeting E2F5

    International Nuclear Information System (INIS)

    Zou, Chengcheng; Li, Yongguo; Cao, Yiyi; Zhang, Jinnan; Jiang, Jingrong; Sheng, Yanrui; Wang, Sen; Huang, Ailong; Tang, Hua

    2014-01-01

    Accumulating evidence showed that microRNAs are involved in development and progression of multiple tumors. Recent studies have found that miR-181a were dysregulated in several types of cancers, however, the function of miR-181a in hepatocellular carcinoma (HCC) remains unclear. In this study we assessed the potential association between miR-181a, HBV and HCC. The expression of miR-181a in HBV-expressing cells was determined by using qRT-PCR. Dual-Luciferase reporter Assay, qRT-PCR and western blot were performed to investigate the target genes of miR-181a. The effects of miR-181a on HCC proliferation were analyzed by MTS and colony formation assay. Tumor growth assay was used to analyze the effect of miR-181a on tumor formation. HBV up-regulated miR-181a expression by enhancing its promoter activity. Overexpression of miR-181a in hepatoma cells promoted cell growth in vitro and tumor formation in vivo. Conversely, inhibition of miR-181a suppressed the proliferation of HBV-expressing cells. Mechanism investigation revealed that miR-181a inhibited the expression of transcription factor E2F5 by specifically targeting its mRNA 3′UTR. Moreover, E2F5 inhibition induced cell growth and rescued the suppressive effect of miR-181a inhibitor on the proliferation of SMMC-7721 cells. Interestingly, we also discovered that HBV could down-regulate E2F5 expression. Those results strongly suggested that HBV down-regulated E2F5 expression, in part, by up-regulating the expression of miR-181a. Up-regulation of miR-181a by HBV in hepatoma cells may contribute to the progression of HCC possibly by targeting E2F5, suggesting miR-181a plays important role in HCC development

  16. Korean Byungkyul - Citrus platymamma Hort.et Tanaka flavonoids induces cell cycle arrest and apoptosis, regulating MMP protein expression in Hep3B hepatocellular carcinoma cells.

    Science.gov (United States)

    Hong, Gyeong Eun; Lee, Ho Jeong; Kim, Jin A; Yumnam, Silvia; Raha, Suchismita; Venkatarame Gowda Saralamma, Venu; Heo, Jeong Doo; Lee, Sang Joon; Kim, Eun Hee; Won, Chun Kil; Kim, Gon Sup

    2017-02-01

    Citrus platymamma Hort.et Tanaka is an indigenous fruit of Jeju island in Korea. In this study the bioactivity of C. platymamma flavonoids were evaluated on human hepatoma Hep3B cell lines. Eleven flavonoids were identified from the peels of C. platymamma Hort.et Tanaka through high-performance liquid chromatography-Tandem mass spectrometry and the anticancer effect of these C. platymamma flavonoids on human hepatoma Hep3B were studied. Chromatin condensation was observed in Hep3B cells treated with C. platymamma flavonoids. DNA fragmentation was confirmed through agarose gel electrophoresis and TUNEL assay. An increase in the total apoptotic cells and G2/M cell cycle arrest with decreased protein expression of CDC25C, CDK1, cyclin B1 and p21 were observed in Hep3B cells treated with flavonoids of C. platymamma. Further, protein expression of Bcl-XL, Bax, caspase-3 and -9 were also modulated by C. platymamma flavonoids treatment indicating that cell death is through intrinsic apoptotic pathway. Moreover, C. platymamma flavonoids also regulated the phosphorylation of MAPKs, PI3K, and Akt in Hep3B cells. Relevant to inhibiting metastasis, C. platymamma treatment reduced wound closure of Hep3B cells and the protein expression of matrix metalloproteinase-2 and -9 were reduced in C. platymamma treated cells. The results show that C. platymamma flavonoids induce cell cycle arrest and apoptosis following activation of MAPKs and suppression of PI3K/Akt pathway which eventually inhibits cell migration in Hep3B cells. The finding provides evidence on biochemical activities of C. platymamma Hort.et Tanaka, which would be an essential agent for hepatocellular carcinoma (HCC) treatment.

  17. Transhemangioma Ablation of Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Pua, Uei

    2012-01-01

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  18. Transhemangioma Ablation of Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pua, Uei, E-mail: druei@yahoo.com [Tan Tock Seng Hospital, Department of Diagnostic Radiology (Singapore)

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  19. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Gokhan Yildiz

    Full Text Available Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal" by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15

  20. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

    Science.gov (United States)

    Wilson, C. L.; Jurk, D.; Fullard, N.; Banks, P.; Page, A.; Luli, S.; Elsharkawy, A. M.; Gieling, R. G.; Chakraborty, J. Bagchi; Fox, C.; Richardson, C.; Callaghan, K.; Blair, G. E.; Fox, N.; Lagnado, A.; Passos, J. F.; Moore, A. J.; Smith, G. R.; Tiniakos, D. G.; Mann, J.; Oakley, F.; Mann, D. A.

    2015-04-01

    Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1S340A/S340Amice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

  1. MicroRNA-219-5p Promotes Tumor Growth and Metastasis of Hepatocellular Carcinoma by Regulating Cadherin 1

    Directory of Open Access Journals (Sweden)

    Jing Yang

    2018-01-01

    Full Text Available MicroRNAs play significant roles in the development of cancer and may serve as promising therapeutic targets. In our previous work, miR-219-5p was identified as one of the important metastasis-related microRNAs in HCC. Here we demonstrated that miR-219-5p expression was elevated in HCC tissues and was associated with vascular invasion and dismal prognosis. In multivariate analysis, miR-219-5p was identified as an independent prognostic indicator for HCC patients. Functional mechanism analyses showed that miR-219-5p promoted HCC cell proliferation and invasion in in vitro, as well as in vivo, tumor growth and metastasis in nude mice models bearing human HCC tumors. In addition, cadherin 1 (CDH1 was revealed to be a downstream target of miR-219-5p in HCC cells. In conclusion, miR-219-5p promotes tumor growth and metastasis of HCC by regulating CDH1 and can serve as a prognostic marker for HCC patients.

  2. Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM.

    Science.gov (United States)

    Zhou, Yi; Lee, Ji-Hoon; Jiang, Wenxia; Crowe, Jennie L; Zha, Shan; Paull, Tanya T

    2017-01-05

    Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase.

    Science.gov (United States)

    Zhao, Yu; Majid, Mona C; Soll, Jennifer M; Brickner, Joshua R; Dango, Sebastian; Mosammaparast, Nima

    2015-06-12

    Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors. © 2015 The Authors.

  4. MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2.

    Science.gov (United States)

    Xue, Fei; Liang, Yuntian; Li, Zhenrong; Liu, Yanhui; Zhang, Hongwei; Wen, Yu; Yan, Lei; Tang, Qiang; Xiao, Erhui; Zhang, Dongyi

    2018-01-01

    Hepatocellular carcinoma (HCC) is one of the most widespread malignant human tumors worldwide. Treatment options include radiotherapy, surgical intervention and chemotherapy; however, drug resistance is an ongoing treatment concern. In the present study, the effects of a microRNA (miR/miRNA), miR-9, on the sensitivity of HCC cell lines to the epidermal growth factor receptor inhibitor, cetuximab, were examined. miR-9 has been proposed to serve a role in tumorigenesis and tumor progression. In the present study, bioinformatics analyses identified the eukaryotic translation initiation factor 5A2 (eIF-5A-2) as a target of miR-9. The expression levels of miR-9 and eIF-5A-2 were examined by reverse transcription-quantitative polymerase chain reaction and HCC cell lines were transfected with miR-9 mimics and inhibitors to determine the effects of the miRNA on cell proliferation and viability. The miR-9 mimic was revealed to significantly increase the sensitivity of epithelial phenotype HCC cells (Hep3B and Huh7) to cetuximab, while the miR-9 inhibitor triggered the opposite effect. There were no significant differences in sensitivity to cetuximab observed in mesenchymal phenotype HCC cells (SNU387 and SNU449). Cells lines displaying high expression levels of eIF-5A-2 were more resistant to cetuximab. Transfection of cells with a miR-9 mimic resulted in downregulation of the expression of eIF-5A-2 mRNA, while an miR-9 inhibitor increased expression. When expression of eIF-5A-2 was knocked down with siRNA, the effects of miR-9 on cetuximab sensitivity were no longer observed. Taken together, these data support a role for miR-9 in enhancing the sensitivity of epithelial phenotype HCC cells to cetuximab through regulation of eIF-5A-2.

  5. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma.

    Science.gov (United States)

    Shan, Juanjuan; Shen, Junjie; Liu, Limei; Xia, Feng; Xu, Chuan; Duan, Guangjie; Xu, Yanmin; Ma, Qinghua; Yang, Zhi; Zhang, Qianzhen; Ma, Leina; Liu, Jia; Xu, Senlin; Yan, Xiaochu; Bie, Ping; Cui, Youhong; Bian, Xiu-wu; Qian, Cheng

    2012-09-01

    Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell-related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). Nanog(Pos) CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that Nanog(Pos) CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in Nanog(Pos) CSCs could decrease self-renewal accompanied with decreased expression of stem-cell-related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in Nanog(Pos) CSCs. Knock-down expression of Nanog in Nanog(Pos) CSCs inhibited the expression of IGF1R, and overexpression of Nanog in Nanog(Neg) cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R

  6. Drosophila UTX coordinates with p53 to regulate ku80 expression in response to DNA damage.

    Directory of Open Access Journals (Sweden)

    Chengwan Zhang

    Full Text Available UTX is known as a general factor that activates gene transcription during development. Here, we demonstrate an additional essential role of UTX in the DNA damage response, in which it upregulates the expression of ku80 in Drosophila, both in cultured cells and in third instar larvae. We further showed that UTX mediates the expression of ku80 by the demethylation of H3K27me3 at the ku80 promoter upon exposure to ionizing radiation (IR in a p53-dependent manner. UTX interacts physically with p53, and both UTX and p53 are recruited to the ku80 promoter following IR exposure in an interdependent manner. In contrast, the loss of utx has little impact on the expression of ku70, mre11, hid and reaper, suggesting the specific regulation of ku80 expression by UTX. Thus, our findings further elucidate the molecular function of UTX.

  7. DNA damage regulates alternative splicing through changes in POL II elongation

    International Nuclear Information System (INIS)

    Munoz, M.J.; Perez Santangelo, M.S.; De la Mata, M.; Kornblihtt, A.R.

    2008-01-01

    Many apoptotic genes are regulated via alternative splicing (AS) but little is known about the mechanisms controlling AS in stress situations derived from DNA damage. Here we show that ultraviolet (UV) radiation affects co-transcriptional, but not post transcriptional, AS through a systemic mechanism involving a CDK-9-dependent hyper phosphorylation of RNA polymerase II carboxy terminal domain (CTD) and a subsequent and unprecedented inhibition of transcriptional elongation, estimated in vivo and in real time by FRAP. To mimic this hyper phosphorylation we used CTD mutants with serines 2 or 5 substituted by glutamic acids and found that they not only display lower elongation rates but duplicate the effects of UV light on AS in the absence of irradiation. Consistently, substitution of the serines with alanines prevents the UV effect on splicing. These results represent the first in vivo proof of modulation of elongation in response to an environmental signal, affecting in turn the kinetic coupling between transcription and splicing. (authors)

  8. Regulation of radiation protective agents on cell damage induced by reactive oxygen species

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jeong Hee; Lee, Si Eun; Ju, Eun Mi; Gao, Eu Feng [Kyung Hee University, Seoul (Korea)

    2002-04-01

    In this study, we developed candidates of new radio-protective agents and elucidated the regulation mechanism of these candidates on cell damage induced by reactive oxygen species. The methanol extracts and ethylacetate fractions of NP-1, NP-5, NP-7, NP-11, NP-12 and NP-14 showed higher radical scavenging activity. The extracts of NP-7, NP-12 and NP-14 showed strong protective effect against oxidative damage induced by UV and H{sub 2}O{sub 2}. The most of samples enhanced SOD, CAT and GPX activity in V79-4 cells. The protective effect of samples on H{sub 2}O{sub 2}-induced apoptosis was observed with microscope and flow cytometer. Cells exposed to H{sub 2}O{sub 2} exhibit distinct morphological features of programmed cell death, such as nuclear fragmentation and increase in the percentage of cells with a sub-G1 DNA content. However, cells which was pretreated with samples significantly reduced the characteristics of apoptotic cells. Their morphological observation and DNA profiles were similar to those of the control cells. NP-14 which had excellent antioxidant activity restored G2/M arrest induced by oxidative stress. These data suggested that natural medicinal plants protected H{sub 2}O{sub 2}-induced apoptosis. 42 refs., 29 figs., 11 tabs. (Author)

  9. ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice

    Science.gov (United States)

    Gannon, Hugh S.; Woda, Bruce A.; Jones, Stephen N.

    2012-01-01

    Summary DNA damage induced by ionizing radiation (IR) activates the ATM kinase, which subsequently stabilizes and activates the p53 tumor suppressor protein. Although phosphorylation of p53 by ATM was found previously to modulate p53 levels and transcriptional activities in vivo, it does not appear to be a major regulator of p53 stability. We have utilized mice bearing altered Mdm2 alleles to demonstrate that ATM phosphorylation of Mdm2 serine 394 is required for robust p53 stabilization and activation after DNA damage. In addition, we demonstrate that dephosphorylation of Mdm2 Ser394 regulates attenuation of the p53-mediated response to DNA damage. Therefore, the phosphorylation status of Mdm2 Ser394 governs p53 protein levels and functions in cells undergoing DNA damage. PMID:22624716

  10. Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1–RAGE and AKT pathways

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ping; Dai, Weiqi; Wang, Fan; Lu, Jie; Shen, Miao; Chen, Kan; Li, Jingjing; Zhang, Yan; Wang, Chengfen; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan; Guo, Chuan-Yong, E-mail: guochuanyong@hotmail.com; Xu, Ling, E-mail: xuling606@sina.com

    2014-01-24

    Highlights: • Ethyl pyruvate inhibits liver cancer. • Promotes apoptosis. • Decreased the expression of HMGB1, p-Akt. - Abstract: Ethyl pyruvate (EP) was recently identified as a stable lipophilic derivative of pyruvic acid with significant antineoplastic activities. The high mobility group box-B1 (HMGB1)–receptor for advanced glycation end-products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. We tried to observe the effects of ethyl pyruvate on liver cancer growth and explored its effects in hepatocellular carcinoma model. In this study, three hepatocellular carcinoma cell lines were treated with ethyl pyruvate. An MTT colorimetric assay was used to assess the effects of EP on cell proliferation. Flow cytometry and TUNEL assays were used to analyze apoptosis. Real-time PCR, Western blotting and immunofluorescence demonstrated ethyl pyruvate reduced the HMGB1–RAGE and AKT pathways. The results of hepatoma orthotopic tumor model verified the antitumor effects of ethyl pyruvate in vivo. EP could induce apoptosis and slow the growth of liver cancer. Moreover, EP decreased the expression of HMGB1, RAGE, p-AKT and matrix metallopeptidase-9 (MMP9) and increased the Bax/Bcl-2 ratio. In conclusion, this study demonstrates that ethyl pyruvate induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells, plays a critical role in the treatment of cancer.

  11. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling.

    Science.gov (United States)

    Wang, Ying; Branicky, Robyn; Noë, Alycia; Hekimi, Siegfried

    2018-04-18

    Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling. © 2018 Wang et al.

  12. Radiosensitivity of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hennequin, C.; Quero, L.; Rivera, S.

    2011-01-01

    The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radio-biologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its α/β ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. (authors)

  13. Cryotherapy for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Awad, Tahany; Thorlund, Kristian; Gluud, Christian

    2009-01-01

    BACKGROUND: Hepatocellular carcinoma is the most common primary malignant cancer of the liver. Evidence for the role of cryotherapy in the treatment of hepatocellular carcinoma is controversial. OBJECTIVES: The aim of this review is to evaluate the potential benefits and harms of cryotherapy...... for the treatment of hepatocellular carcinoma. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS until June 2009. We identified further studies by searching...... of benefit but included for the assessment of harm. Both severe and non-severe adverse events were reported, but the true nature and extent of harm was difficult to asses. AUTHORS' CONCLUSIONS: At present, there is no evidence to recommend or refute cryotherapy for patients with hepatocellular carcinoma...

  14. Understanding the tumor suppressor PTEN in chronic alcoholism and hepatocellular carcinoma.

    Science.gov (United States)

    Shearn, Colin T; Petersen, Dennis R

    2015-01-01

    The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatidylinositol (PtdIns) phosphatase that regulates Akt activation via PtdIns 3 kinase. Changes in PTEN expression and/or activity have been identified in a variety of chronic hepatocellular disorders including obesity, NAFLD, NASH, and alcoholism. In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumors. Mutations, decreased promoter activity, and decreased expression in PTEN are frequently identified in patients with hepatocellular carcinoma. While the majority of research on PTEN concerns obesity and NASH, PTEN clearly has a role in hepatic insulin sensitivity and in the development of steatosis during chronic alcoholism. Yet, in chronic alcoholics and HCC, very little is known concerning PTEN mutation/deletion or low PTEN expression. This review is focused on an overview of the current knowledge on molecular mechanisms of dysregulation of PTEN expression/activity in the liver and their relationship to development of ethanol-induced hepatocellular damage and cancer.

  15. The Aspergillus fumigatus Damage Resistance Protein Family Coordinately Regulates Ergosterol Biosynthesis and Azole Susceptibility

    Directory of Open Access Journals (Sweden)

    Jinxing Song

    2016-02-01

    Full Text Available Ergosterol is a major and specific component of the fungal plasma membrane, and thus, the cytochrome P450 enzymes (Erg proteins that catalyze ergosterol synthesis have been selected as valuable targets of azole antifungals. However, the opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in the cytochrome P450 enzyme Cyp51 (Erg11. In this study, we demonstrate that a cytochrome b5-like heme-binding damage resistance protein (Dap family, comprised of DapA, DapB, and DapC, coordinately regulates the functionality of cytochrome P450 enzymes Erg5 and Erg11 and oppositely affects susceptibility to azoles. The expression of all three genes is induced in an azole concentration-dependent way, and the decreased susceptibility to azoles requires DapA stabilization of cytochrome P450 protein activity. In contrast, overexpression of DapB and DapC causes dysfunction of Erg5 and Erg11, resulting in abnormal accumulation of sterol intermediates and further accentuating the sensitivity of ΔdapA strains to azoles. The results of exogenous-hemin rescue and heme-binding-site mutagenesis experiments demonstrate that the heme binding of DapA contributes the decreased azole susceptibility, while DapB and -C are capable of reducing the activities of Erg5 and Erg11 through depletion of heme. In vivo data demonstrate that inactivated DapA combined with activated DapB yields an A. fumigatus mutant that is easily treatable with azoles in an immunocompromised mouse model of invasive pulmonary aspergillosis. Compared to the single Dap proteins found in Saccharomyces cerevisiae and Schizosaccharomyces pombe, we suggest that this complex Dap family regulatory system emerged during the evolution of fungi as an adaptive means to regulate ergosterol synthesis in response to environmental stimuli.

  16. UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation

    Science.gov (United States)

    Matsunuma, Ryoichi; Ohhata, Tatsuya; Kitagawa, Kyoko; Sakai, Satoshi; Uchida, Chiharu; Shiotani, Bunsyo; Matsumoto, Masaki; Nakayama, Keiichi I.; Ogura, Hiroyuki; Shiiya, Norihiko; Kitagawa, Masatoshi

    2015-01-01

    Histone acetyltransferase binding to ORC-1 (HBO1) is a critically important histone acetyltransferase for forming the prereplicative complex (pre-RC) at the replication origin. Pre-RC formation is completed by loading of the MCM2-7 heterohexameric complex, which functions as a helicase in DNA replication. HBO1 recruited to the replication origin by CDT1 acetylates histone H4 to relax the chromatin conformation and facilitates loading of the MCM complex onto replication origins. However, the acetylation status and mechanism of regulation of histone H3 at replication origins remain elusive. HBO1 positively regulates cell proliferation under normal cell growth conditions. Whether HBO1 regulates proliferation in response to DNA damage is poorly understood. In this study, we demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were phosphorylated in an ATM/ATR DNA damage sensor-dependent manner after UV treatment. ATM/ATR-dependently phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4DDB2. Replacement of endogenous HBO1 in Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV irradiation. Our findings demonstrate that HBO1 is one of the targets in the DNA damage checkpoint. These results show that ubiquitin-dependent control of the HBO1 protein contributes to cell survival during UV irradiation. PMID:26572825

  17. The regulation for enforcing the law concerning indemnification of nuclear damage

    International Nuclear Information System (INIS)

    1980-01-01

    The regulation is set up under the provisions of the law concerning the indemnification for atomic energy damages, to enforce them. An atomic energy business enterpriser who intends to get the approval of indemnification measures specified under the law shall file an application to the General Director of the Science Technology Agency, attaching particular documents and writing the following matters: his name and address; the kinds of operation of reactors; the names and addresses of works or places of business where reactors are operated; the thermal output of reactors; the kinds and quantities of nuclear fuel materials processed or employed; the kinds and quantities of nuclear fuel materials or contaminated materials to be transported; the kinds and quantities of nuclear fuel materials or contaminated materials to be disposed; beginning dates and expected ending dates of the operation of reactors; and other items stipulated concerning liability insurance and indemnification contracts. The negotiable securities qualified to be trusted include government bonds; municipal bonds; bonds issued by particular legal persons; bonds issued by banks, Central Cooperative Bank for Agriculture and Forestry, or Bank for Commerce and Industrial Cooperatives, and secured debentures under the secured debenture trust law. The recovering of trusted securities and identification cards are defined, respectively. (Okada, K.)

  18. Percutaneous cryoablation for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Kyoung Doo Song

    2016-12-01

    Full Text Available Local ablation therapy is considered as a conventional treatment option for patients with early stage hepatocellular carcinoma (HCC. Although radiofrequency (RF ablation is widely used for HCC, the use of cryoablation has been increasing as newer and safer cryoablation systems have developed. The thermodynamic mechanism of freezing and thawing used in cryoablation is the Joule-Thomson effect. Cryoablation destroys tissue via direct tissue destruction and vascular-related injury. A few recent comparative studies have shown that percutaneous cryoablation for HCCs is comparable to percutaneous RF ablation in terms of long term therapeutic outcomes and complications. Cryoablation has several advantages over RF ablation such as well visualization of iceball, no causation of severe pain, and lack of severe damage to great vessels and gallbladder. It is important to know the advantages and disadvantages of cryoablation compared with RF ablation for improvement of therapeutic efficacy and safety.

  19. Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

    Directory of Open Access Journals (Sweden)

    Yuan-Hao Lee

    2015-04-01

    Full Text Available Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERβ and negatively regulate the expression and function of the estrogen receptor α (ERα in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα downstream effector, BCA2 (Breast Cancer Associated gene 2, correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 up-regulation and ataxia telangiectasia mutated (ATM activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, γH2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair.

  20. Functional link between DNA damage responses and transcriptional regulation by ATM in response to a histone deacetylase inhibitor TSA.

    Science.gov (United States)

    Lee, Jong-Soo

    2007-09-01

    Mutations in the ATM (ataxia-telangiectasia mutated) gene, which encodes a 370 kd protein with a kinase catalytic domain, predisposes people to cancers, and these mutations are also linked to ataxia-telangiectasia (A-T). The histone acetylaion/deacetylation- dependent chromatin remodeling can activate the ATM kinase-mediated DNA damage signal pathway (in an accompanying work, Lee, 2007). This has led us to study whether this modification can impinge on the ATM-mediated DNA damage response via transcriptional modulation in order to understand the function of ATM in the regulation of gene transcription. To identify the genes whose expression is regulated by ATM in response to histone deaceylase (HDAC) inhibition, we performed an analysis of oligonucleotide microarrays with using the appropriate cell lines, isogenic A-T (ATM(-)) and control (ATM(+)) cells, following treatment with a HDAC inhibitor TSA. Treatment with TSA reprograms the differential gene expression profile in response to HDAC inhibition in ATM(-) cells and ATM(+) cells. We analyzed the genes that are regulated by TSA in the ATM-dependent manner, and we classified these genes into different functional categories, including those involved in cell cycle/DNA replication, DNA repair, apoptosis, growth/differentiation, cell- cell adhesion, signal transduction, metabolism and transcription. We found that while some genes are regulated by TSA without regard to ATM, the patterns of gene regulation are differentially regulated in an ATM-dependent manner. Taken together, these finding indicate that ATM can regulate the transcription of genes that play critical roles in the molecular response to DNA damage, and this response is modulated through an altered HDAC inhibition-mediated gene expression.

  1. Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export

    Directory of Open Access Journals (Sweden)

    Marriott Susan J

    2007-12-01

    Full Text Available Abstract Background The HTLV-I oncoprotein, Tax, is a pleiotropic protein whose activity is partially regulated by its ability to interact with, and perturb the functions of, numerous cellular proteins. Tax is predominantly a nuclear protein that localizes to nuclear foci known as Tax Speckled Structures (TSS. We recently reported that the localization of Tax and its interactions with cellular proteins are altered in response to various forms of genotoxic and cellular stress. The level of cytoplasmic Tax increases in response to stress and this relocalization depends upon the interaction of Tax with CRM1. Cellular pathways and signals that regulate the subcellular localization of Tax remain to be determined. However, post-translational modifications including sumoylation and ubiquitination are known to influence the subcellular localization of Tax and its interactions with cellular proteins. The sumoylated form of Tax exists predominantly in the nucleus while ubiquitinated Tax exists predominantly in the cytoplasm. Therefore, we hypothesized that post-translational modifications of Tax that occur in response to DNA damage regulate the localization of Tax and its interactions with cellular proteins. Results We found a significant increase in mono-ubiquitination of Tax in response to UV irradiation. Mutation of specific lysine residues (K280 and K284 within Tax inhibited DNA damage-induced ubiquitination. In contrast to wild-type Tax, which undergoes transient nucleocytoplasmic shuttling in response to DNA damage, the K280 and K284 mutants were retained in nuclear foci following UV irradiation and remained co-localized with the cellular TSS protein, sc35. Conclusion This study demonstrates that the localization of Tax, and its interactions with cellular proteins, are dynamic following DNA damage and depend on the post-translational modification status of Tax. Specifically, DNA damage induces the ubiquitination of Tax at K280 and K284

  2. Histone H3 lysine 36 methyltransferase mobilizes NER factors to regulate tolerance against alkylation damage in fission yeast.

    Science.gov (United States)

    Lim, Kim Kiat; Nguyen, Thi Thuy Trang; Li, Adelicia Yongling; Yeo, Yee Phan; Chen, Ee Sin

    2018-04-09

    The Set2 methyltransferase and its target, histone H3 lysine 36 (H3K36), affect chromatin architecture during the transcription and repair of DNA double-stranded breaks. Set2 also confers resistance against the alkylating agent, methyl methanesulfonate (MMS), through an unknown mechanism. Here, we show that Schizosaccharomyces pombe (S. pombe) exhibit MMS hypersensitivity when expressing a set2 mutant lacking the catalytic histone methyltransferase domain or a H3K36R mutant (reminiscent of a set2-null mutant). Set2 acts synergistically with base excision repair factors but epistatically with nucleotide excision repair (NER) factors, and determines the timely nuclear accumulation of the NER initiator, Rhp23, in response to MMS. Set2 facilitates Rhp23 recruitment to chromatin at the brc1+ locus, presumably to repair alkylating damage and regulate the expression of brc1+ in response to MMS. Set2 also show epistasis with DNA damage checkpoint proteins; regulates the activation of Chk1, a DNA damage response effector kinase; and acts in a similar functional group as proteins involved in homologous recombination. Consistently, Set2 and H3K36 ensure the dynamicity of Rhp54 in DNA repair foci formation after MMS treatment. Overall, our results indicate a novel role for Set2/H3K36me in coordinating the recruitment of DNA repair machineries to timely manage alkylating damage.

  3. Nitric Oxide Synthase Type III Overexpression By Gene Therapy Exerts Antitumoral Activity In Mouse Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Raúl González

    2015-08-01

    Full Text Available Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO synthase type III (NOS-3 overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP and Rous Sarcoma Virus (RSV promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

  4. Piper betle leaf extracts induced human hepatocellular carcinoma Hep3B cell death via MAPKs regulating the p73 pathway in vitro and in vivo.

    Science.gov (United States)

    Wu, Pei-Fang; Tseng, Hsien-Chun; Chyau, Charng-Cherng; Chen, Jing-Hsien; Chou, Fen-Pi

    2014-12-01

    Extracts of Piper betle leaf (PBLs) are rich in bioactive compounds with potential chemopreventive ability. In this study, Hep3B cells which are p53 null were used to investigate the anti-tumor effect of PBLs in the cell and in the xenograft model. The results revealed that PBLs (0.1 to 1 mg mL(-1)) induced a dose- and time-dependent increase of cell toxicity. The underlying mechanisms as evidenced by flow cytometry and western blot analysis showed that PBLs triggered ATM, cAbl, and p73 expressions and activated JNK and p38 pathways that subsequently led to cell cycle arrest and mitochondria-dependent apoptosis. PBLs also inhibited tumor growth in Hep3B-bearing mice via inducing the MAPK-p73 pathway. Our results demonstrated the in vitro and in vivo anti-tumor potential of PBLs, supporting their application as a novel chemopreventive agent for the treatment of human hepatocellular carcinoma (HCC) in the future via targeting the p73 pathway.

  5. p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage

    DEFF Research Database (Denmark)

    Borisova, Marina E; Voigt, Andrea; Tollenaere, Maxim A X

    2018-01-01

    quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins......Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ...

  6. Down-regulation of miR-181a can reduce heat stress damage in PBMCs of Holstein cows.

    Science.gov (United States)

    Chen, Kun-Lin; Fu, Yuan-Yuan; Shi, Min-Yan; Li, Hui-Xia

    2016-09-01

    Heat stress can weaken the immune system and even increase livestock's susceptibility to disease. MicroRNA (miR) is short non-coding RNA that functions in post-transcriptional regulation of gene expression and some phenotypes. Our recent study found that miR-181a is highly expressed in the serum of heat-stressed Holstein cows, but the potential function of miR-181a is still not clarified. In this study, peripheral blood mononuclear cells (PBMCs), isolated from Holstein cows' peripheral blood, were used to investigate the effects of miR-181a inhibitor on heat stress damage. Our results showed that significant apoptosis and oxidative damage were induced by heat stress in PBMCs. However, with apoptosis, the levels of reactive oxygen species (ROS) and content of malondialdehyde (MDA) were reduced, while the content of glutathione (GSH) and the activity of superoxide dismutase (SOD) were increased even under heat stress conditions after transfecting miR-181a inhibitors to PBMCs. Meanwhile, mRNA expression of bax and caspase-3 was significantly decreased, but mRNA expression of bcl-2 was increased in transfected PBMCs. In conclusion, our results demonstrated that down-regulation of miR-181a can reduce heat stress damage in PBMCs of Holstein cows.

  7. Dynamic CT of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Nobuyuki; Shirato, Hiroki; Shinohara, Masahiro; Miyasaka, Kazuo; Morita, Yutaka; Irie, Goro

    1983-03-01

    We performed dynamic CT in 30 cases of hepatocellular carcinoma, and concluded as below. Detecting the stain in the early phase of the dynamic series, it is possible to make a diagnosis of hepatocellular carcinoma. The dynamic CT is effective in a case of small hepatocellular carcinoma in which it is difficult to gain an accurate diagnosis in the routine CT study. The dynamic CT is also effective in the differential diagnosis of hepatic lesions, as other hepatic lesions such as hemangioma and metastatic liver cancer show different patterns compared with hepatocellular carcinoma.

  8. Dynamic CT of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Fujita, Nobuyuki; Shirato, Hiroki; Shinohara, Masahiro; Miyasaka, Kazuo; Morita, Yutaka; Irie, Goro

    1983-01-01

    We performed dynamic CT in 30 cases of hepatocellular carcinoma, and concluded as below. 1 Decting the stain in the early phase of the dynamic series, it is possible to make a diagnosis of hepatocellular carcinoma. 2 The dinamic CT is effective in a case of small hepatocellular carcinoma in which it is difficult to gain an accurate diagnosis in the routine CT study. 3 The dynamic CT is also effective in the differential diagnosis of hepatic lesions, as other hepatic lesions such as hemangioma and metastatic liver cancer show different patterns compared with hepatocellular carcinoma. (author)

  9. Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control

    Czech Academy of Sciences Publication Activity Database

    Horvath, B.M.; Kourová, Hana; Nagy, S.; Nemeth, E.; Magyar, Z.; Papdi, C.; Ahmad, Z.; Sanchez-Perez, G.F.; Perilli, S.; Blilou, I.; Pettko-Szandtner, A.; Darula, Z.; Meszaros, T.; Binarová, Pavla; Bogre, L.; Scheres, B.

    2017-01-01

    Roč. 36, č. 9 (2017), s. 1261-1278 ISSN 0261-4189 R&D Projects: GA ČR GA15-11657S Institutional support: RVO:61388971 Keywords : Arabidopsis * BRCA1 * DNA damage response Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 9.792, year: 2016

  10. Hepatitis C Virus and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Masao Omata

    2013-01-01

    Full Text Available Hepatitis C virus (HCV, a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC. It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.

  11. IFN-γ Induces Mimic Extracellular Trap Cell Death in Lung Epithelial Cells Through Autophagy-Regulated DNA Damage.

    Science.gov (United States)

    Lin, Chiou-Feng; Chien, Shun-Yi; Chen, Chia-Ling; Hsieh, Chia-Yuan; Tseng, Po-Chun; Wang, Yu-Chih

    2016-02-01

    Treatment of interferon-γ (IFN-γ) causes cell growth inhibition and cytotoxicity in lung epithelial malignancies. Regarding the induction of autophagy related to IFN-γ signaling, this study investigated the link between autophagy and IFN-γ cytotoxicity. In A549 human lung cancer cells, IFN-γ treatment induced concurrent apoptotic and nonapoptotic events. Unexpectedly, the nonapoptotic cells present mimic extracellular trap cell death (ETosis), which was regulated by caspase-3 and by autophagy induction through immunity-related GTPase family M protein 1 and activating transcription factor 6. Furthermore, IFN-γ signaling controlled mimic ETosis through a mechanism involving an autophagy- and Fas-associated protein with death domain-controlled caspase-8/-3 activation. Following caspase-mediated lamin degradation, IFN-γ caused DNA damage-associated ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM)-regulated mimic ETosis. Upon ATR/ATM signaling, peptidyl arginine deiminase 4 (PAD4)-mediated histone 3 citrullination promoted mimic ETosis. Such IFN-γ-induced effects were defective in PC14PE6/AS2 human lung cancer cells, which were unsusceptible to IFN-γ-induced autophagy. Due to autophagy-based caspase cascade activation, IFN-γ triggers unconventional caspase-mediated DNA damage, followed by ATR/ATM-regulated PAD4-mediated histone citrullination during mimic ETosis in lung epithelial malignancy.

  12. Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma.

    Science.gov (United States)

    Mazzocca, Antonio; Fransvea, Emilia; Dituri, Francesco; Lupo, Luigi; Antonaci, Salvatore; Giannelli, Gianluigi

    2010-02-01

    Tumor-stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor beta (TGF-beta) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-beta-dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-beta1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-beta1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-beta-dependent CTGF expression may offer clinical benefits. Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials.

  13. Viral hepatitis and hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Juei-Low, Sung [ed.; National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Department of Internal Medicine; Ding-Shinn, Chen [ed.; National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Hepatitis Research Center National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Graduate Institute of Clinical Medicine

    1990-01-01

    Two papers in this volume are in INIS scope, respectively dealing with MRI in the study of viral hepatitis and hepatocellular carcinoma, and The use of {sup 131}I-labeled Lipidol in the diagnosis of hepato-cellular carcinoma. (H.W.). refs.; figs.; tabs.

  14. Viral hepatitis and hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Sung Juei-Low; Chen Ding-Shinn

    1990-01-01

    Two papers in this volume are in INIS scope, respectively dealing with MRI in the study of viral hepatitis and hepatocellular carcinoma, and The use of 131 I-labeled Lipidol in the diagnosis of hepato-cellular carcinoma. (H.W.). refs.; figs.; tabs

  15. Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway

    Science.gov (United States)

    Liang, Dun; Burkhart, Sarah Lyn; Singh, Rakesh Kumar; Kabbaj, Marie-Helene Miquel; Gunjan, Akash

    2012-01-01

    In eukaryotes, multiple genes encode histone proteins that package genomic deoxyribonucleic acid (DNA) and regulate its accessibility. Because of their positive charge, ‘free’ (non-chromatin associated) histones can bind non-specifically to the negatively charged DNA and affect its metabolism, including DNA repair. We have investigated the effect of altering histone dosage on DNA repair in budding yeast. An increase in histone gene dosage resulted in enhanced DNA damage sensitivity, whereas deletion of a H3–H4 gene pair resulted in reduced levels of free H3 and H4 concomitant with resistance to DNA damaging agents, even in mutants defective in the DNA damage checkpoint. Studies involving the repair of a HO endonuclease-mediated DNA double-strand break (DSB) at the MAT locus show enhanced repair efficiency by the homologous recombination (HR) pathway on a reduction in histone dosage. Cells with reduced histone dosage experience greater histone loss around a DSB, whereas the recruitment of HR factors is concomitantly enhanced. Further, free histones compete with the HR machinery for binding to DNA and associate with certain HR factors, potentially interfering with HR-mediated repair. Our findings may have important implications for DNA repair, genomic stability, carcinogenesis and aging in human cells that have dozens of histone genes. PMID:22850743

  16. DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds.

    Science.gov (United States)

    Waterworth, Wanda M; Footitt, Steven; Bray, Clifford M; Finch-Savage, William E; West, Christopher E

    2016-08-23

    Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production.

  17. LIVER AND BONE MARROW STEM/PROGENITOR CELLS AS REGULATORS OF REPARATIVE REGENERATION OF DAMAGED LIVER

    Directory of Open Access Journals (Sweden)

    А. V. Lundup

    2010-01-01

    Full Text Available In this review the modern information about effectiveness of liver insufficiency treatment by stem/ progenitor cells of liver (oval cells and bone marrow (hemopoietic cells and mesenchymal cells was presented. It is shown that medical action of these cells is referred on normalization of liver cell interaction and reorganization of processes of a reparative regeneration in damaged liver. It is believed that application of mesenchymal stromal cells from an autological bone marrow is the most perspective strategy. However, for definitive judgement about regenerative possibilities of the autological bone marrow cells it is necessary to carry out large-scale double blind clinical researches. 

  18. Rare sugar D-allose induces specific up-regulation of TXNIP and subsequent G1 cell cycle arrest in hepatocellular carcinoma cells by stabilization of p27kip1.

    Science.gov (United States)

    Yamaguchi, Fuminori; Takata, Maki; Kamitori, Kazuyo; Nonaka, Machiko; Dong, Youyi; Sui, Li; Tokuda, Masaaki

    2008-02-01

    'Rare sugars' are defined as monosaccharides that exist in nature but are only present in limited quantities. The development of mass production method of rare sugars revealed some interesting physiological effects of these on animal cells, but the mechanisms have not been well studied. We examined the effect of D-allose on the proliferation of cancer cells and the underlying molecular mechanism of the action. The HuH-7 hepatocellular carcinoma cells were treated with various monosaccharides for 48 h and D-allose was shown to inhibit cell growth by 40% in a dose-dependent manner. D-allose induced G1 cell cycle arrest but not apoptosis. The microarray analysis revealed that D-allose significantly up-regulated thioredoxin interacting protein (TXNIP) gene expression, which is often suppressed in tumor cells and western blot analysis confirmed its increase at protein level. The overexpression of TXNIP also induced G1 cell cycle arrest. Analysis of cell cycle regulatory genes showed p27kip1, a key regulator of G1/S cell cycle transition, to be increased at the protein but not the transcriptional level. Protein interaction between TXNIP and jab1, and p27kip1 and jab1, was observed, suggesting stabilization of p27kip1 protein by the competitive inhibition of jab1-mediated nuclear export of p27kip1 by TXNIP. In addition, increased interaction and nuclear localization of TXNIP and p27kip1 were apparent after D-allose treatment. Our findings surprisingly suggest that D-allose, a simple monosaccharide, may act as a novel anticancer agent via unique TXNIP induction and p27kip1 protein stabilization.

  19. Regulation of autophagy by AMP-activated protein kinase/ sirtuin 1 pathway reduces spinal cord neurons damage

    Directory of Open Access Journals (Sweden)

    Peng Yan

    2017-09-01

    Full Text Available Objective(s: AMP-activated protein kinase/sirtuin 1 (AMPK/SIRT1 signaling pathway has been proved to be involved in the regulation of autophagy in various models. The aim of this study was to evaluate the effect of AMPK/SIRT1 pathway on autophagy after spinal cord injury (SCI. Materials and Methods:The SCI model was established in rats in vivo and the primary spinal cord neurons were subjected to mechanical injury (MI in vitro. The apoptosis in spinal cord tissue and neurons was assessed by TUNEL staining and Hoechst 33342 staining, respectively. The autophagy-related proteins levels were detected by Western blot. The activation of AMPK/SIRT1 pathway was determined by Western blot and immunohistochemical staining. Results: We found that the apoptosis of spinal cord tissue and cell damage of spinal cord neurons was obvious after the trauma. The ratio of LC3II/LC3I and level of p62 were first increased significantly and then decreased after the trauma in vivo and in vitro, indicating the defect in autophagy. The levels of p-AMPK and SIRT1 were increased obviously after the trauma in vivo and in vitro. Further activation of the AMPK/SIRT1 pathway by pretreatment with resveratrol, a confirmed activator of the AMPK/SIRT1 pathway, alleviated the cell damage and promoted the autophagy flux via downregulation of p62 in spinal cord neurons at 24 hr after MI. Conclusion: Our results demonstrate that regulation of autophagy by AMPK/SIRT1 pathway can restrain spinal cord neurons damage, which may be a potential intervention of SCI.

  20. Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage

    Directory of Open Access Journals (Sweden)

    Olsen Birgitte B

    2012-03-01

    Full Text Available Abstract Background The DNA-dependent protein kinase (DNA-PK is a nuclear complex composed of a large catalytic subunit (DNA-PKcs and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the non-homologous end-joining (NHEJ repair mechanism, which is activated in the presence of DNA double-strand breaks induced by ionizing radiation, reactive oxygen species and radiomimetic drugs. We have recently reported that down-regulation of protein kinase CK2 by siRNA interference results in enhanced cell death specifically in DNA-PKcs-proficient human glioblastoma cells, and this event is accompanied by decreased autophosphorylation of DNA-PKcs at S2056 and delayed repair of DNA double-strand breaks. Results In the present study, we show that CK2 co-localizes with phosphorylated histone H2AX to sites of DNA damage and while CK2 gene knockdown is associated with delayed DNA damage repair, its overexpression accelerates this process. We report for the first time evidence that lack of CK2 destabilizes the interaction of DNA-PKcs with DNA and with Ku80 at sites of genetic lesions. Furthermore, we show that CK2 regulates the phosphorylation levels of DNA-PKcs only in response to direct induction of DNA double-strand breaks. Conclusions Taken together, these results strongly indicate that CK2 plays a prominent role in NHEJ by facilitating and/or stabilizing the binding of DNA-PKcs and, possibly other repair proteins, to the DNA ends contributing to efficient DNA damage repair in mammalian cells.

  1. Regulation of autophagy by AMP-activated protein kinase/sirtuin 1 pathway reduces spinal cord neurons damage.

    Science.gov (United States)

    Yan, Peng; Bai, Liangjie; Lu, Wei; Gao, Yuzhong; Bi, Yunlong; Lv, Gang

    2017-09-01

    AMP-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway has been proved to be involved in the regulation of autophagy in various models. The aim of this study was to evaluate the effect of AMPK/SIRT1 pathway on autophagy after spinal cord injury (SCI). The SCI model was established in rats in vivo and the primary spinal cord neurons were subjected to mechanical injury (MI) in vitro . The apoptosis in spinal cord tissue and neurons was assessed by TUNEL staining and Hoechst 33342 staining, respectively. The autophagy-related proteins levels were detected by Western blot. The activation of AMPK/SIRT1 pathway was determined by Western blot and immunohistochemical staining. We found that the apoptosis of spinal cord tissue and cell damage of spinal cord neurons was obvious after the trauma. The ratio of LC3II/LC3I and level of p62 were first increased significantly and then decreased after the trauma in vivo and in vitro , indicating the defect in autophagy. The levels of p-AMPK and SIRT1 were increased obviously after the trauma in vivo and in vitro . Further activation of the AMPK/SIRT1 pathway by pretreatment with resveratrol, a confirmed activator of the AMPK/SIRT1 pathway, alleviated the cell damage and promoted the autophagy flux via downregulation of p62 in spinal cord neurons at 24 hr after MI. Our results demonstrate that regulation of autophagy by AMPK/SIRT1 pathway can restrain spinal cord neurons damage, which may be a potential intervention of SCI.

  2. Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.

    Directory of Open Access Journals (Sweden)

    Carolin Wippel

    Full Text Available Streptococcus pneumoniae (pneumococcal meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

  3. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis

    Science.gov (United States)

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-01-01

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways. PMID:28277539

  4. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis.

    Science.gov (United States)

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-03-09

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.

  5. 49 CFR 192.355 - Customer meters and regulators: Protection from damage.

    Science.gov (United States)

    2010-10-01

    ... SAFETY TRANSPORTATION OF NATURAL AND OTHER GAS BY PIPELINE: MINIMUM FEDERAL SAFETY STANDARDS Customer... terminal must— (1) Be rain and insect resistant; (2) Be located at a place where gas from the vent can... that houses a customer meter or regulator at a place where vehicular traffic is anticipated, must be...

  6. The regulation for enforcing the law concerning indemnification of nuclear damage

    International Nuclear Information System (INIS)

    1977-01-01

    The atomic energy entrepreneurs wishing to obtain the approval according to Item 1, Article 7 of the Law Concerning Indemnification of Nuclear Damage should file application (one original and one duplicate) describing the following items to the Director of the Science and Technology Agency: (1) in case of taking indemnification measures including the conclusion of responsibility insurance contracts and indemnification contracts, the particulars of the contracts including the sum of money involved, (2) in case of taking indemnification measures including deposit, the particulars of the deposit including the sum of money involved, and (3) in case of taking loss indemnification measures including the conclusion of responsibility insurance contracts and indemnification contracts or other measures than deposit, the particulars of such measures. (Rikitake, Y.)

  7. Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling

    Directory of Open Access Journals (Sweden)

    Eunice Yuen Ting Lau

    2016-05-01

    Full Text Available Like normal stem cells, tumor-initiating cells (T-ICs are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs would regulate liver T-ICs. We found that the presence of α-SMA(+ CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC.

  8. Chk2 regulates transcription-independent p53-mediated apoptosis in response to DNA damage

    International Nuclear Information System (INIS)

    Chen Chen; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Motoyama, Noboru

    2005-01-01

    The tumor suppressor protein p53 plays a central role in the induction of apoptosis in response to genotoxic stress. The protein kinase Chk2 is an important regulator of p53 function in mammalian cells exposed to ionizing radiation (IR). Cells derived from Chk2-deficient mice are resistant to the induction of apoptosis by IR, and this resistance has been thought to be a result of the defective transcriptional activation of p53 target genes. It was recently shown, however, that p53 itself and histone H1.2 translocate to mitochondria and thereby induces apoptosis in a transcription-independent manner in response to IR. We have now examined whether Chk2 also regulates the transcription-independent induction of apoptosis by p53 and histone H1.2. The reduced ability of IR to induce p53 stabilization in Chk2-deficient thymocytes was associated with a marked impairment of p53 and histone H1 translocation to mitochondria. These results suggest that Chk2 regulates the transcription-independent mechanism of p53-mediated apoptosis by inducing stabilization of p53 in response to IR

  9. Ursolic Acid-Regulated Energy Metabolism—Reliever or Propeller of Ultraviolet-Induced Oxidative Stress and DNA Damage?

    Directory of Open Access Journals (Sweden)

    Yuan-Hao Lee

    2014-08-01

    Full Text Available Ultraviolet (UV light is a leading cause of diseases, such as skin cancers and cataracts. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS. Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers and result in stalled DNA replication forks. In addition, ROS promotes phosphorylation of tyrosine kinase-coupled hormone receptors and alters downstream energy metabolism. With respect to the risk of UV-induced photocarcinogenesis and photodamage, the antitumoral and antioxidant functions of natural compounds become important for reducing UV-induced adverse effects. One important question in the field is what determines the differential sensitivity of various types of cells to UV light and how exogenous molecules, such as phytochemicals, protect normal cells from UV-inflicted damage while potentiating tumor cell death, presumably via interaction with intracellular target molecules and signaling pathways. Several endogenous molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK (phosphatidylinositol 3-kinase-related kinase family members, which include DNA-PKcs, ATM (ataxia telangiectasia mutated and mTOR (mammalian target of rapamycin, whose signaling can be affected by energy metabolism; however, it remains unclear to what extent the activation of hormone receptors regulates PIKKs and whether this crosstalk occurs in all types of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of the insulin/insulin-like growth receptor. It covers the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interactions with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin

  10. Ultrasound manifestation of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, M S; Yoo, H S; Park, C Y; Choi, H J; Moon, Y M; Lee, S I [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1982-06-15

    With the advent of gray scale ultrasonographic equipment, the parenchymal disease of liver is more easily evaluated. Ultrasonography is a non-invasive technique, different from angiography, and performed without discomfort to patient. And also ultrasonography can be used in assessing the liver in cases showing equivocal scintigraphy and in differentiation of solid and cystic masses, first detected on scintigrams. Therefore, the complementary use of ultrasonography, Tc-99m-sulfur colloid scan and angiography provides better diagnostic accuracy for the detection of hepatocellular carcinoma, and moreover, sequential ultrasonographic studies in the same patient are valuable of following the course of hepatocellular carcinoma and monitoring the effectiveness of therapy for hepatocellular carcinoma. In thirty patients with histologically proven hepatocellular carcinoma, an analysis of ultrasound manifestation is made and the results are as follows; 1. Ultrasound manifestation of hepatocellular carcinoma by gray scale showed four different sonographic patterns including discrete echo free, discrete echogenic, ill defined echogenic and mixed patterns. 2. The size of hepatocellular carcinoma by ultrasonographic measurement was larger than 5 cm in diameter in 28 cases. 3. In 7 cases performed with angiography, all echogenicities of hepatocellualr carcinoma were correlated with the findings of vascularity of angiography. 4. In cases combined with liver cirrhosis, the sonographic pattern of hepatocellular carcinoma appeared to be discrete or ill defined echogenic patterns.

  11. Ultrasound manifestation of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hwang, M. S.; Yoo, H. S.; Park, C. Y.; Choi, H. J.; Moon, Y. M.; Lee, S. I.

    1982-01-01

    With the advent of gray scale ultrasonographic equipment, the parenchymal disease of liver is more easily evaluated. Ultrasonography is a non-invasive technique, different from angiography, and performed without discomfort to patient. And also ultrasonography can be used in assessing the liver in cases showing equivocal scintigraphy and in differentiation of solid and cystic masses, first detected on scintigrams. Therefore, the complementary use of ultrasonography, Tc-99m-sulfur colloid scan and angiography provides better diagnostic accuracy for the detection of hepatocellular carcinoma, and moreover, sequential ultrasonographic studies in the same patient are valuable of following the course of hepatocellular carcinoma and monitoring the effectiveness of therapy for hepatocellular carcinoma. In thirty patients with histologically proven hepatocellular carcinoma, an analysis of ultrasound manifestation is made and the results are as follows; 1. Ultrasound manifestation of hepatocellular carcinoma by gray scale showed four different sonographic patterns including discrete echo free, discrete echogenic, ill defined echogenic and mixed patterns. 2. The size of hepatocellular carcinoma by ultrasonographic measurement was larger than 5 cm in diameter in 28 cases. 3. In 7 cases performed with angiography, all echogenicities of hepatocellualr carcinoma were correlated with the findings of vascularity of angiography. 4. In cases combined with liver cirrhosis, the sonographic pattern of hepatocellular carcinoma appeared to be discrete or ill defined echogenic patterns

  12. CT of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, H; Tanaka, T; Sai, H; Kawamoto, S; Morimoto, K [Osaka Univ. (Japan). Faculty of Medicine

    1982-06-01

    CT was investigated in 125 cases of hepatocelluar carcinoma and 47 cases of metastatic hepatic neoplasm. The entire contour of each tumor was traced and the average CT value in the tumor was estimated. As a result, the CT value for hepatocellular carcinoma tended to be higher on plain CT and also after contrast enhancement. The CT findings seen frequently were as follows: capsule in 76 cases (60.8%) and septum in 67 cases (53.6%); tumor thrombus in portal vein in 39 cases (31.2%) and that in inferior vena cava in 3 cases (2.4%); localized enlargement of hepatic bile duct in 24 cases (19.2%). These findings were rarely seen in the cases of metastatic hepatic neoplasm. As a relatively outstanding feature of hepatic metastases, a double contour, like concentric circles or contour lines, with a relatively large inner circle or contour line, was found in 21 cases (44.7%). By paying attention to the change of CT value on contrast enhancement and the characteristic image of each case, hepatocellular carcinoma could be differentiated from metastatic hepatic neoplasm with high probability.

  13. Histopathology of hepatocellular carcinoma.

    Science.gov (United States)

    Schlageter, Manuel; Terracciano, Luigi Maria; D'Angelo, Salvatore; Sorrentino, Paolo

    2014-11-21

    Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

  14. The regulation for enforcing the law concerning indemnification of nuclear damage

    International Nuclear Information System (INIS)

    1978-01-01

    These provisions are established on the basis of and to enforce the ''Law concerning the indemnification of nuclear damage''. Atomic energy enterprises who want to get the approval in connection with the Law shall file the applications to the Director General of Science and Technology Agency, in which the name and the address of the applicant, kinds of the operation of nuclear reactors, the name and the address of the factory or the establishment concerning the operation of nuclear reactors, the thermal output of the reactors, the kinds and quantities of nuclear fuel materials or the things contaminated by such materials to be transported, and the time of starting and the expected time of ending the operation of the reactors, etc. To such applications, shall be attached actually surveyed maps indicating the area of the factory or the establishment concerning the operation of the reactors and the documents certifying the conclusion of obligatory insurances and indemnification contracts, etc. The securities which can be deposited and recovering of such securities are prescribed. (Okada, K.)

  15. An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Yan; Fang, Lin; Zhang, Quan'an; Zheng, Qin; Tong, Jinlong; Fu, Xiaohui; Jiang, Xiaoqing; Su, Changqing; Zheng, Junnian

    2013-06-01

    Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  16. Identification of BC005512 as a DNA damage responsive murine endogenous retrovirus of GLN family involved in cell growth regulation.

    Directory of Open Access Journals (Sweden)

    Yuanfeng Wu

    Full Text Available Genotoxicity assessment is of great significance in drug safety evaluation, and microarray is a useful tool widely used to identify genotoxic stress responsive genes. In the present work, by using oligonucleotide microarray in an in vivo model, we identified an unknown gene BC005512 (abbreviated as BC, official full name: cDNA sequence BC005512, whose expression in mouse liver was specifically induced by seven well-known genotoxins (GTXs, but not by non-genotoxins (NGTXs. Bioinformatics revealed that BC was a member of the GLN family of murine endogenous retrovirus (ERV. However, the relationship to genotoxicity and the cellular function of GLN are largely unknown. Using NIH/3T3 cells as an in vitro model system and quantitative real-time PCR, BC expression was specifically induced by another seven GTXs, covering diverse genotoxicity mechanisms. Additionally, dose-response and linear regression analysis showed that expression level of BC in NIH/3T3 cells strongly correlated with DNA damage, measured using the alkaline comet assay,. While in p53 deficient L5178Y cells, GTXs could not induce BC expression. Further functional studies using RNA interference revealed that down-regulation of BC expression induced G1/S phase arrest, inhibited cell proliferation and thus suppressed cell growth in NIH/3T3 cells. Together, our results provide the first evidence that BC005512, a member from GLN family of murine ERV, was responsive to DNA damage and involved in cell growth regulation. These findings could be of great value in genotoxicity predictions and contribute to a deeper understanding of GLN biological functions.

  17. Gonadotropin-Releasing Hormone Regulates Expression of the DNA Damage Repair Gene, Fanconi anemia A, in Pituitary Gonadotroph Cells1

    Science.gov (United States)

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2007-01-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse LβT2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regulation of gene expression and differential display reverse transcription-polymerase chain reaction (RT-PCR) to identify and isolate hormonally induced changes. This approach identified Fanconi anemia a (Fanca), a gene implicated in DNA damage repair, as a differentially expressed transcript. Mutations in Fanca account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility, and cancer susceptibility. We confirmed expression and hormonal regulation of Fanca mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in Fanca mRNA. Fanca protein was also acutely upregulated after GnRH treatment of LβT2 cells. In addition, Fanca gene expression was confined to mature pituitary gonadotrophs and adult mouse pituitary and was not expressed in the immature αT3-1 gonadotroph cell line. Thus, this study extends the expression profile of Fanca into a highly specialized endocrine cell and demonstrates hormonal regulation of expression of the Fanca locus. We suggest that this regulatory mechanism may have a crucial role in the GnRH-response mechanism of mature gonadotrophs and perhaps the etiology of FA. PMID:15128600

  18. Gonadotropin-releasing hormone regulates expression of the DNA damage repair gene, Fanconi anemia A, in pituitary gonadotroph cells.

    Science.gov (United States)

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2004-09-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse L beta T2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regulation of gene expression and differential display reverse transcription-polymerase chain reaction (RT-PCR) to identify and isolate hormonally induced changes. This approach identified Fanconi anemia a (Fanca), a gene implicated in DNA damage repair, as a differentially expressed transcript. Mutations in Fanca account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility, and cancer susceptibility. We confirmed expression and hormonal regulation of Fanca mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in Fanca mRNA. Fanca protein was also acutely upregulated after GnRH treatment of L beta T2 cells. In addition, Fanca gene expression was confined to mature pituitary gonadotrophs and adult mouse pituitary and was not expressed in the immature alpha T3-1 gonadotroph cell line. Thus, this study extends the expression profile of Fanca into a highly specialized endocrine cell and demonstrates hormonal regulation of expression of the Fanca locus. We suggest that this regulatory mechanism may have a crucial role in the GnRH-response mechanism of mature gonadotrophs and perhaps the etiology of FA.

  19. USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt

    OpenAIRE

    Zhang, Jing; Luo, Nan; Tian, Yu; Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

    2017-01-01

    USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in c...

  20. USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt.

    Science.gov (United States)

    Zhang, Jing; Luo, Nan; Tian, Yu; Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

    2017-04-11

    USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.

  1. Morphologic Subtypes of Hepatocellular Carcinoma.

    Science.gov (United States)

    Torbenson, Michael S

    2017-06-01

    Hepatocellular carcinomas can be further divided into distinct subtypes that provide important clinical information and biological insights. These subtypes are distinct from growth patterns and are on based on morphologic and molecular findings. There are 12 reasonably well-defined subtypes as well as 6 provisional subtypes, together making up 35% of all hepatocellular carcinomas. These subtypes are discussed, with an emphasis on their definitions and the key morphologic findings. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

    Directory of Open Access Journals (Sweden)

    Linlin Chen

    2017-12-01

    Full Text Available Dysregulated alternative splicing events have been implicated in many types of cancer, but the underlying molecular mechanisms remain unclear. Here, we observe that the splicing factor SRSF1 regulates DBF4B exon6 splicing by specifically binding and promoting its inclusion. Knockdown of the exon6-containing isoform (DBF4B-FL significantly inhibits the tumorigenic potential of colon cancer cells in vitro and in mice, and SRSF1 inactivation phenocopies DBF4B-FL depletion. DBF4B-FL and SRSF1 are required for cancer cell proliferation and for the maintenance of genomic stability. Overexpression of DBF4B-FL can protect against DNA damage induced by SRSF1 knockdown and rescues growth defects in SRSF1-depleted cells. Increased DBF4B exon6 inclusion parallels SRSF1 upregulation in clinical colorectal cancer samples. Taken together, our findings identify SRSF1 as a key regulator of DBF4B pre-mRNA splicing dysregulation in colon cancer, with possible clinical implications as candidate prognostic factors in cancer patients.

  3. Metformin affects the features of a human hepatocellular cell line (HepG2) by regulating macrophage polarization in a co-culture microenviroment.

    Science.gov (United States)

    Chen, Miaojiao; Zhang, Jingjing; Hu, Fang; Liu, Shiping; Zhou, Zhiguang

    2015-11-01

    Accumulating evidence suggests an association between diabetes and cancer. Inflammation is a key event that underlies the pathological processes of the two diseases. Metformin displays anti-cancer effects, but the mechanism is not completely clear. This study investigated whether metformin regulated the microenvironment of macrophage polarization to affect the characteristics of HepG2 cells and the possible role of the Notch-signalling pathway. RAW264.7 macrophages were cultured alone or co-cultured with HepG2 cells and treated with metformin. We analysed classical (M1) and alternative (M2) gene expression in RAW264.7 cells using quantitative real-time polymerase chain reaction. Changes in mRNA and protein expressions of Notch signalling in both cell types were also detected using quantitative real-time polymerase chain reaction and Western-blotting analyses. The proliferation, apoptosis and migration of HepG2 cells were detected using Cell Titer 96 AQueous One Solution Cell Proliferation Assay (MTS) (Promega Corporation, Fitchburg, WI, USA), Annexin V-FITC/PI (7SeaPharmTech, Shanghai, China) and the cell scratch assay, respectively. Metformin induced single-cultured RAW264.7 macrophages with an M2 phenotype but attenuated the M2 macrophage differentiation and inhibited monocyte chemoattractant protein-1 (MCP-1) secretion in a co-culture system. The co-cultured group of metformin pretreatment activated Notch signalling in macrophages but repressed it inHepG2 cells. Co-culture also promoted the proliferation and migration of HepG2 cells. However, along with the enhanced apoptosis, the proliferation and the migration of HepG2 cells were remarkably inhibited in another co-culture system with metformin pretreatment. Metformin can skew RAW264.7 macrophages toward different phenotypes according to changes in the microenvironment, which may affect the inflammatory conditions mediated by macrophages, induce apoptosis and inhibit the proliferation and migration of HepG2

  4. Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma.

    Science.gov (United States)

    Yahagi, Naoya; Shimano, Hitoshi; Hasegawa, Kiyoshi; Ohashi, Kenichi; Matsuzaka, Takashi; Najima, Yuho; Sekiya, Motohiro; Tomita, Sachiko; Okazaki, Hiroaki; Tamura, Yoshiaki; Iizuka, Yoko; Ohashi, Ken; Nagai, Ryozo; Ishibashi, Shun; Kadowaki, Takashi; Makuuchi, Masatoshi; Ohnishi, Shin; Osuga, Jun-ichi; Yamada, Nobuhiro

    2005-06-01

    Hepatocellular carcinoma is a very common neoplastic disease in countries where hepatitis viruses B and/or C are prevalent. Small hepatocellular carcinoma lesions detected by ultrasonography at an early stage are often hyperechoic because they are composed of well-differentiated cancer cells that are rich in triglyceride droplets. The triglyceride content of hepatocytes depends in part on the rate of lipogenesis. Key lipogenic enzymes, such as fatty acid synthase, are co-ordinately regulated at the transcriptional level. We therefore examined the mRNA expression of lipogenic enzymes in human hepatocellular carcinoma samples from 10 patients who had undergone surgical resection. All of the samples exhibited marked elevation of expression of mRNA for lipogenic enzymes, such as fatty acid synthase, acetyl-CoA carboxylase and ATP citrate lyase, compared with surrounding non-cancerous liver tissue. In contrast, the changes in mRNA expression of SREBP-1, a transcription factor that regulates a battery of lipogenic enzymes, did not show a consistent trend. In some cases where SREBP-1 was elevated, the main contributing isoform was SREBP-1c rather than SREBP-1a. Thus, lipogenic enzymes are markedly induced in hepatocellular carcinomas, and in some cases SREBP-1c is involved in this activation.

  5. Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling.

    Science.gov (United States)

    Liu, Xiaobai; Wang, Zhenhua; Wang, Ping; Yu, Bo; Liu, Yunhui; Xue, Yixue

    2013-07-21

    It has been supposed that green tea polyphenols (GTPs) have neuroprotective effects on brain damage after brain ischemia in animal experiments. Little is known regarding GTPs' protective effects against the blood-brain barrier (BBB) disruption after ischemic stroke. We investigated the effects of GTPs on the expression of claudin-5, occludin, and ZO-1, and the corresponding cellular mechanisms involved in the early stage of cerebral ischemia. Male Wistar rats were subjected to a middle cerebral artery occlusion (MCAO) for 0, 30, 60, and 120 min. GTPs (400 mg/kg/day) or vehicle was administered by intragastric gavage twice a day for 30 days prior to MCAO. At different time points, the expression of claudin-5, occludin, ZO-1, and PKCα signaling pathway in microvessel fragments of cerebral ischemic tissue were evaluated. GTPs reduced BBB permeability at 60 min and 120 min after ischemia as compared with the vehicle group. Transmission electron microscopy also revealed that GTPs could reverse the opening of tight junction (TJ) barrier at 60 min and 120 min after MACO. The decreased mRNA and protein expression levels of claudin-5, occludin, and ZO-1 in microvessel fragments of cerebral ischemic tissue were significantly prevented by treatment with GTPs at the same time points after ischemia in rats. Furthermore, GTPs could attenuate the increase in the expression levels of PKCα mRNA and protein caused by cerebral ischemia. These results demonstrate that GTPs may act as a potential neuroprotective agent against BBB damage at the early stage of focal cerebral ischemia through the regulation of TJ and PKCα signaling.

  6. Coagulin-L ameliorates TLR4 induced oxidative damage and immune response by regulating mitochondria and NOX-derived ROS

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Sukka Santosh [Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Chauhan, Parul [Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Maurya, Preeti [Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Academy of Scientific and Innovative Research, New Delhi 110025 (India); Saini, Deepika [Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Yadav, Prem Prakash, E-mail: pp_yadav@cdri.res.in [Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Barthwal, Manoj Kumar, E-mail: manojbarthwal@cdri.res.in [Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India)

    2016-10-15

    Withanolides possess diverse biological and pharmacological activity but their immunomodulatory function is less realized. Hence, coagulin-L, a withanolide isolated from Withania coagulans Dunal has been studied for such an effect in human and murine cells, and mice model. Coagulin-L (1, 3, 10 μM) exhibited immunomodulatory effect by suppressing TLR4 induced immune mediators such as cytokines (GMCSF, IFNα, IFNγ, IL-1α, IL-1Rα, IL-1β, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17), chemokines (IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10, KC, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, eotaxin/CCL11), growth factors (FGF-basic, VEGF), nitric oxide and intracellular superoxide. Mechanistically, coagulin-L abrogated LPS induced total and mitochondrial ROS generation, NOX2, NOX4 mRNA expression, IRAK and MAPK (p38, JNK, ERK) activation. Coagulin-L also attenuated IκBα degradation, which prevented NFκB downstream iNOS expression and pro-inflammatory cytokine release. Furthermore, coagulin-L (10, 25, 50 mg/kg, p.o.), undermined the LPS (10 mg/kg, i.p.) induced endotoxemia response in mice as evinced from diminished cytokine release, nitric oxide, aortic p38 MAPK activation and endothelial tissue impairment besides suppressing NOX2 and NOX4 expression in liver and aorta. Moreover, coagulin-L also alleviated the ROS mediated oxidative damage which was assessed through protein carbonyl, lipid hydroperoxide, 8-isoprostane and 8-hydroxy-2-deoxyguanosine quantification. To extend, coagulin-L also suppressed carrageenan-induced paw edema and thioglycollate-induced peritonitis in mice. Therefore, coagulin-L can be of therapeutic importance in pathological conditions induced by oxidative damage. - Highlights: • Coagulin-L demonstrates immunomodulatory effects in vivo and in vitro by modulating ROS. • Coagulin-L modulates TH1/TH2/TH17 immunokines. • Coagulin-L exerts immunomodulatory effect by regulating TLR4-IRAK- ROS

  7. Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.

    Science.gov (United States)

    Kuriyama, Shigeki; Hitomi, Misuzu; Yoshiji, Hitoshi; Nonomura, Takako; Tsujimoto, Tatsuhiro; Mitoro, Akira; Akahane, Takami; Ogawa, Mutsumi; Nakai, Seiji; Deguchi, Akihiro; Masaki, Tsutomu; Uchida, Naohito

    2005-08-01

    A number of studies have shown that various vitamins K, specifically vitamin K2, possessed antitumor activity on various types of rodent- and human-derived neoplastic cell lines. However, there are only a small number of reports demonstrating in vivo antitumor effects of vitamins K. Furthermore, the mechanism of antitumor effects of vitamins K still remains to be examined. In the present study, we examined the antitumor effects of vitamins K2, K3 and K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vivo. Furthermore, to examine the mechanism of antitumor actions of these vitamins K, mRNA expression levels of various G1 phase-related cell cycle molecules were evaluated by using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. HCC-bearing animals were produced by implanting PLC/PRF/5 cells subcutaneously into athymic nude mice, and drinking water containing vitamin K2, K3 or K5 was given to the animals. Treatments with vitamins K2, K3 and K5 were shown to markedly inhibit the growth of HCC tumors. To examine the mechanism of in vivo antitumor effects of vitamins K, total RNA was extracted from HCC tumors, and the expression of G1 phase-related cell cycle molecules was quantitatively examined. Real-time RT-PCR demonstrated that the expression of the cell cycle-driving molecule, cyclin-dependent kinase 4 (Cdk4), in HCC was significantly reduced by the treatments with vitamin K2, K3 and K5. Conversely, the expression of the cell cycle-suppressing molecules, Cdk inhibitor p16INK4a and retinoblastoma, in HCC was significantly enhanced by the treatments with vitamins K2, K3 and K5. These results indicate that vitamins K2, K3 and K5 exert antitumor effects on HCC by regulating the expression of G1 phase-related cell cycle molecules. These results also indicate that vitamins K2, K3 and K5 may be useful agents for the treatment of patients with HCC.

  8. Hepatocellular carcinoma: a review

    Directory of Open Access Journals (Sweden)

    Balogh J

    2016-10-01

    Full Text Available Julius Balogh,1,2 David Victor III,1,3,4 Emad H Asham,1,2 Sherilyn Gordon Burroughs,1,2 Maha Boktour,1,2 Ashish Saharia,1,2 Xian Li,1,2 R Mark Ghobrial,1,2 Howard P Monsour Jr,1,3,4 1Sherrie and Alan Conover Center for Liver Disease and Transplantation, 2Division of Transplantation, Department of Surgery, 3Department of Gastroenterology and Transplant Hepatology, 4Department of Medicine, Houston Methodist Hospital, Houston, TX, USA Abstract: Hepatocellular carcinoma (HCC is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an

  9. FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2.

    Directory of Open Access Journals (Sweden)

    Maria Castella

    2015-10-01

    Full Text Available The Fanconi anemia (FA-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex. However, the regulation of the FA core complex itself is poorly understood. Here we show that the FA core complex proteins are recruited to sites of DNA damage and form nuclear foci in S and G2 phases of the cell cycle. ATR kinase activity, an intact FA core complex and FANCM-FAAP24 were crucial for this recruitment. Surprisingly, FANCI, but not its partner FANCD2, was needed for efficient FA core complex foci formation. Monoubiquitination or ATR-dependent phosphorylation of FANCI were not required for the FA core complex recruitment, but FANCI deubiquitination by USP1 was. Additionally, BRCA1 was required for efficient FA core complex foci formation. These findings indicate that FANCI functions upstream of FA core complex recruitment independently of FANCD2, and alter the current view of the FA-BRCA pathway.

  10. Rottlerin upregulates DDX3 expression in hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Zhong; Shen, Gen-Hai; Xie, Jia-Ming; Li, Bin; Gao, Quan-Gen

    2018-01-01

    Rottlerin has been reported to exert its anti-tumor activity in various types of human cancers. However, the underlying molecular mechanism has not been fully elucidated. In the current study, we explored whether rottlerin exhibits its tumor suppressive function in hepatocellular carcinoma cells. Our MTT assay results showed that rottlerin inhibited cell growth in hepatocellular carcinoma cells. Moreover, we found that rottlerin induced cell apoptosis and caused cell cycle arrest at G1 phase. Furthermore, our wound healing assay result demonstrated that rottlerin retarded cell migration in hepatocellular carcinoma cells. Additionally, rottlerin suppressed cell migration and invasion. Notably, we found that rottlerin upregulated DDX3 expression and subsequently downregulated Cyclin D1 expression and increased p21 level. Importantly, down-regulation of DDX3 abrogated the rottlerin-mediated tumor suppressive function, whereas overexpression of DDX3 promoted the anti-tumor activity of rottlerin. Our study suggests that rottlerin exhibits its anti-cancer activity partly due to upregulation of DDX3 in hepatocellular carcinoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma.

    Science.gov (United States)

    Nooron, Nattakarn; Ohba, Koji; Takeda, Kazuhisa; Shibahara, Shigeki; Chiabchalard, Anchalee

    2017-08-01

    Cholangiocarcinoma represents the second most common primary liver tumor after hepatocellular carcinoma. Mahanine, a carbazole alkaloid derived from Murraya koenigii (Linn.) Spreng, has been used as folk medicine in Thailand, where the liver fluke-associated cholangiocarcinoma is common. The expression of microphthalmia-associated transcription factor (MITF) is maintained at immunohistochemically undetectable levels in hepatocytes and cholangiocytes. To explore the regulation of MITF expression in the liver, we immunohistochemically analyzed the MITF expression using hepatocellular carcinoma and cholangiocarcinoma specimens of the human liver cancer tissue array. MITF immunoreactivity was detected in subsets of hepatocellular carcinoma (6 out of 38 specimens; 16%) and cholangiocarcinoma (2/7 specimens; 29%). Moreover, immunoreactivity for glioma-associated oncogene 1 (GLI1), a transcription factor of the Hedgehog signaling pathway, was detected in 55% of hepatocellular carcinoma (21/38 specimens) and 86% of cholangiocarcinoma (6/7 specimens). Importantly, MITF was detectable only in the GLI1-positive hepatocellular carcinoma and cholangiocarcinoma, and MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. Subsequently, the effect of mahanine was analyzed in HepG2 human hepatocellular carcinoma and HuCCT1 and KKU-100 human cholangiocarcinoma cells. Mahanine (25 µM) showed the potent cytotoxicity in these hepatic cancer cell lines, which was associated with increased expression levels of MITF, as judged by Western blot analysis. MITF is over-expressed in subsets of hepatocellular carcinoma and cholangiocarcinoma, and detectable MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. MITF expression levels may be determined in hepatic cancer cells by the balance between the Hedgehog signaling and the cellular stress.

  12. Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation.

    Directory of Open Access Journals (Sweden)

    Mehtap Kilic Eren

    agent doxorubicin also induced senescence in BJ fibroblasts associated with decreased SIRT1/2 levels. In conclusion our data reveal that resveratrol induced premature senescence is associated with SIRT1 and SIRT2 down regulation in human dermal fibroblasts. Here we suggest that the concomitant decline in SIRT1/2 expression in response to resveratrol treatment may be a cause for induction of senescence, which is most likely mediated by a regulatory mechanism activated by DNA damage response.

  13. Epigenetic modification of miR-10a regulates renal damage by targeting CREB1 in type 2 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Qun, E-mail: shanp@jsnu.edu.cn; Zheng, Guihong, E-mail: ghzhengsd@jsnu.edu.cn; Zhu, Aihua, E-mail: ahzhu@jsnu.edu.cn; Cao, Li, E-mail: 948113717@qq.com; Lu, Jun, E-mail: lu-jun75@163.com; Wu, Dongmei, E-mail: wdm8610@jsnu.edu.cn; Zhang, ZiFeng, E-mail: zhangzifengsuper@jsnu.edu.cn; Fan, Shaohua, E-mail: fshfly@126.com; Sun, Chunhui, E-mail: 306484866@qq.com; Hu, Bin, E-mail: hubin@jsnu.edu.cn; Zheng, Yuanlin, E-mail: ylzheng@jsnu.edu.cn

    2016-09-01

    implicates in kidney impairment. • HDAC3 regulates kidney damage by epigenetically modulating miR-10a.

  14. Epigenetic modification of miR-10a regulates renal damage by targeting CREB1 in type 2 diabetes mellitus

    International Nuclear Information System (INIS)

    Shan, Qun; Zheng, Guihong; Zhu, Aihua; Cao, Li; Lu, Jun; Wu, Dongmei; Zhang, ZiFeng; Fan, Shaohua; Sun, Chunhui; Hu, Bin; Zheng, Yuanlin

    2016-01-01

    implicates in kidney impairment. • HDAC3 regulates kidney damage by epigenetically modulating miR-10a.

  15. C/EBPα Expression is Partially Regulated by C/EBPβ in Response to DNA Damage and C/EBPα Deficient Fibroblasts Display an Impaired G1 Checkpoint

    Science.gov (United States)

    Ranjan, Rakesh; Thompson, Elizabeth A.; Yoon, Kyungsil; Smart, Robert C.

    2009-01-01

    We observed that C/EBPα is highly inducible in primary fibroblasts by DNA damaging agents that induce strand breaks, alkylate and crosslink DNA as well as those that produce bulky DNA lesions. Fibroblasts deficient in C/EBPα (C/EBPα-/-) display an impaired G1 checkpoint as evidenced by inappropriate entry into S-phase in response to DNA damage and these cells also display an enhanced G1 to S transition in response to mitogens. The induction of C/EBPα by DNA damage in fibroblasts does not require p53. EMSA analysis of nuclear extracts prepared from UVB- and MNNG-treated fibroblasts revealed increased binding of C/EBPβ to a C/EBP consensus sequence and ChIP analysis revealed increased C/EBPβ binding to the C/EBPα promoter. To determine whether C/EBPβ has a role in the regulation of C/EBPα we treated C/EBPβ-/- fibroblasts with UVB or MNNG. We observed C/EBPα induction was impaired in both UVB- and MNNG- treated C/EBPβ-/- fibroblasts. Our study reveals a novel role for C/EBPβ in the regulation of C/EBPα in response to DNA damage and provides definitive genetic evidence that C/EBPα has a critical role in the DNA damage G1 checkpoint. PMID:19581927

  16. Differences in the regulation by poly(ADP-ribose) of repair of DNA damage from alkylating agents and ultraviolet light according to cell type

    Energy Technology Data Exchange (ETDEWEB)

    Cleaver, J.E.; Bodell, W.J.; Morgan, W.F.; Zelle, B.

    1983-08-10

    Inhibition of poly(ADP-ribose) synthesis by 3-aminobenzamide in various human and hamster cells influenced the responses to DNA damage from methyl methanesulfonate, but not from ultraviolet light. After exposure to methyl methanesulfonate, 3-aminobenzamide increased the strand break frequency in all cell types studied, but only stimulated repair replication in lymphoid and HeLa cells, suggesting these are independent effects. 3-Aminobenzamide also inhibited the pathway for de novo synthesis of DNA purines, suggesting that some of its effects may be due to disturbance of precursor pathways and irrelevant to the role of poly(ADP-ribose) in repair. Previous claims that 3-aminobenzamide stimulates repair synthesis after exposure to UV light are probably artifacts, because the stimulations are only observed in lymphocytes in the presence of a high concentration of hydroxyurea that itself inhibits repair. The initial inhibition of semiconservative DNA synthesis and the excision of the major alkylation products and pyrimidine dimers were unaffected by 3-aminobenzamide. In general poly(ADP-ribose) synthesis appears to be uniquely involved in regulating the ligation stage of repair of alkylation damage but not ultraviolet damage. By regulating the ligation efficiency, poly(ADP-ribosylation) modulates the dynamic balance between incision and ligation, so as to minimize the frequency of DNA breaks. The ligation stage of repair of UV damage appears different and is not regulated by poly(ADP-ribosylation).

  17. Radioembolization of hepatocellular carcinoma.

    Science.gov (United States)

    Van de Wiele, Christophe

    2010-12-01

    In this review paper, available data on radioembolization of unresectable hepatocellular carcinoma (HCC) using commercially available radiopharmaceuticals, respectively (131)I-Lipiodol, Therasphere (glass-microspheres) and SIRspheres (resin-microspheres) are reviewed. In the palliative setting, (131)I-Lipiodol was shown to yield response rates of 17-92% which in patients with portal vein thrombosis (PVT) translate into a survival benefit as evidenced by a phase III randomized trial. Furthermore, in terms of efficacy, (131)I-Lipiodol is as efficacious as trans-arterial chemoembolization (TACE) but far better tolerated. In the adjuvant setting, improved recurrence-free and overall survival when compared to surgery alone have been reported but these results warrant confirmation by randomized prospective trials. Similar to (131)I-Lipiodol, when administered in a palliative setting, radioembolization using (90)Y microspheres was proven effective for selected cases of non-resectable HCC and well tolerated. Available data suggest that Therasphere treatment outperforms TACE both in terms of response as in terms of event-free survival in unresectable HCC. However, this finding needs confirmation by randomized prospective trials. Therasphere treatment was also shown to limit progression of HCC allowing potential candidates for orthotopic liver transplantation (OLT) more time to wait for donor organs as well as to downstage the HCC disease to such an extent that patients that were initially not, as yet become eligible for OLT with a gain in survival. Finally, Therasphere was shown to be safe and efficacious in HCC patients presenting with PVT, reason for which approval was granted for this indication by the FDA.

  18. Cape gooseberry (Physalis peruviana) juice as a modulator agent for hepatocellular carcinoma-linked apoptosis and cell cycle arrest.

    Science.gov (United States)

    Hassan, Hanaa A; Serag, Hanaa M; Qadir, Makwan S; Ramadan, Mohamed Fawzy

    2017-10-01

    Cape gooseberry (Physalis peruviana) fruit is highly nutritious with high content of health-promoting compounds including minerals, phenolic compounds, as well as vitamins A and C. Physalis peruviana fruits were used as mutagenic, antispasmodic, anticoagulant, and antileucemis agents. The objective of the present work was to study the role of cape gooseberry juice (CG) as a natural modulator agent for adverse aspects associated with hepatocellular carcinoma (HCC). The results recorded that HCC rats had a significant disturbance in blood indices. An elevation in serum level of the inflammatory (TNF-ά, CRP, and Argenase), hepatic apoptotic markers (P53, Bax, and Caspase 3) and a reduction of Blc2% were recorded in HCC rats. The results exhibited the significant disturbance and arrest in hepatic cell cycle (% of M1: SubG1 phase, M2: G0/1 phase of diploid cycle, M3: S phase, and M4: G2/M phase) as well as liver cell viability status in HCC rats. Numerous histopathological alterations were detected in hepatic tissues of HCC rats such as inflammation, damage of hepatocytes, dilated congested central vein with degenerated endothelial cells and congested blood sinusoids in addition to collagen fibers in hepatocytes and central vein indicating hepatic fibrosis. The tested parameters were little improved upon treatment of HCC rats with Adriamycin (ADR, Doxorubicin is a generic name of a drug). HCC rats received CG showed an improvement in all tested parameters. The effects of CG were through down regulation of p53 expression and up-regulation of Bcl2 domain protected hepatic structure from extensive damage. CG plus ADR exhibited an enhanced antitumor impact in HCC and this combination might have an important value in the treatment of HCC. CG was more effective than ADR, and it has a remarkable role in the management of hepatic disorders besides its success as a chemo-sensitizer for ADR treatment of hepatocellular carcinoma. Copyright © 2017 Elsevier Masson SAS. All rights

  19. C/EBPα regulates CRL4Cdt2-mediated degradation of p21 in response to UVB-induced DNA damage to control the G1/S checkpoint

    Science.gov (United States)

    Hall, Jonathan R; Bereman, Michael S; Nepomuceno, Angelito I; Thompson, Elizabeth A; Muddiman, David C; Smart, Robert C

    2014-01-01

    The bZIP transcription factor, C/EBPα is highly inducible by UVB and other DNA damaging agents in keratinocytes. C/EBPα-deficient keratinocytes fail to undergo cell cycle arrest in G1 in response to UVB-induced DNA damage and mice lacking epidermal C/EBPα are highly susceptible to UVB-induced skin cancer. The mechanism through which C/EBPα regulates the cell cycle checkpoint in response to DNA damage is unknown. Here we report untreated C/EBPα-deficient keratinocytes have normal levels of the cyclin-dependent kinase inhibitor, p21, however, UVB-treated C/EBPα-deficient keratinocytes fail to up-regulate nuclear p21 protein levels despite normal up-regulation of Cdkn1a mRNA levels. UVB-treated C/EBPα-deficient keratinocytes displayed a 4-fold decrease in nuclear p21 protein half-life due to the increased proteasomal degradation of p21 via the E3 ubiquitin ligase CRL4Cdt2. Cdt2 is the substrate recognition subunit of CRL4Cdt2 and Cdt2 mRNA and protein levels were up-regulated in UVB-treated C/EBPα-deficient keratinocytes. Knockdown of Cdt2 restored p21 protein levels in UVB-treated C/EBPα-deficient keratinocytes. Lastly, the failure to accumulate p21 in response to UVB in C/EBPα-deficient keratinocytes resulted in decreased p21 interactions with critical cell cycle regulatory proteins, increased CDK2 activity, and inappropriate entry into S-phase. These findings reveal C/EBPα regulates G1/S cell cycle arrest in response to DNA damage via the control of CRL4Cdt2 mediated degradation of p21. PMID:25483090

  20. The importance of regulation of blood glucose levels through activation of peripheral 5'-AMP-activated protein kinase on ischemic neuronal damage.

    Science.gov (United States)

    Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

    2010-09-10

    5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in energy homeostasis. Recently, it was reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In addition, we have previously reported that the development of post-ischemic glucose intolerance could be one of the triggers for the aggravation of neuronal damage. In this study, we focused on effect of activation of peripheral or central AMPK on the development of ischemic neuronal damage. Male ddY mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histological and behavioral analysis after MCAO. In the liver and skeletal muscle, AMPK activity was not affected by MCAO. But, application of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly suppressed the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, application of intracerebroventricular metformin (25, 100 microg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO, in a dose-dependent manner. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK was activated by ischemic stress per se, however, peripheral AMPK was not altered. Furthermore, the regulation of post-ischemic glucose intolerance by activation of peripheral AMPK is of assistance for the suppression of cerebral ischemic neuronal damage. 2010 Elsevier B.V. All rights reserved.

  1. Hepatocellular carcinoma in Danish patients

    DEFF Research Database (Denmark)

    Stefansdottir, Jenna; Christensen, Erik; Schiødt, Frank Vinholt

    2017-01-01

    OBJECTIVE: Hepatocellular carcinoma (HCC) is a common cause of cancer, and most HCC patients have underlying cirrhosis. Retrospectively, we aimed to characterize patients with newly diagnosed HCC at a Danish hospital and to investigate survival and identify predictive factors for survival. METHODS...

  2. Glutathione treatment of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Dalhoff, K; Ranek, L; Mantoni, M

    1992-01-01

    This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH...

  3. Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

    Science.gov (United States)

    Diaz, Giacomo; Engle, Ronald E; Tice, Ashley; Melis, Marta; Montenegro, Stephanie; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Emmert-Buck, Michael R; Bock, Kevin W; Moore, Ian N; Zamboni, Fausto; Govindarajan, Sugantha; Kleiner, David; Farci, Patrizia

    2018-06-01

    There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n-5) and with non-HCC HDV cirrhosis (n=7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and non-malignant hepatocytes, tumorous and non-tumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of up-regulated transcripts associated with pathways involved in cell cycle/DNA replication, damage and repair (sonic hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell cycle regulation, cell cycle: G2/M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being over-expressed, these genes were also strongly co-regulated. Gene co-regulation was high not only when compared to non-malignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and co-regulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. This study identifies a molecular signature of HDV

  4. SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage.

    Science.gov (United States)

    Brun, Sonia; Abella, Neus; Berciano, Maria T; Tapia, Olga; Jaumot, Montserrat; Freire, Raimundo; Lafarga, Miguel; Agell, Neus

    2017-01-01

    We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO-conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus.

  5. GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

    Directory of Open Access Journals (Sweden)

    Daowen Li

    2017-01-01

    Full Text Available Olaquindox, a quinoxaline 1,4-dioxide derivative, is widely used as a feed additive in many countries. The potential genotoxicity of olaquindox, hence, is of concern. However, the proper mechanism of toxicity was unclear. The aim of the present study was to investigate the effect of growth arrest and DNA damage 45 alpha (GADD45a on olaquindox-induced DNA damage and cell cycle arrest in HepG2 cells. The results showed that olaquindox could induce reactive oxygen species (ROS-mediated DNA damage and S-phase arrest, where increases of GADD45a, cyclin A, Cdk 2, p21 and p53 protein expression, decrease of cyclin D1 and the activation of phosphorylation-c-Jun N-terminal kinases (p-JNK, phosphorylation-p38 (p-p38 and phosphorylation-extracellular signal-regulated kinases (p-ERK were involved. However, GADD45a knockdown cells treated with olaquindox could significantly decrease cell viability, exacerbate DNA damage and increase S-phase arrest, associated with the marked activation of p-JNK, p-p38, but not p-ERK. Furthermore, SP600125 and SB203580 aggravated olaquindox-induced DNA damage and S-phase arrest, suppressed the expression of GADD45a. Taken together, these findings revealed that GADD45a played a protective role in olaquindox treatment and JNK/p38 pathways may partly contribute to GADD45a regulated olaquindox-induced DNA damage and S-phase arrest. Our findings increase the understanding on the molecular mechanisms of olaquindox.

  6. Dataset on the regulation of banana weevil abundance and corm damage associated with plant richness and the ground-dwelling arthropods’ food web

    Directory of Open Access Journals (Sweden)

    Charlotte Poeydebat

    2017-12-01

    Full Text Available The data presented in this article are related to the research article entitled ̎Plant richness enhances banana weevil regulation in a tropical agroecosystem by affecting a multitrophic food web ̎ [1]. It provides information about plant species richness, weevil corm damage and the abundance of different arthropod groups, including the banana weevil and its potential natural enemies and alternative preys.

  7. A miR-590/Acvr2a/Rad51b Axis Regulates DNA Damage Repair during mESC Proliferation

    Directory of Open Access Journals (Sweden)

    Qidong Liu

    2014-12-01

    Full Text Available Embryonic stem cells (ESCs enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF, which maintains the self-renewal capability of mouse ESCs (mESCs, significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB and double-strand break (DSB damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal.

  8. The clinical significance and biological function of lncRNA RGMB-AS1 in hepatocellular carcinoma.

    Science.gov (United States)

    Sheng, Nan; Li, Yannan; Qian, Ruikun; Li, Yichun

    2018-02-01

    LncRNA RGMB-AS1 has been suggested to play significant roles in lung cancer progression. However, it remains unknown whether lncRNA RGMB-AS1 is involved in the development and progression of hepatocellular carcinoma. In our results, lncRNA RGMB-AS1 was low-expressed in hepatocellular carcinoma tissues and cell lines, and associated with clinical stage, tumor size and metastasis. Survival analysis indicated that lncRNA RGMB-AS1 high was an independent favorable prognostic factor for hepatocellular carcinoma patients. Gain-of-function studies showed up-regulated lncRNA RGMB-AS1 expression suppressed hepatocellular carcinoma cells proliferation, migration and invasion, and promoted cells apoptosis. There was a positively association between lncRNA RGMB-AS1 and RGMB in hepatocellular carcinoma tissues, and up-regulated lncRNA RGMB-AS1 expression increased RGMB mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, lncRNA RGMB-AS1 serves an anti-oncogenic role in hepatocellular carcinoma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. A damage-responsive DNA binding protein regulates transcription of the yeast DNA repair gene PHR1

    International Nuclear Information System (INIS)

    Sebastian, J.; Sancar, G.B.

    1991-01-01

    The PHR1 gene of Saccharomyces cerevisiae encodes the DNA repair enzyme photolyase. Transcription of PHR1 increases in response to treatment of cells with 254-nm radiation and chemical agents that damage DNA. The authors here the identification of a damage-responsive DNA binding protein, termed photolyase regulatory protein (PRP), and its cognate binding site, termed the PHR1 transcription after DNA damage. PRP activity, monitored by electrophoretic-mobility-shift assay, was detected in cells during normal growth but disappeared within 30 min after irradiation. Copper-phenanthroline footprinting of PRP-DNA complexes revealed that PRP protects a 39-base-pair region of PHR1 5' flanking sequence beginning 40 base pairs upstream from the coding sequence. Thus these observations establish that PRP is a damage-responsive repressor of PHR1 transcription

  10. Mitochondrial fission promotes cell migration by Ca2+ /CaMKII/ERK/FAK pathway in hepatocellular carcinoma.

    Science.gov (United States)

    Sun, Xiacheng; Cao, Haiyan; Zhan, Lei; Yin, Chun; Wang, Gang; Liang, Ping; Li, Jibin; Wang, Zhe; Liu, Bingrong; Huang, Qichao; Xing, Jinliang

    2018-07-01

    Mitochondrial dynamics of fission and fusion plays critical roles in a diverse range of important cellular functions, and its deregulation has been increasingly implicated in human diseases. Previous studies have shown that increased mitochondrial fission significantly promoted the proliferation of hepatocellular carcinoma (HCC) cells. However, how they influence the migration of tumour cells remained largely unknown. In the present study, we further investigated the effect of mitochondrial fission on the migration and metastasis of hepatocellular carcinoma cells. Moreover, the underlying molecular mechanisms and therapeutic application were explored. Our data showed that dynamin-1-like protein expression was strongly increased in distant metastasis of hepatocellular carcinoma when compared to primary hepatocellular carcinoma. In contrast, the mitochondrial fusion protein mitofusin 1 showed an opposite trend. Moreover, the expression of dynamin-1-like protein and mitofusin 1 was significantly associated with the disease-free survival of hepatocellular carcinoma patients. In addition, our data further showed that mitochondrial fission significantly promoted the reprogramming of focal-adhesion dynamics and lamellipodia formation in hepatocellular carcinoma cells mainly by activating typical Ca 2+ /CaMKII/ERK/FAK pathway. Importantly, treatment with mitochondrial division inhibitor-1 significantly decreased calcium signalling in hepatocellular carcinoma cells and had a potential treatment effect for hepatocellular carcinoma metastasis in vivo. Taken together, our findings demonstrate that mitochondrial fission plays a critical role in the regulation of hepatocellular carcinoma cell migration, which provides strong evidence for this process as a drug target in hepatocellular carcinoma metastasis treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs.

    Science.gov (United States)

    Bisicchia, Elisa; Sasso, Valeria; Catanzaro, Giuseppina; Leuti, Alessandro; Besharat, Zein Mersini; Chiacchiarini, Martina; Molinari, Marco; Ferretti, Elisabetta; Viscomi, Maria Teresa; Chiurchiù, Valerio

    2018-01-22

    Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b- and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage.

  12. Prophage induction and differential RecA and UmuDAb transcriptome regulation in the DNA damage responses of Acinetobacter baumannii and Acinetobacter baylyi.

    Directory of Open Access Journals (Sweden)

    Janelle M Hare

    Full Text Available The SOS response to DNA damage that induces up to 10% of the prokaryotic genome requires RecA action to relieve LexA transcriptional repression. In Acinetobacter species, which lack LexA, the error-prone polymerase accessory UmuDAb is instead required for ddrR induction after DNA damage, suggesting it might be a LexA analog. RNA-Seq experiments defined the DNA damage transcriptome (mitomycin C-induced of wild type, recA and umuDAb mutant strains of both A. baylyi ADP1 and A. baumannii ATCC 17978. Of the typical SOS response genes, few were differentially regulated in these species; many were repressed or absent. A striking 38.4% of all ADP1 genes, and 11.4% of all 17978 genes, were repressed under these conditions. In A. baylyi ADP1, 66 genes (2.0% of the genome, including a CRISPR/Cas system, were DNA damage-induced, and belonged to four regulons defined by differential use of recA and umuDAb. In A. baumannii ATCC 17978, however, induction of 99% of the 152 mitomycin C-induced genes depended on recA, and only 28 of these genes required umuDAb for their induction. 90% of the induced A. baumannii genes were clustered in three prophage regions, and bacteriophage particles were observed after mitomycin C treatment. These prophages encoded esvI, esvK1, and esvK2, ethanol-stimulated virulence genes previously identified in a Caenorhabditis elegans model, as well as error-prone polymerase alleles. The induction of all 17978 error-prone polymerase alleles, whether prophage-encoded or not, was recA dependent, but only these DNA polymerase V-related genes were de-repressed in the umuDAb mutant in the absence of DNA damage. These results suggest that both species possess a robust and complex DNA damage response involving both recA-dependent and recA-independent regulons, and further demonstrates that although umuDAb has a specialized role in repressing error-prone polymerases, additional regulators likely participate in these species' transcriptional

  13. The SFP1 gene product of Saccharomyces cerevisiae regulates G2/M transitions during the mitotic cell cycle and DNA-damage response

    International Nuclear Information System (INIS)

    Xu, Z.; Norris, D.

    1998-01-01

    In eukaryotic cells, checkpoint pathways arrest cell-cycle progression if a particular event has failed to complete appropriately or if an important intracellular structure is defective or damaged. Saccharomyces cerevisiae strains that lack the SFP1 gene fail to arrest at the G2 DNA-damage checkpoint in response to genomic injury, but maintain their ability to arrest at the replication and spindle-assembly checkpoints. sfp1D mutants are characterized by a premature entrance into mitosis during a normal (undamaged) cell cycle, while strains that overexpress Sfp1p exhibit delays in G2. Sfp1p therefore acts as a repressor of the G2/M transition, both in the normal cell cycle and in the G2 checkpoint pathway. Sfp1 is a nuclear protein with two Cys2His2 zinc-finger domains commonly found in transcription factors. We propose that Sfp1p regulates the expression of gene products involved in the G2/M transition during the mitotic cell cycle and the DNA-damage response. In support of this model, overexpression of Sfp1p induces the expression of the PDS1 gene, which is known to encode a protein that regulates the G2 checkpoint. (author)

  14. Up-regulation of A1M/α1-microglobulin in skin by heme and reactive oxygen species gives protection from oxidative damage.

    Science.gov (United States)

    Olsson, Magnus G; Allhorn, Maria; Larsson, Jörgen; Cederlund, Martin; Lundqvist, Katarina; Schmidtchen, Artur; Sørensen, Ole E; Mörgelin, Matthias; Akerström, Bo

    2011-01-01

    During bleeding the skin is subjected to oxidative insults from free heme and radicals, generated from extracellular hemoglobin. The lipocalin α(1)-microglobulin (A1M) was recently shown to have reductase properties, reducing heme-proteins and other substrates, and to scavenge heme and radicals. We investigated the expression and localization of A1M in skin and the possible role of A1M in the protection of skin tissue from damage induced by heme and reactive oxygen species. Skin explants, keratinocyte cultures and purified collagen I were exposed to heme, reactive oxygen species, and/or A1M and investigated by biochemical methods and electron microscopy. The results demonstrate that A1M is localized ubiquitously in the dermal and epidermal layers, and that the A1M-gene is expressed in keratinocytes and up-regulated after exposure to heme and reactive oxygen species. A1M inhibited the heme- and reactive oxygen species-induced ultrastructural damage, up-regulation of antioxidation and cell cycle regulatory genes, and protein carbonyl formation in skin and keratinocytes. Finally, A1M bound to purified collagen I (K(d) = 0.96×10(-6) M) and could inhibit and repair the destruction of collagen fibrils by heme and reactive oxygen species. The results suggest that A1M may have a physiological role in protection of skin cells and matrix against oxidative damage following bleeding.

  15. Inhibition of Ku70 acetylation by INHAT subunit SET/TAF-Iβ regulates Ku70-mediated DNA damage response.

    Science.gov (United States)

    Kim, Kee-Beom; Kim, Dong-Wook; Park, Jin Woo; Jeon, Young-Joo; Kim, Daehwan; Rhee, Sangmyung; Chae, Jung-Il; Seo, Sang-Beom

    2014-07-01

    DNA double-strand breaks (DSBs) can cause either cell death or genomic instability. The Ku heterodimer Ku70/80 is required for the NHEJ (non-homologous end-joining) DNA DSB repair pathway. The INHAT (inhibitor of histone acetyltransferases) complex subunit, SET/TAF-Iβ, can inhibit p300- and PCAF-mediated acetylation of both histone and p53, thereby repressing general transcription and that of p53 target genes. Here, we show that SET/TAF-Iβ interacts with Ku70/80, and that this interaction inhibits CBP- and PCAF-mediated Ku70 acetylation in an INHAT domain-dependent manner. Notably, DNA damage by UV disrupted the interaction between SET/TAF-Iβ and Ku70. Furthermore, we demonstrate that overexpressed SET/TAF-Iβ inhibits recruitment of Ku70/80 to DNA damage sites. We propose that dysregulation of SET/TAF-Iβ expression prevents repair of damaged DNA and also contributes to cellular proliferation. All together, our findings indicate that SET/TAF-Iβ interacts with Ku70/80 in the nucleus and inhibits Ku70 acetylation. Upon DNA damage, SET/TAF-Iβ dissociates from the Ku complex and releases Ku70/Ku80, which are then recruited to DNA DSB sites via the NHEJ DNA repair pathway.

  16. Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

    Science.gov (United States)

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients. PMID:26560447

  17. "Opening an emotional dimension in me": changes in emotional reactivity and emotion regulation in a case of executive impairment after left fronto-parietal damage.

    Science.gov (United States)

    Salas, Christian E; Radovic, Darinka; Yuen, Kenneth S L; Yeates, Giles N; Castro, O; Turnbull, Oliver H

    2014-01-01

    Dysexecutive impairment is a common problem after brain injury, particularly after damage to the lateral surface of the frontal lobes. There is a large literature describing the cognitive deficits associated with executive impairment after dorsolateral damage; however, little is known about its impact on emotional functioning. This case study describes changes in a 72-year-old man (Professor F) who became markedly dysexecutive after a left fron-to-parietal stroke. Professor F's case is remarkable in that, despite exhibiting typical executive impairments, abstraction and working memory capacities were spared. Such preservation of insight-related capacities allowed him to offer a detailed account of his emotional changes. Quantitative and qualitative tools were used to explore changes in several well-known emotional processes. The results suggest that Professor F's two main emotional changes were in the domain of emotional reactivity (increased experience of both positive and negative emotions) and emotion regulation (down-regulation of sadness). Professor F related both changes to difficulties in his thinking process, especially a difficulty generating and manipulating thoughts during moments of negative arousal. These results are discussed in relation to the literature on executive function and emotion regulation. The relevance of these findings for neuropsychological rehabilitation and for the debate on the neural basis of emotional processes is addressed.

  18. Grp78 promotes the invasion of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Li Hongdan

    2010-01-01

    Full Text Available Abstract Background Glucose regulated protein 78 (Grp78 is involved in the invasion and metastasis in many human cancers including gastric cancer, breast cancer, prostate cancer. But the role of Grp78 in the invasion of human hepatocellular carcinoma has not been reported. In this article, we examined if Grp78 was associated with the invasion of hepatocellular carcinoma and explored the possible underlying mechanism. Methods The Grp78 and FAK expression levels in 44 patients with hepatocellular carcinoma were examined using immunohistochemistry. Grp78 overexpressing SMMC7721 cells were established by pcDNA3.1 (+-Grp78 transfection and screened by G418. Grp78 and FAK levels in Grp78 overexpressing cells were down-regulated by siRNA transfection. The invasion status of tumor cells was evaluated by transwell assay in vitro, and chick embryo metastasis model in vivo. Cell spreading was determined by cell spreading assay, and quantitatively measured by Orisis software HUG. Grp78, pY397 FAK, pY576/577 FAK and FAK levels were detected by western blot. RhoA activity was detected by GST pulldown assay. The distribution of actin cytoskeleton was observed by fluorescent staining. Results Grp78 expression levels in 44 patients with hepatocellular carcinoma were negatively correlated with tumor grading, and positively correlated with portal invasion and intra-hepatic invasion. Overexpression of Grp78 in SMMC7721 cells promoted the invasion of cancer cells in vitro and in vivo, and this increase in tumor cell invasion was blocked by Grp78 siRNA knockdown. Our results also revealed that overexpression of Grp78 in SMMC7721 cells accelerated the process of cell spreading and promoted lamellipodia formation. Further analysis showed that overexpression of Grp78 in SMMC7721 cells increased pY397 and pY576/577 levels of FAK. Grp78 siRNA knockdown decreased FAK activation and activity. Our results also revealed that Grp78 overexpression in SMMC7721 cells decreased

  19. Grp78 promotes the invasion of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Su, Rongjian; Li, Zhen; Li, Hongdan; Song, Huijuan; Bao, Cuifen; Wei, Jia; Cheng, Liufang

    2010-01-01

    Glucose regulated protein 78 (Grp78) is involved in the invasion and metastasis in many human cancers including gastric cancer, breast cancer, prostate cancer. But the role of Grp78 in the invasion of human hepatocellular carcinoma has not been reported. In this article, we examined if Grp78 was associated with the invasion of hepatocellular carcinoma and explored the possible underlying mechanism. The Grp78 and FAK expression levels in 44 patients with hepatocellular carcinoma were examined using immunohistochemistry. Grp78 overexpressing SMMC7721 cells were established by pcDNA3.1 (+)-Grp78 transfection and screened by G418. Grp78 and FAK levels in Grp78 overexpressing cells were down-regulated by siRNA transfection. The invasion status of tumor cells was evaluated by transwell assay in vitro, and chick embryo metastasis model in vivo. Cell spreading was determined by cell spreading assay, and quantitatively measured by Orisis software HUG. Grp78, pY397 FAK, pY576/577 FAK and FAK levels were detected by western blot. RhoA activity was detected by GST pulldown assay. The distribution of actin cytoskeleton was observed by fluorescent staining. Grp78 expression levels in 44 patients with hepatocellular carcinoma were negatively correlated with tumor grading, and positively correlated with portal invasion and intra-hepatic invasion. Overexpression of Grp78 in SMMC7721 cells promoted the invasion of cancer cells in vitro and in vivo, and this increase in tumor cell invasion was blocked by Grp78 siRNA knockdown. Our results also revealed that overexpression of Grp78 in SMMC7721 cells accelerated the process of cell spreading and promoted lamellipodia formation. Further analysis showed that overexpression of Grp78 in SMMC7721 cells increased pY397 and pY576/577 levels of FAK. Grp78 siRNA knockdown decreased FAK activation and activity. Our results also revealed that Grp78 overexpression in SMMC7721 cells decreased RhoA-GTP level, and Grp78 siRNA knockdown rescued Rho

  20. Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model.

    Science.gov (United States)

    Sia, Kian Chuan; Huynh, Hung; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Hui, Kam Man; Lam, Paula Yeng Po

    2013-08-01

    Gene regulation of many key cell-cycle players in S-, G(2) phase, and mitosis results from transcriptional repression in their respective promoter regions during the G(0) and G(1) phases of cell cycle. Within these promoter regions are phylogenetically conserved sequences known as the cell-cycle-dependent element (CDE) and cell-cycle genes homology regions (CHR) sites. Thus, we hypothesize that transcriptional regulation of cell-cycle regulation via the CDE/CHR region together with liver-specific apolipoprotein E (apoE)-hAAT promoter could bring about a selective transgene expression in proliferating human hepatocellular carcinoma. We show that the newly generated vector AH-6CC-L2C could mediate hepatocyte-targeted luciferase gene expression in tumor cells and freshly isolated short-term hepatocellular carcinoma cultures from patient biopsy. In contrast, normal murine and human hepatocytes infected with AH-6CC-L2C expressed minimal or low luciferase activities. In the presence of prodrug 5-fluorocytosine (5-FC), AH-6CC-L2C effectively suppressed the growth of orthotopic hepatocellular carcinoma patient-derived xenograft mouse model via the expression of yeast cytosine deaminase (yCD) that converts 5-FC to anticancer metabolite 5-fluoruracil. More importantly, we show that combination treatment of AH-6CC-L2C with an EZH2 inhibitor, DZNep, that targets EpCAM-positive hepatocellular carcinoma, can bring about a greater therapeutic efficacy compared with a single treatment of virus or inhibitor. Our study showed that targeting proliferating human hepatocellular carcinoma cells through the transcriptional control of therapeutic gene could represent a feasible approach against hepatocellular carcinoma.

  1. Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

    2012-09-01

    Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

  2. Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma.

    Science.gov (United States)

    Porcu, Cristiana; Antonucci, Laura; Barbaro, Barbara; Illi, Barbara; Nasi, Sergio; Martini, Maurizio; Licata, Anna; Miele, Luca; Grieco, Antonio; Balsano, Clara

    2018-02-06

    Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies.

  3. Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma

    Science.gov (United States)

    Barbaro, Barbara; Illi, Barbara; Nasi, Sergio; Martini, Maurizio; Licata, Anna; Miele, Luca; Grieco, Antonio; Balsano, Clara

    2018-01-01

    Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies. PMID:29507693

  4. Current management of hepatocellular carcinoma

    Science.gov (United States)

    Tabrizian, Parissa; Roayaie, Sasan; Schwartz, Myron E

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and leading cause of death among patients with cirrhosis. Treatment guidelines are based according to the Barcelona Clinic Liver Cancer staging system. The choice among therapeutic options that include liver resection, liver transplantation, locoregional, and systemic treatments must be individualized for each patient. The aim of this paper is to review the outcomes that can be achieved in the treatment of HCC with the heterogeneous therapeutic options currently available in clinical practice. PMID:25132740

  5. Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

    Science.gov (United States)

    Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

    2016-06-01

    Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis.

  6. PRMT1 and PRMT4 Regulate Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage in SIRT1-Dependent and SIRT1-Independent Manners

    Directory of Open Access Journals (Sweden)

    Dong-Il Kim

    2015-01-01

    Full Text Available Oxidative stress-induced retinal pigment epithelial (RPE cell damage is involved in the progression of diabetic retinopathy. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs has emerged as an important histone modification involved in diverse diseases. Sirtuin (SIRT1 is a protein deacetylase implicated in the onset of metabolic diseases. Therefore, we examined the roles of type I PRMTs and their relationship with SIRT1 in human RPE cells under H2O2-induced oxidative stress. H2O2 treatment increased PRMT1 and PRMT4 expression but decreased SIRT1 expression. Similar to H2O2 treatment, PRMT1 or PRMT4 overexpression increased RPE cell damage. Moreover, the H2O2-induced RPE cell damage was attenuated by PRMT1 or PRMT4 knockdown and SIRT1 overexpression. In this study, we revealed that SIRT1 expression was regulated by PRMT1 but not by PRMT4. Finally, we found that PRMT1 and PRMT4 expression is increased in the RPE layer of streptozotocin-treated rats. Taken together, we demonstrated that oxidative stress induces apoptosis both via PRMT1 in a SIRT1-dependent manner and via PRMT4 in a SIRT1-independent manner. The inhibition of the expression of type I PRMTs, especially PRMT1 and PRMT4, and increased SIRT1 could be therapeutic approaches for diabetic retinopathy.

  7. Cul8/Rtt101 Forms a Variety of Protein Complexes That Regulate DNA Damage Response and Transcriptional Silencing*

    OpenAIRE

    Mimura, Satoru; Yamaguchi, Tsuyoshi; Ishii, Satoru; Noro, Emiko; Katsura, Tomoya; Obuse, Chikashi; Kamura, Takumi

    2010-01-01

    The budding yeast, Saccharomyces cerevisiae, has three cullin proteins, which act as platforms for Cullin-based E3 ubiquitin ligases. Genetic evidence indicates that Cul8, together with Mms1, Mms22, and Esc4, is involved in the repair of DNA damage that can occur during DNA replication. Cul8 is thought to form a complex with these proteins, but the composition and the function of Cul8-based E3 ubiquitin ligases remain largely uncharacterized. Herein, we report a comprehensive biochemical anal...

  8. MiR-34a is up-regulated in response to low dose, low energy X-ray induced DNA damage in breast cells

    International Nuclear Information System (INIS)

    Stankevicins, Luiza; Almeida, Carlos Eduardo de; Moura Gallo, Claudia Vitoria de; Almeida da Silva, Ana Paula; Ventura dos Passos, Flavia; Santos Ferreira, Evelin dos; Menks Ribeiro, Maria Cecilia; G David, Mariano; J Pires, Evandro; Ferreira-Machado, Samara Cristina; Vassetzky, Yegor

    2013-01-01

    MicroRNAs are non-coding RNAs involved in the regulation of gene expression including DNA damage responses. Low doses of low energy X-ray radiation, similar to those used in mammographic exams, has been described to be genotoxic. In the present work we investigated the expression of miR-34a; a well described p53-regulated miRNA implicated in cell responses to X-ray irradiation at low doses. Non-cancerous breast cell line MCF-10A and cancerous T-47D and MCF-7 cell lines were submitted to a low-energy X-ray irradiation (ranging from 28–30 Kv) using a dose of 5 Gy. The expression level of miR-34a, let-7a and miR-21 was assessed by qRT-PCR at 4 and 24 hours post-irradiation. DNA damage was then measured by comet assay and micronuclei estimation in MCF-10A and MCF-7 cell lines, where an increase of miR-34a levels could be observed after irradiation. The rate of apoptotic cells was estimated by nuclear staining and fluorescence microscopy. These experiments were also performed at low doses (3; 12 and 48 mGy) in MCF-10A and MCF-7 cell lines. We have observed an increase in miR-34a expression 4 hours post-irradiation at 5 Gy in MCF-10A and MCF-7 cell lines while its level did not change in T-47D, a breast cancer cell line bearing non-functional p53. At low doses, miR-34a was up-regulated in non-tumoral MCF-10A to a higher extent as compared to MCF-7. MiR-34a levels decreased 24 hours post-irradiation. We have also observed DNA damage and apoptosis at low-energy X-ray irradiation at low doses and the high dose in MCF-10A and MCF-7 4 and 24 hours post-irradiation relative to the mock control. Low energy X-ray is able to promote DNA strand breaks and miR-34a might be involved in cell responses to low energy X-ray DNA damage. MiR-34a expression correlates with X-ray dose, time after irradiation and cell type. The present study reinforces the need of investigating consequences of low dose X-ray irradiation of breast cells

  9. The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation.

    Directory of Open Access Journals (Sweden)

    Shiyuan Hong

    Full Text Available High-risk human papillomavirus (HPV must evade innate immune surveillance to establish persistent infections and to amplify viral genomes upon differentiation. Members of the JAK-STAT family are important regulators of the innate immune response and HPV proteins downregulate expression of STAT-1 to allow for stable maintenance of viral episomes. STAT-5 is another member of this pathway that modulates the inflammatory response and plays an important role in controlling cell cycle progression in response to cytokines and growth factors. Our studies show that HPV E7 activates STAT-5 phosphorylation without altering total protein levels. Inhibition of STAT-5 phosphorylation by the drug pimozide abolishes viral genome amplification and late gene expression in differentiating keratinocytes. In contrast, treatment of undifferentiated cells that stably maintain episomes has no effect on viral replication. Knockdown studies show that the STAT-5β isoform is mainly responsible for this activity and that this is mediated through the ATM DNA damage response. A downstream target of STAT-5, the peroxisome proliferator-activated receptor γ (PPARγ contributes to the effects on members of the ATM pathway. Overall, these findings identify an important new regulatory mechanism by which the innate immune regulator, STAT-5, promotes HPV viral replication through activation of the ATM DNA damage response.

  10. The relationship between emotion regulation capacity, heart rate variability, and quality of life in individuals with alcohol-related brain damage

    Directory of Open Access Journals (Sweden)

    Steinmetz JP

    2016-08-01

    Full Text Available Jean-Paul Steinmetz,1,2 Claus Vögele,3,4 Christiane Theisen-Flies,5 Carine Federspiel,1,2 Stefan Sütterlin6,7 1Department of Research and Development, ZithaSenior, 2Centre for Memory and Mobility, ZithaSenior, 3Institute for Health and Behaviour, Integrative Research Unit on Social and Individual Development (INSIDE, University of Luxembourg, Luxembourg; 4Research Group Health Psychology, University of Leuven, Leuven, Belgium; 5Home St Joseph, ZithaSenior, Luxembourg; 6Department of Psychology, Lillehammer University College, Lillehammer, 7Division of Surgery and Clinical Neuroscience, Department of Psychosomatic Medicine, Oslo University Hospital – Rikshospitalet, Oslo, Norway Abstract: The reliable measurement of quality of life (QoL presents a challenge in individuals with alcohol-related brain damage. This study investigated vagally mediated heart rate variability (vmHRV as a physiological predictor of QoL. Self- and proxy ratings of QoL and dysexecutive symptoms were collected once, while vmHRV was repeatedly assessed over a 3-week period at weekly intervals in a sample of nine alcohol-related brain damaged patients. We provide robustness checks, bootstrapped correlations with confidence intervals, and standard errors for mean scores. We observed low to very low heart rate variability scores in our patients in comparison to norm values found in healthy populations. Proxy ratings of the QoL scale “subjective physical and mental performance” and everyday executive dysfunctions were strongly related to vmHRV. Better proxy-rated QoL and fewer dysexecutive symptoms were observed in those patients with higher vmHRV. Overall, patients showed low parasympathetic activation favoring the occurrence of dysfunctional emotion regulation strategies. Keywords: heart rate variability, emotion regulation, alcohol-related brain damage, quality of life

  11. DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression.

    Science.gov (United States)

    Hampp, Stephanie; Kiessling, Tina; Buechle, Kerstin; Mansilla, Sabrina F; Thomale, Jürgen; Rall, Melanie; Ahn, Jinwoo; Pospiech, Helmut; Gottifredi, Vanesa; Wiesmüller, Lisa

    2016-07-26

    DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.

  12. Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma.

    Science.gov (United States)

    Fatima, Naz; Akhtar, Tasleem; Sheikh, Nadeem

    2017-01-01

    Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect.

  13. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LIU Jia

    2015-02-01

    Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

  14. Ultrasonographic finding of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Han Soo; Woo, Seong Ku; Lim, Jae Hoon; Ko, Young Tae; Kim, Ho Kyun; Kim, Soon Yong [Kyung Hee University Hospital, Seoul (Korea, Republic of)

    1983-12-15

    With the development of gray scale ultrasonography, detection and evaluation of hepatic parenchymal disease including space occupying lesion are easily performed and frequently used in the world. Thrity five cases of histopathologically proven and ultrasonographically suggested hepatocellular carcinoma are retrospectively studied. The results were as follows; 1. Ultrasonographic findings of hepatocellular carcinoma show hyperechoic pattern in 22 cases (63%), hypoechoic pattern in 2 cases (6%), and mixed pattern in 11 cases (31%). 2. The margin of tumor is ill-defined in 19 cases (54%) and well defined in16 cases (46%). 3. The size of tumor by sonographic measurement was large than 5 cm in diameter in 33 cases (94%). 4. The number of tumor is solitary in 19 cases and multiple in 16 cases. The sites of involved lobe were right lobe in 22 cases (63%), left lobe in 2 cases (6%), and both lobes in 11 cases (31%). 5. Associated sonographic findings were hepatomegaly with focal contour change in 25 cases (71%), splenomegaly in 16 cases (46%), cirrhosis of liver in 15 cases (43%), ascites in 11 cases (31%) and tumoral thrombosis in portal vein in 8 cases (23%). 6. The sex ratio is 6 : 1 male predominence and the age ranges from 32 to 76 years with highest incidence in 5th and 6th decades.

  15. Synchronous gastric neuroendocrine carcinoma and hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Ewertsen, Caroline; Henriksen, Birthe Merete; Hansen, Carsten Palnæs

    2009-01-01

    of synchronous gastric NEC and hepatocellular carcinoma in a patient with several other precancerous lesions is presented. The patient had anaemia, and a gastric tumour and two duodenal polyps were identified on upper endoscopy. A CT scan of the abdomen revealed several lesions in the liver. The lesions were...... invisible on B-mode sonography and real-time sonography fused with CT was used to identify and biopsy one of the lesions. Histology showed hepatocellular carcinoma. A literature search showed that only one case of a hepatocellular carcinoma synchronous with a gastric NEC has been reported previously. TRIAL...

  16. Gonadotropin-Releasing Hormone Regulates Expression of the DNA Damage Repair Gene, Fanconi anemia A, in Pituitary Gonadotroph Cells1

    OpenAIRE

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2004-01-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse LβT2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regu...

  17. Potentiality of immunotherapy against hepatocellular carcinoma

    Science.gov (United States)

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID:26420958

  18. Hepatic protection and anticancer activity of curcuma: A potential chemopreventive strategy against hepatocellular carcinoma

    OpenAIRE

    LI, YAN; SHI, XUE; ZHANG, JINGWEN; ZHANG, XIANG; MARTIN, ROBERT C.G.

    2013-01-01

    Malignant transformation of hepatocellular carcinoma (HCC) occurs through repetitive liver injury in a context of inflammation and oxidative DNA damage. A spectrum of natural sesquiterpenoids from curcuma oil has displayed anti-oxidant, anti-inflammatory and anti-carcinogenic properties. The aim of the study was to investigate the hepatoprotective and anti-HCC effects of curcuma oil in vivo and in vitro. Mice were pretreated with curcuma oil (100 mg/kg) for 3 days, then treated with Concanava...

  19. Risks of Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... cancer. Having hepatitis or cirrhosis can increase the risk of developing liver cancer. Anything that increases the ... clinical trials is available from the NCI website . Risks of Liver (Hepatocellular) Cancer Screening Key Points Screening ...

  20. Salicylic acid and nitric oxide alleviate high temperature induced oxidative damage in Lablab purpureus L plants by regulating bio-physical processes and DNA methylation.

    Science.gov (United States)

    Rai, Krishna Kumar; Rai, Nagendra; Rai, Shashi Pandey

    2018-07-01

    Salicylic acid (SA) and sodium nitroprusside (SNP, NO donor) modulates plant growth and development processes and recent findings have also revealed their involvement in the regulation of epigenetic factors under stress condition. In the present study, some of these factors were comparatively studied in hyacinth bean plants subjected to high temperature (HT) environment (40-42 °C) with and without exogenous application of SA and SNP under field condition. Exogenous application of SA and SNP substantially modulated the growth and biophysical process of hyacinth bean plants under HT environment. Exogenous application of SA and SNP also remarkably regulated the activities of antioxidant enzymes, modulated mRNA level of certain enzymes, improves plant water relation, enhance photosynthesis and thereby increasing plant defence under HT. Coupled restriction enzyme digestion-random amplification (CRED-RA) technique revealed that many methylation changes were "dose dependent" and HT significantly increased DNA damages as evidenced by both increase and decrease in bands profiles, methylation and de-methylation pattern. Thus, the result of the present study clearly shows that exogenous SA and SNP regulates DNA methylation pattern, modulates stress-responsive genes and can impart transient HT tolerance by synchronizing growth and physiological acclimatization of plants, thus narrowing the gaps between physio-biochemical and molecular events in addressing HT tolerance. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  1. Prevention of noise damages causes by shooting fire of Kalashnikov (AK-47) rifle by regulation of suitable distance

    OpenAIRE

    Gholamhossein Pourtaghi; Hamidreza Mokarami; Firouz Valipour; Mohammad Ghasemi

    2014-01-01

    The aims of this study were control of rifle shooting noise by regulation of suitable distance and investigation of frequency characteristic of the noise caused by single Kalashnikov rifle (AK-47) in an open shooting field. Due to the condition of the trainees and other people in the shooting fields, the measurements were done in 2 stages of individual and groups of 20 individuals and at 1, 30 and 50 meters distance, respectively. At each stage of the experiment the sound pressure level and p...

  2. Phytometabolite Dehydroleucodine Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Human Astrocytoma Cells through p73/p53 Regulation.

    Directory of Open Access Journals (Sweden)

    Natalia Bailon-Moscoso

    Full Text Available Accumulating evidence supports the idea that secondary metabolites obtained from medicinal plants (phytometabolites may be important contributors in the development of new chemotherapeutic agents to reduce the occurrence or recurrence of cancer. Our study focused on Dehydroleucodine (DhL, a sesquiterpene found in the provinces of Loja and Zamora-Chinchipe. In this study, we showed that DhL displayed cytostatic and cytotoxic activities on the human cerebral astrocytoma D384 cell line. With lactone isolated from Gynoxys verrucosa Wedd, a medicinal plant from Ecuador, we found that DhL induced cell death in D384 cells by triggering cell cycle arrest and inducing apoptosis and DNA damage. We further found that the cell death resulted in the increased expression of CDKN1A and BAX proteins. A marked induction of the levels of total TP73 and phosphorylated TP53, TP73, and γ-H2AX proteins was observed in D384 cells exposed to DhL, but no increase in total TP53 levels was detected. Overall these studies demonstrated the marked effect of DhL on the diminished survival of human astrocytoma cells through the induced expression of TP73 and phosphorylation of TP73 and TP53, suggesting their key roles in the tumor cell response to DhL treatment.

  3. Phytometabolite Dehydroleucodine Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Human Astrocytoma Cells through p73/p53 Regulation.

    Science.gov (United States)

    Bailon-Moscoso, Natalia; González-Arévalo, Gabriela; Velásquez-Rojas, Gabriela; Malagon, Omar; Vidari, Giovanni; Zentella-Dehesa, Alejandro; Ratovitski, Edward A; Ostrosky-Wegman, Patricia

    2015-01-01

    Accumulating evidence supports the idea that secondary metabolites obtained from medicinal plants (phytometabolites) may be important contributors in the development of new chemotherapeutic agents to reduce the occurrence or recurrence of cancer. Our study focused on Dehydroleucodine (DhL), a sesquiterpene found in the provinces of Loja and Zamora-Chinchipe. In this study, we showed that DhL displayed cytostatic and cytotoxic activities on the human cerebral astrocytoma D384 cell line. With lactone isolated from Gynoxys verrucosa Wedd, a medicinal plant from Ecuador, we found that DhL induced cell death in D384 cells by triggering cell cycle arrest and inducing apoptosis and DNA damage. We further found that the cell death resulted in the increased expression of CDKN1A and BAX proteins. A marked induction of the levels of total TP73 and phosphorylated TP53, TP73, and γ-H2AX proteins was observed in D384 cells exposed to DhL, but no increase in total TP53 levels was detected. Overall these studies demonstrated the marked effect of DhL on the diminished survival of human astrocytoma cells through the induced expression of TP73 and phosphorylation of TP73 and TP53, suggesting their key roles in the tumor cell response to DhL treatment.

  4. Radiation-Induced Upregulation of Gene Expression From Adenoviral Vectors Mediated by DNA Damage Repair and Regulation

    International Nuclear Information System (INIS)

    Nokisalmi, Petri; Rajecki, Maria; Pesonen, Sari; Escutenaire, Sophie; Soliymani, Rabah; Tenhunen, Mikko; Ahtiainen, Laura; Hemminki, Akseli

    2012-01-01

    Purpose: In the present study, we evaluated the combination of replication-deficient adenoviruses and radiotherapy in vitro. The purpose of the present study was to analyze the mechanism of radiation-mediated upregulation of adenoviral transgene expression. Methods and Materials: Adenoviral transgene expression (luciferase or green fluorescent protein) was studied with and without radiation in three cell lines: breast cancer M4A4-LM3, prostate cancer PC-3MM2, and lung cancer LNM35/enhanced green fluorescent protein. The effect of the radiation dose, modification of the viral capsid, and five different transgene promoters were studied. The cellular responses were studied using mass spectrometry and immunofluorescence analysis. Double strand break repair was modulated by inhibitors of heat shock protein 90, topoisomerase-I, and DNA protein kinase, and transgene expression was measured. Results: We found that a wide range of radiation doses increased adenoviral transgene expression regardless of the cell line, transgene, promoter, or viral capsid modification. Treatment with adenovirus, radiation, and double strand break repair inhibitors resulted in persistence of double strand breaks and subsequent increases in adenovirus transgene expression. Conclusions: Radiation-induced enhancement of adenoviral transgene expression is linked to DNA damage recognition and repair. Radiation induces a global cellular response that results in increased production of RNA and proteins, including adenoviral transgene products. This study provides a mechanistic rationale for combining radiation with adenoviral gene delivery.

  5. FBX8 Acts as an Invasion and Metastasis Suppressor and Correlates with Poor Survival in Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Feifei Wang

    Full Text Available F-box only protein 8 (FBX8, a novel component of F-box proteins, is lost in several cancers and has been associated with invasiveness of cancer cells. However, its expression pattern and role in the progression of hepatocellular carcinoma remain unclear. This study investigated the prognostic significance of FBX8 in hepatocellular carcinoma samples and analyzed FBX8 function in hepatocellular carcinoma cells by gene manipulation.The expression of FBX8 was detected in 120 cases of clinical paraffin-embedded hepatocellular carcinoma tissues, 20 matched pairs of fresh tissues and five hepatocellular carcinoma cell lines by immunohistochemistry with clinicopathological analyses, real-time RT-PCR or Western blot. The correlation of FBX8 expression with cell proliferation and invasion in five HCC cell lines was analyzed. Moreover, loss of function and gain of function assays were performed to evaluate the effect of FBX8 on cell proliferation, motility, invasion in vitro and metastasis in vivo.We found that FBX8 was obviously down-regulated in HCC tissues and cell lines (P<0.05. The FBX8 down-regulation correlated significantly with poor prognosis, and FBX8 status was identified as an independent significant prognostic factor. Over-expression of FBX8 decreased proliferation, migration and invasion in HepG2 and 97H cells, while knock-down of FBX8 in 7721 cells showed the opposite effect. FBX8 negatively correlated with cell proliferation and invasion in 7701, M3, HepG2 and 97H cell lines. In vivo functional assays showed FBX8 suppressed tumor growth and pulmonary metastatic potential in mice. Our results indicate that down-regulation of FBX8 significantly correlates with invasion, metastasis and poor survival in hepatocellular carcinoma patients. It may be a useful biomarker for therapeutic strategy and control in hepatocellular carcinoma treatment.

  6. Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease

    Science.gov (United States)

    Moreno-Fernandez, Maria E.; Giles, Daniel A.; Stankiewicz, Traci E.; Sheridan, Rachel; Karns, Rebekah; Cappelletti, Monica; Lampe, Kristin; Mukherjee, Rajib; Sina, Christian; Sallese, Anthony; Bridges, James P.; Hogan, Simon P.; Aronow, Bruce J.; Hoebe, Kasper

    2018-01-01

    Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression. PMID:29563328

  7. Computed tomographic findings of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Jo, In Su; Jong, Woo Yung; Lee, Jong Yul; Choi, Han Yong; Kim, Bong Ki

    1987-01-01

    With Development of Computed Tomography, detection of the Hepatocellular Carcinoma are easily performed and frequently used in the world. During 15 months, from December 1985 to February 1987, 59 patients with hepatocellular carcinoma were evaluated with computed tomography in department of radiology at Wallace Memorial Baptist Hospital. The results were as follow: 1. The most prevalent age group was 5th to 7th decades, male to female ratio was 4.9:1. 2. Classification with incidence of computed tomographic appearance of the hepatocellular carcinoma were solitary type 28 cases (48%), multinodular type 24 cases (40%), and diffuse type 7 cases (12%), Association with liver cirrhosis was noted in 22 cases (38%). 3. Inhomogenous internal consistency of hepatocellular carcinoma due to central necrosis were 35 cases (60%). Portal vein invasion by hepatocellular carcinoma was noted in 15 cases (25%), and particularly most common in diffuse type 4 cases (55%). 4. On precontrast scan, all hepatocellular carcinoma were seen as area of low density except for 3 cases(0.5%) of near isodensity which turned out to be remarkable low density on postcontrast scan. 5. In solitary type, posterior segment of right lobe was most common site of involvement 12 cases (43%). In diffuse type, bilobar involvement was most common, 6 cases (85%)

  8. Medical treatment of hepatocellular carcinoma.

    Science.gov (United States)

    Granito, Alessandro; Bolondi, Luigi

    2009-12-16

    Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Cirrhosis, most often due to viral hepatitis, is the predominant risk factors for HCC and geographical differences in both risk factors and incidence are largely due to epidemiological variations in hepatitis B and C infection. Hepatic function is a relevant parameter in selecting therapy in HCC. The current clinical classification of HCC split patients into 5 stages, with a specific treatment schedule for any stage. As patients with early stages can receive curative treatments, such as surgical resection, liver transplantation or local ablation, surveillance program in high-risk populations has become mandatory. Sorafenib, a multikinase inhibitor, has recently shown survival benefits in patients at advanced stage of disease. Hopefully, new molecular targeted therapies and their combination with sorafenib or interventional and surgical procedures, should expand the therapeutic armamentarium against HCC.

  9. [Radiofrequency ablation of hepatocellular carcinoma].

    Science.gov (United States)

    Widmann, Gerlig; Schullian, Peter; Bale, Reto

    2013-03-01

    Percutaneous radiofrequency ablation (RFA) is well established in the treatment of hepatocellular carcinoma (HCC). Due to its curative potential, it is the method of choice for non resectable BCLC (Barcelona Liver Clinic) 0 and A. RFA challenges surgical resection for small HCC and is the method of choice in bridging for transplantation and recurrence after resection or transplantation. The technical feasibility of RFA depends on the size and location of the HCC and the availability of ablation techniques (one needle techniques, multi-needle techniques). More recently, stereotactic multi-needle techniques with 3D trajectory planning and guided needle placement substantially improve the spectrum of treatable lesions including large volume tumors. Treatment success depends on the realization of ablations with large intentional margins of tumor free tissue (A0 ablation in analogy to R0 resection), which has to be documented by fusion of post- with pre-ablation images, and confirmed during follow-up imaging.

  10. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben

    2015-01-01

    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due...... to alterations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In the diagnostic setting, sub classification of HCA is based primarily on immunohistochemical analyzes, and has had an increasing impact on choice of treatment and individual prognostic assessment....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  11. Angiographic findings of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Han, Man Chung; Cho, Byung Jae; Huh, Seung Jae; Bae, Sang Hoon; Kim, Ung Jin; Kim, Chung Yong; Kim, Noe Kyeong [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1985-12-15

    From March 1977 to July 1979, 69 cases of angiograms of hepatocellular carcinoma were observed in Seoul National University Hospital. The findings of selective celiac and/or hepatic arteriography in total 69 cases of confirmed hepatocellular carcinoma, with clinical and laboratory findings, were analyzed. The summarized results are as follows; 1. Among 69 cases od hepatoma, 62 were male and 7 were female with sex ratio of 8.9 : 1. Peak incidence is 5th to 7th decades (72.5%). Epigastric pain, indigestion, and palpable mass in right upper quadrant were common symptoms and sign. Laboratory findings showed elevated serum alkaline phosphatase more than 5 Bodansky unit in 75.4%. Alpha-feto protein was positive in 65.2% of all the patients. 2 All 69 cases were classified into 31 cases of massive type, 22 cases of diffuse type, and 16 cases of nodular type, in accordance with angiographic gross anatomy. The frequency of angiographic findings were hypervascularities and tumor vessels (100%), tumor stainings (98.5%), arteriovenous shunt (71.0%), displacement of intrahepatic arteries (66.7%), vascular lakes and channel (59.4%). Encasement of hepatic artery and portal vein regurgitation was respectively 4 cases. Tumor mass in portal vein were 6 cases and tumor mass in hepatic vein was 1 case. 3. Intraarterial infusion of 5-FU was performed in 15 hepatoma patients, and the results were that angiographic improvement was demonstrated in 3 cases, no improvement in 8 cases, and incomplete infusion in 4 cases. 4. The selective celiac and/or hepatic angiograms are excellent diagnostic tools as well as therapeutic management for intraarterial infusion of anticancerous drugs.

  12. Angiographic findings of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Han, Man Chung; Cho, Byung Jae; Huh, Seung Jae; Bae, Sang Hoon; Kim, Ung Jin; Kim, Chung Yong; Kim, Noe Kyeong

    1985-01-01

    From March 1977 to July 1979, 69 cases of angiograms of hepatocellular carcinoma were observed in Seoul National University Hospital. The findings of selective celiac and/or hepatic arteriography in total 69 cases of confirmed hepatocellular carcinoma, with clinical and laboratory findings, were analyzed. The summarized results are as follows; 1. Among 69 cases od hepatoma, 62 were male and 7 were female with sex ratio of 8.9 : 1. Peak incidence is 5th to 7th decades (72.5%). Epigastric pain, indigestion, and palpable mass in right upper quadrant were common symptoms and sign. Laboratory findings showed elevated serum alkaline phosphatase more than 5 Bodansky unit in 75.4%. Alpha-feto protein was positive in 65.2% of all the patients. 2 All 69 cases were classified into 31 cases of massive type, 22 cases of diffuse type, and 16 cases of nodular type, in accordance with angiographic gross anatomy. The frequency of angiographic findings were hypervascularities and tumor vessels (100%), tumor stainings (98.5%), arteriovenous shunt (71.0%), displacement of intrahepatic arteries (66.7%), vascular lakes and channel (59.4%). Encasement of hepatic artery and portal vein regurgitation was respectively 4 cases. Tumor mass in portal vein were 6 cases and tumor mass in hepatic vein was 1 case. 3. Intraarterial infusion of 5-FU was performed in 15 hepatoma patients, and the results were that angiographic improvement was demonstrated in 3 cases, no improvement in 8 cases, and incomplete infusion in 4 cases. 4. The selective celiac and/or hepatic angiograms are excellent diagnostic tools as well as therapeutic management for intraarterial infusion of anticancerous drugs.

  13. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells

    Science.gov (United States)

    Mortusewicz, Oliver; Amé, Jean-Christophe; Leonhardt, Heinrich

    2007-01-01

    Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage dependent poly(ADP-ribose) polymerases (PARP) PARP-1 and PARP-2 are recruited to DNA damage sites, however, with different kinetics and roles. With specific PARP inhibitors and mutations, we could show that the initial recruitment of PARP-1 is mediated by the DNA-binding domain. PARP-1 activation and localized poly(ADP-ribose) synthesis then generates binding sites for a second wave of PARP-1 recruitment and for the rapid accumulation of the loading platform XRCC1 at repair sites. Further PARP-1 poly(ADP-ribosyl)ation eventually initiates the release of PARP-1. We conclude that feedback regulated recruitment of PARP-1 and concomitant local poly(ADP-ribosyl)ation at DNA lesions amplifies a signal for rapid recruitment of repair factors enabling efficient restoration of genome integrity. PMID:17982172

  14. USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

    Directory of Open Access Journals (Sweden)

    Aman Wang

    2017-05-01

    Full Text Available Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22 with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

  15. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiang-Yuan; Wang, Zhen [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Bei [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Ying-Jian, E-mail: yjzhang111@aliyun.com [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Ying-Yi, E-mail: liyingyi@fudan.edu.cn [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2016-04-22

    Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human pancreatic

  16. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Chen, Xiang-Yuan; Wang, Zhen; Li, Bei; Zhang, Ying-Jian; Li, Ying-Yi

    2016-01-01

    Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human pancreatic

  17. Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism.

    Science.gov (United States)

    Yu, Li; Sun, Yifan; Li, Jingjing; Wang, Yan; Zhu, Yuxing; Shi, Yong; Fan, Xiaojun; Zhou, Jianda; Bao, Ying; Xiao, Jie; Cao, Ke; Cao, Peiguo

    2017-08-15

    Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of Girdin silencing on cellular radiosensitivity. Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the signaling pathway downstream of Girdin. Finally, animal experiments were performed to demonstrate the effect of CCDC88A silencing on the radiosensitivity of hepatoma in vivo. shRNA-induced Girdin silencing suppressed glycolysis and enhanced the radio-sensitivity of hepatic cell lines, HepG2 and Huh-7. Furthermore, silencing of Girdin inhibited the PI3K/AKT/HIF-1α signaling pathway, which is a central regulator of glycolysis. Girdin can regulate glycolysis in hepatocellular carcinoma cells through the PI3K/AKT/HIF-1α signaling pathway, which decreases the sensitivity of tumor cells to radiotherapy.

  18. Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.

    Science.gov (United States)

    Wang, Shiquan; Wei, Haidong; Cai, Min; Lu, Yan; Hou, Wugang; Yang, Qianzi; Dong, Hailong; Xiong, Lize

    2014-01-01

    Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.

  19. DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization

    Directory of Open Access Journals (Sweden)

    Hengguang Zhao

    2016-11-01

    Full Text Available Mice and human patients with impaired vitamin D receptor (VDR signaling have normal developmental hair growth but display aberrant post-morphogenic hair cycle progression associated with alopecia. In addition, VDR–/– mice exhibit impaired cutaneous wound healing. We undertook experiments to determine whether the stress-inducible regulator of energy homeostasis, DNA damage-inducible transcript 4 (Ddit4, is involved in these processes. By analyzing hair cycle activation in vivo, we show that VDR−/− mice at day 14 exhibit increased Ddit4 expression within follicular stress compartments. At day 29, degenerating VDR−/− follicular keratinocytes, but not bulge stem cells, continue to exhibit an increase in Ddit4 expression. At day 47, when normal follicles and epidermis are quiescent and enriched for Ddit4, VDR−/− skin lacks Ddit4 expression. In a skin wound healing assay, the re-epithelialized epidermis in wildtype (WT but not VDR−/− animals harbor a population of Ddit4- and Krt10-positive cells. Our study suggests that VDR regulates Ddit4 expression during epidermal homeostasis and the wound healing process, while elevated Ddit4 represents an early growth-arresting stress response within VDR−/− follicles.

  20. DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization.

    Science.gov (United States)

    Zhao, Hengguang; Rieger, Sandra; Abe, Koichiro; Hewison, Martin; Lisse, Thomas S

    2016-11-26

    Mice and human patients with impaired vitamin D receptor (VDR) signaling have normal developmental hair growth but display aberrant post-morphogenic hair cycle progression associated with alopecia. In addition, VDR -/- mice exhibit impaired cutaneous wound healing. We undertook experiments to determine whether the stress-inducible regulator of energy homeostasis, DNA damage-inducible transcript 4 (Ddit4), is involved in these processes. By analyzing hair cycle activation in vivo, we show that VDR -/- mice at day 14 exhibit increased Ddit4 expression within follicular stress compartments. At day 29, degenerating VDR -/- follicular keratinocytes, but not bulge stem cells, continue to exhibit an increase in Ddit4 expression. At day 47, when normal follicles and epidermis are quiescent and enriched for Ddit4, VDR -/- skin lacks Ddit4 expression. In a skin wound healing assay, the re-epithelialized epidermis in wildtype (WT) but not VDR -/- animals harbor a population of Ddit4- and Krt10-positive cells. Our study suggests that VDR regulates Ddit4 expression during epidermal homeostasis and the wound healing process, while elevated Ddit4 represents an early growth-arresting stress response within VDR -/- follicles.

  1. CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3.

    Science.gov (United States)

    Jin, Xiaoxin; Cai, Lifeng; Wang, Changfa; Deng, Xiaofeng; Yi, Shengen; Lei, Zhao; Xiao, Qiangsheng; Xu, Hongbo; Luo, Hongwu; Sun, Jichun

    2018-02-23

    Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies.

  2. Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice*

    Science.gov (United States)

    Lei, Wei; Feng, Xu-Hui; Deng, Wen-Bo; Ni, Hua; Zhang, Zhi-Rong; Jia, Bo; Yang, Xin-Ling; Wang, Tong-Song; Liu, Ji-Long; Su, Ren-Wei; Liang, Xiao-Huan; Qi, Qian-Rong; Yang, Zeng-Ming

    2012-01-01

    Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus. PMID:22403396

  3. Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC.

    Science.gov (United States)

    Li, Yuan; Ge, Chang; Feng, Guoxing; Xiao, Huiwen; Dong, Jiali; Zhu, Changchun; Jiang, Mian; Cui, Ming; Fan, Saijun

    2018-03-24

    Irradiation exposure positive correlates with tumor formation, such as breast cancer and lung cancer. However, whether low dose irradiation induces hepatocarcinogenesis and the underlying mechanism remain poorly defined. In the present study, we reported that low dose irradiation facilitated the proliferation of hepatocyte through up-regulating HULC in vitro and in vivo. Low dose irradiation exposure elevated HULC expression level in hepatocyte. Deletion of heightened HULC erased the cells growth accelerated following low dose irradiation exposure. CDKN1, the neighbor gene of HULC, was down-regulated by overexpression of HULC following low dose irradiation exposure via complementary base pairing, resulting in promoting cell cycle process. Thus, our findings provide new insights into the mechanism of low dose irradiation-induced hepatocarcinogenesis through HULC/CDKN1 signaling, and shed light on the potential risk of low dose irradiation for the development of hepatocellular carcinoma in pre-clinical settings. © 2018 Wiley Periodicals, Inc.

  4. Surgical management of spontaneous ruptured hepatocellular adenoma

    Directory of Open Access Journals (Sweden)

    Marcelo Augusto Fontenelle Ribeiro Junior

    2009-01-01

    Full Text Available AIMS: Spontaneous ruptured hepatocellular adenoma (SRHA is a rare life-threatening condition that may require surgical treatment to control hemorrhaging and also stabilize the patient. We report a series of emergency surgeries performed at our institution for this condition. METHODS: We reviewed medical records and radiology files of 28 patients (from 1989 to 2006 with a proven diagnosis of hepatocellular adenoma (HA. Three (10.7% of 28 patients had spontaneous ruptured hepatocellular adenoma, two of which were associated with intrahepatic hemorrhage while one had intraperitoneal bleeding. Two patients were female and one was male. Both female patients had a background history of oral contraceptive use. Sudden abdominal pain associated with hemodynamic instability occurred in all patients who suffered from spontaneous ruptured hepatocellular adenoma. The mean age was 41.6 years old. The preoperative assessment included liver function tests, ultrasonography and computed tomography. RESULTS: The surgical approaches were as follows: right hemihepatectomy for controlling intraperitoneal bleeding, and right extended hepatectomy and non-anatomic resection of the liver for intrahepatic hemorrhage. There were no deaths, and the postoperative complications were bile leakage and wound infection (re-operation, as well as intraperitoneal abscess (re-operation and pleural effusion. CONCLUSION: Spontaneous ruptured hepatocellular adenoma may be treated by surgery for controlling hemorrhages and stabilizing the patient, and the decision to operate depends upon both the patient's condition and the expertise of the surgical team.

  5. Giant hepatocellular adenoma; case report

    Energy Technology Data Exchange (ETDEWEB)

    Pitella, F.A.; Coutinho, A.M.N.; Coura Filho, G.B.; Costa, P.L.A.; Ono, C.R.; Watanabe, T.; Sapienza, M.T.; Hironaka, F.; Cerri, G.G.; Buchpiguel, C.A. [Universidade de Sao Paulo (FM/USP), SP (Brazil). Inst. de Radiologia. Servico de Medicina Nuclear

    2008-07-01

    Full text: Introduction: Hepatocellular adenoma is a benign hepatic tumor identified mainly in women during fertility age, with estimated incidence of 4/1000 inhabitants. It is usually unique, well circumscribed, with or without a capsule, size varying from 1 to 30 cm, with possible central areas of necrosis and hemorrhage. Case Report: A 37-year-old female patient presenting with no comorbities, use of hormonal birth control pills for 18 years, a condition of reduction in the consistency of feces, increase in number of daily defecations, abdominal cramps, and a stuffed sensation after meals for two years. A palpable abdominal mass extending from the right hypochondriac to the right iliac fossa was noticed four months ago. A computerized tomography (CT) showed an extensive hepatic mass on the right which was considered, within the diagnostic hypotheses, hepatic adenomatosis, without ruling out secondary lesions. A hepatic scintillography with {sup 99m}Tc-DISIDA showed an extensive exophytic area from segment V to the right iliac fossa with arterialized blood flow and hepatocytic activity, as well as a hepatic nodule in segment VII with hepatocytic activity consistent with the hepatic adenomas hypothesis. The biopsy confirmed the hepatic adenoma diagnosis and the patient was submitted to a partial hepatectomy and cholecystectomy with good clinical evolution. Conclusion: Nuclear Medicine may supplement the assessment of hepatic nodules, including giant masses, thus suggesting new hypotheses and direction to therapeutic conduct. (author)

  6. Treatment options for hepatocellular carcinoma.

    Science.gov (United States)

    Sandhu, Dalbir S; Tharayil, Vivek S; Lai, Jin-Ping; Roberts, Lewis R

    2008-02-01

    Hepatocellular carcinoma (HCC) is frequently diagnosed at advanced stages and has a high mortality rate. With improved survival of patients with cirrhotic liver disease and increased prevalence of chronic hepatitis C viral infections, a rise in the number of HCC cases is being reported worldwide. Early diagnosis and treatment can significantly improve the prognosis of patients with HCC. Although surgical resection is an important potentially curative therapy for liver tumors, in appropriately selected patients, liver transplantation has been shown to achieve excellent survival rates for a solid tumor. Locally ablative and locoregional therapies in the form of percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization and transcatheter arterial radioembolization (TheraSphere) are viable options in patients with unresectable HCC. Unfortunately, the role of systemic therapy has been very limited in the treatment of these patients. Novel treatment options based on an improved understanding of the molecular pathogenesis of HCC are being explored. These targeted molecular therapies are aimed at growth factors and their receptors, intracellular signal transduction and cell cycle control. A substantial improvement in outcomes of intermediate and advanced stage HCC is expected with the advent of these targeted therapies, used in combination with surgical or locoregional therapies. Recent positive results from a large Phase III study of the receptor tyrosine kinase inhibitor, sorafenib, hold great promise in the treatment of HCC.

  7. High-resolution characterization of a hepatocellular carcinoma genome.

    Science.gov (United States)

    Totoki, Yasushi; Tatsuno, Kenji; Yamamoto, Shogo; Arai, Yasuhito; Hosoda, Fumie; Ishikawa, Shumpei; Tsutsumi, Shuichi; Sonoda, Kohtaro; Totsuka, Hirohiko; Shirakihara, Takuya; Sakamoto, Hiromi; Wang, Linghua; Ojima, Hidenori; Shimada, Kazuaki; Kosuge, Tomoo; Okusaka, Takuji; Kato, Kazuto; Kusuda, Jun; Yoshida, Teruhiko; Aburatani, Hiroyuki; Shibata, Tatsuhiro

    2011-05-01

    Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide. By massively parallel sequencing of a primary hepatitis C virus-positive hepatocellular carcinoma (36× coverage) and matched lymphocytes (>28× coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T>C/A>G transition and a decrease of the T>C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing at a higher sequence depth (>76× coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.

  8. DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial–mesenchymal transition

    International Nuclear Information System (INIS)

    Yang, Tao; Li, Xiao-Na; Li, Xing-Guang; Li, Ming; Gao, Peng-Zhi

    2014-01-01

    Highlights: • DNAJC6 is up-regulated in hepatocellular carcinoma tissues. • DNAJC6 promotes hepatocellular carcinoma cell proliferation and invasion. • DNAJC6 induces epithelial–mesenchymal transition by activating transforming growth factor β signaling. - Abstract: Epithelial–mesenchymal transition (EMT) is a developmental program, which is associated with hepatocellular carcinoma (HCC) development and progression. DNAJC6 (DNA/HSP40 homolog subfamily C member 6) encodes auxilin, which is responsible for juvenile Parkinsonism with phenotypic variability. However, the role of DNAJC6 in HCC development and progression is limited. Here, we report that DNAJC6 is up-regulated in HCC tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC. Furthermore, overexpression of DNAJC6 enhances the ability for acquisition of mesenchymal traits, enhanced cell proliferation and invasion. DNAJC6 positively regulated expression of EMT-related transcription factor, also activating transforming growth factor β (TGF-β) pathway to contribute to EMT. Our findings demonstrated an important function of DNAJC6 in the progression of HCC by induction of EMT, and they implicate DNAJC6 as a marker of poor outcome in HCC

  9. DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial–mesenchymal transition

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Tao [Hepatobiliary Surgery, The First Hospital of Shijiazhuang City, Shijiazhuang 050011 (China); Li, Xiao-Na [General Surgery, Sports Science Institute of Hebei Province, Shijiazhuang 050011 (China); Li, Xing-Guang; Li, Ming [General Surgery, The First Hospital of Shijiazhuang City, Shijiazhuang 050011 (China); Gao, Peng-Zhi, E-mail: pengzhigaovip@163.com [Hepatobiliary Surgery, The First Hospital of Shijiazhuang City, Shijiazhuang 050011 (China)

    2014-12-12

    Highlights: • DNAJC6 is up-regulated in hepatocellular carcinoma tissues. • DNAJC6 promotes hepatocellular carcinoma cell proliferation and invasion. • DNAJC6 induces epithelial–mesenchymal transition by activating transforming growth factor β signaling. - Abstract: Epithelial–mesenchymal transition (EMT) is a developmental program, which is associated with hepatocellular carcinoma (HCC) development and progression. DNAJC6 (DNA/HSP40 homolog subfamily C member 6) encodes auxilin, which is responsible for juvenile Parkinsonism with phenotypic variability. However, the role of DNAJC6 in HCC development and progression is limited. Here, we report that DNAJC6 is up-regulated in HCC tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC. Furthermore, overexpression of DNAJC6 enhances the ability for acquisition of mesenchymal traits, enhanced cell proliferation and invasion. DNAJC6 positively regulated expression of EMT-related transcription factor, also activating transforming growth factor β (TGF-β) pathway to contribute to EMT. Our findings demonstrated an important function of DNAJC6 in the progression of HCC by induction of EMT, and they implicate DNAJC6 as a marker of poor outcome in HCC.

  10. Current radiologic interventions in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Masoud, I.; Naeem, M.Q.T.; Saeed, F.; Mirza, S.A.M.; Khan, A.; Bhatti, M.A.

    2006-01-01

    With the rising incidence of chronic liver disease caused by viral hepatitis, hepatocellular carcinoma is showing a corresponding rise worldwide. Surgery remains the mainstay of treatment, but patients unfit for surgery or liver transplantation form the bulk of those presenting with this disease. Palliative treatments are being used to treat those and radiological modalities form the mainstay of the treatment. Radiology plays a major role in the diagnosis, treatment and follow-up of hepatocellular carcinoma. Current radiological treatment modalities include percutaneous ethanol ablation, radiofrequency ablation and trans-arterial chemoembolization. This update highlights the recent advancements in the field and compares their relative merits and demerits. (author)

  11. Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example.

    Science.gov (United States)

    Antoniali, Giulia; Lirussi, Lisa; Poletto, Mattia; Tell, Gianluca

    2014-02-01

    An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world.

  12. Surgical Treatment of Hepatocellular Carcinoma

    Science.gov (United States)

    Zamora-Valdes, Daniel; Taner, Timucin; Nagorney, David M.

    2017-01-01

    Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. In select patients, surgical treatment in the form of either resection or transplantation offers a curative option. The aims of this review are to (1) review the current American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines on the surgical management of HCC and (2) review the proposed changes to these guidelines and analyze the strength of evidence underlying these proposals. Three authors identified the most relevant publications in the literature on liver resection and transplantation for HCC and analyzed the strength of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. In the United States, the liver allocation system provides priority for liver transplantation to patients with HCC within the Milan criteria. Current evidence suggests that liver transplantation may also be indicated in certain patient groups beyond Milan criteria, such as pediatric patients with large tumor burden or adult patients who are successfully downstaged. Patients with no underlying liver disease may also benefit from liver transplantation if the HCC is unresectable. In patients with no or minimal (compensated) liver disease and solitary HCC ≥2 cm, liver resection is warranted. If liver transplantation is not available or contraindicated, liver resection can be offered to patients with multinodular HCC, provided that the underlying liver disease is not decompensated. Many patients may benefit from surgical strategies adapted to local resources and policies (hepatitis B prevalence, organ availability, etc). Although current low-quality evidence shows better overall survival with aggressive surgical strategies, this approach is limited to select patients. Larger and well-designed prospective studies are needed to better define the benefits and limits of such approach. PMID:28975836

  13. New advances in hepatocellular carcinoma

    Science.gov (United States)

    Pascual, Sonia; Herrera, Iván; Irurzun, Javier

    2016-01-01

    Hepatocellular carcinoma (HCC) is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths. Most HCC are associated with well known underlying risk factors, in fact, HCC arise in cirrhotic patients in up to 90% of cases, mainly due to chronic viral hepatitis and alcohol abuse. The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients. HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified. The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient at-risk for developing HCC. The diagnosis of HCC can be based on non-invasive criteria (only in cirrhotic patient) or pathology. Accurately staging patients is essential to oncology practice. The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function. Treatment allocation is based on several factors: Liver function, size and number of tumours, macrovascular invasion or extrahepatic spread. The recommendations in terms of selection for different treatment strategies must be based on evidence-based data. Resection, liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates. Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment. Finally, in patients with advanced HCC with preserved liver function, sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients. PMID:27028578

  14. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    International Nuclear Information System (INIS)

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy; Bronson, Roderick T.; Hornick, Jason L.; Cohen, David E.; Ukomadu, Chinweike

    2015-01-01

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors

  15. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  16. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    Energy Technology Data Exchange (ETDEWEB)

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Bronson, Roderick T. [Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115 (United States); Hornick, Jason L. [Department of Pathology, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Cohen, David E. [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Ukomadu, Chinweike, E-mail: cukomadu@partners.org [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2015-09-18

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors.

  17. Hyperkalaemia after radiofrequency ablation of hepatocellular carcinoma

    NARCIS (Netherlands)

    Verhoevena, BH; Haagsma, EB; Appeltans, BMG; Slooff, MJH; de Jong, KP

    Radiofrequency ablation of liver tumours is a useful therapy for otherwise unresectable tumours. The complication rate is said to be low. In this case report we describe hyperkalaemia after radiofrequency ablation of a hepatocellular carcinoma in a patient with end-stage renal insufficiency. (C)

  18. Radioembolisation for treatment of pediatric hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, Clifford Matthew; Kukreja, Kamlesh [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States); Geller, James I. [Cincinnati Children' s Hospital Medical Center, Department of Hematology/Oncology, Cincinnati, OH (United States); Schatzman, Carmen; Ristagno, Ross [University of Cincinnati, UC Health, Department of Radiology, Division of Interventional Radiology, Cincinnati, OH (United States)

    2013-07-15

    Transarterial radioembolisation with yttrium-90 (TARE-Y90), a catheter-directed therapy, has been used extensively in adults to treat primary and secondary hepatic malignancies. To our knowledge, the use of this palliative technique has not been described in children. We present two children with unresectable hepatocellular carcinoma (HCC) treated with TARE-Y90. (orig.)

  19. Small hepatocellular carcinoma versus small cavernous hemangioma

    International Nuclear Information System (INIS)

    Choi, B.I.; Park, H.W.; Kim, S.H.; Han, M.C.; Kim, C.W.

    1989-01-01

    To determine the optimal pulse sequence for detection and differential diagnosis of small hepatocellular carcinomas and cavernous hemangiomas less than 5 cm in diameter, the authors have analyzed spin-echo (SE) images of 15 small hepatocellular carcinomas and 31 small cavernous hemangiomas obtained at 2.0 T. Pulse sequences used included repetition times (TRs) of 500 and 2,000 msec and echo times (TEs) of 30,60,90,120,150, and 180 msec. Mean tumor-liver contrast-to-noise ratios on the SE 2,000/60 (TR msec/TE msec) sequence were 23.90 ± 16.33 and 62.10 ± 25.94 for small hepatocellular carcinomas and hemangiomas, respectively, and were significantly greater than for all other pulse sequences. Mean tumor-liver signal intensity ratios on the SE 2,000/150 sequence were 2.34 ± 1.72 and 6.04 ± 2.72 for small hepatocellular carcinomas and hemangiomas, respectively, and were significantly greater than for all other pulse sequences in hemangiomas

  20. Liver transplantation in patients with hepatocellular carcinoma

    NARCIS (Netherlands)

    Polak, Wojciech G.; Soyama, Akihiko; Slooff, Maarten J. H.

    2008-01-01

    Liver transplantation has a definitive place in the treatment of patients with hepatocellular carcinoma (HCC) in a cirrhotic liver. Patients with a tumor load within the Milan criteria have excellent survival comparable to survival in patients with benign indications. When tumor load exceeds the

  1. Delayed presentation and diagnosis of metastatic hepatocellular ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is rarely diagnosed in women of reproductive age. ... an adverse effect on HCC, and that high levels of oestrogen associated with pregnancy may ... A 30-year-old pregnant woman presented at 23 weeks' gestation and was diagnosed as HIV-infected, with anaemia. She was initiated on.

  2. Hepatocellular carcinoma: risk groups, surveillance and outcome

    NARCIS (Netherlands)

    van Meer, S

    2016-01-01

    The burden of hepatocellular carcinoma (HCC) has changed in the past few decades. Although the majority of HCC cases develops in East Asia and Sub-Saharan Africa, HCC has become an increasing problem in Western countries such as the Netherlands. Surveillance for HCC is controversial because of

  3. Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Laura Santangelo

    2017-01-01

    Full Text Available Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA from donor to recipient cells. Notably, tumor-derived exosomes (TDEs appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC, the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined.

  4. Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Naz Fatima

    2017-01-01

    Full Text Available Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect.

  5. Research advances in cellular immunotherapy for primary hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    ZHANG Ye

    2014-09-01

    Full Text Available The present therapy for primary hepatocellular carcinoma (HCC consists of surgery as well as local radiotherapy and chemotherapy. However, the majority of patients are susceptible to recurrence after comprehensive treatment, and the overall treatment outcome is not ideal due to the lack of effective drugs and strategies. Increasing evidence has demonstrated that the immune system is closely related to the development, progression, metastasis, and recurrence of HCC. Thus, immune therapy, especially cellular immunotherapy, could regulate immune function and induce specific antitumor immunity to achieve the goal of controlling HCC and reducing its recurrence and metastasis, which has become an essential part in the comprehensive treatment of HCC. The findings in preclinical and clinical studies on cellular immunotherapy for HCC data are reviewed, and the current problems are discussed.

  6. Hepatocellular carcinoma: a clinico pathological study

    International Nuclear Information System (INIS)

    Abbasi, A.; Butt, N.; Bhutto, A.R.; Gulzar, K.; Munir, S.M.

    2010-01-01

    To describe the clinico-pathological and radiological profile of hepatocellular carcinoma. All consecutive patients suspected of having hepatocellular carcinoma (HCC), were admitted and included in this study. Diagnosis of HCC was established by clinical, biochemical, ultrasonographic and histopathologic findings. Patients with primary carcinoma elsewhere in the body, metastatic in the liver, fibrolamellar carcinoma and benign tumours were excluded from the study. At ultrasonography, the details of tumour size and number, portal vein thrombosis and presence of ascites were recorded. Patients were staged according to Okuda staging system. Results were described in mean and percentage values. There were 82 patients with hepatocellular carcinoma including 58 males and 24 females, with male to female ratio of 2.8:1. The mean age of patients was 56.24 +- 13.65 years. Right hypochondrial pain was the main symptom in 52 (63.4%) patients. The duration of symptoms varied from 1 month to 2 years. Tumour size was larger than 50% of liver size in 42 (51.2%) with portal vein thrombosis in 10 (12.19%). Anti HCV was positive in 44 (53.7%), HBsAg in 26 (31.7%) and both were found positive in 2 (2.44%) patients. Ten patients (12.2/%) found negative both for anti-HCV and HBsAg. According to Okuda staging system 18 patients had stage 1, 50 had stage 2 and 14 had stage 3 hepatocellular carcinoma. The mean age of presentation of hepatocellular carcinoma was younger as compared to western countries with potentially large non-resectable lesions. Chronic hepatitis C and B was found to be the major known factors. Patients with chronic hepatitis C and B should undergo vigorous HCC surveillance to detect early, potentially respectable HCC. (author)

  7. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Roomi, M. Waheed; Roomi, Nusrath W.; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2012-01-01

    The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression

  8. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Roomi, M. Waheed; Roomi, Nusrath W.; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra, E-mail: a.niedz@drrath.com; Rath, Matthias [Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050 (United States)

    2012-03-23

    The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression

  9. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Aleksandra Niedzwiecki

    2012-03-01

    Full Text Available The incidence of hepatocellular carcinoma (HCC, once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs that degrade the extracellular matrix (ECM have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay, MMPs secretion (by gelatinase zymography, cell invasion (through Matrigel and induction of apoptosis (by live green caspase. In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and

  10. File list: Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular mm9 Unclassified Liver Carcinoma, Hepato...cellular http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular.bed ...

  11. File list: His.Liv.10.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.10.AllAg.Carcinoma,_Hepatocellular mm9 Histone Liver Carcinoma, Hepatocellu...lar http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Liv.10.AllAg.Carcinoma,_Hepatocellular.bed ...

  12. Epigallocatechin-gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: A potential role for reducing UVB light-induced retinal damage

    International Nuclear Information System (INIS)

    Li, Chao-Peng; Yao, Jin; Tao, Zhi-Fu; Li, Xiu-Miao; Jiang, Qin; Yan, Biao

    2013-01-01

    Highlights: •UVB irradiation induces RPE autophagy. •EGCG treatment represses UVB-mediated autophagy. •EGCG regulates UVB-mediated autophagy through mTOR signaling pathway. •EGCG sensitizes RPE cells to UVB-induced damage in an autophagy-dependent manner. -- Abstract: Autophagy is an intracellular catabolic process involved in protein and organelle degradation via the lysosomal pathway that has been linked in the pathogenesis of age-related macular degeneration (AMD). UVB irradiation-mediated degeneration of the macular retinal pigment epithelial (RPE) cells is an important hallmark of AMD, which is along with the change in RPE autophagy. Thus, pharmacological manipulation of RPE autophagy may offer an alternative therapeutic target in AMD. Here, we found that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, plays a regulatory role in UVB irradiation-induced autophagy in RPE cells. UVB irradiation results in a marked increase in the amount of LC3-II protein in a dose-dependent manner. EGCG administration leads to a significant reduction in the formation of LC3-II and autophagosomes. mTOR signaling activation is required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation is significantly impaired by rapamycin administration. Moreover, EGCG significantly alleviates the toxic effects of UVB irradiation on RPE cells in an autophagy-dependent manner. Collectively, our study reveals a novel role of EGCG in RPE autophagy. EGCG may be exploited as a potential therapeutic reagent for the treatment of pathological conditions associated with abnormal autophagy

  13. THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Balakrishnan, Meenakshi P.; Cilenti, Lucia; Ambivero, Camilla [Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL (United States); Goto, Yamafumi [Department of Dermatology, Shinshu University School of Medicine, Matsumoto (Japan); Takata, Minoru [Department of Dermatology, Okayama University Graduate School of Medical Dentistry and Pharmaceutical Sciences, Okayama (Japan); Turkson, James; Li, Xiaoman Shawn [Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL (United States); Zervos, Antonis S., E-mail: azervos@mail.ucf.edu [Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL (United States)

    2011-01-07

    Research highlights: {yields} THAP5 is a DNA-binding protein and a transcriptional repressor. {yields} THAP5 is induced in melanoma cells upon exposure to UV or treatment with cisplatin. {yields} THAP5 induction correlates with the degree of apoptosis in melanoma cell population. {yields} THAP5 is a pro-apoptotic protein involved in melanoma cell death. -- Abstract: THAP5 was originally isolated as a specific interactor and substrate of the mitochondrial pro-apoptotic Omi/HtrA2 protease. It is a human zinc finger protein characterized by a restricted pattern of expression and the lack of orthologs in mouse and rat. The biological function of THAP5 is unknown but our previous studies suggest it could regulate G2/M transition in kidney cells and could be involved in human cardiomyocyte cell death associated with coronary artery disease (CAD). In this report, we expanded our studies on the properties and function of THAP5 in human melanoma cells. THAP5 was expressed in primary human melanocytes as well as in all melanoma cell lines that were tested. THAP5 protein level was significantly induced by UV irradiation or cisplatin treatment, conditions known to cause DNA damage. The induction of THAP5 correlated with a significant increase in apoptotic cell death. In addition, we show that THAP5 is a nuclear protein that could recognize and bind a specific DNA motif. THAP5 could also repress the transcription of a reporter gene in a heterologous system. Our work suggests that THAP5 is a DNA-binding protein and a transcriptional repressor. Furthermore, THAP5 has a pro-apoptotic function and it was induced in melanoma cells under conditions that promoted cell death.

  14. THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death

    International Nuclear Information System (INIS)

    Balakrishnan, Meenakshi P.; Cilenti, Lucia; Ambivero, Camilla; Goto, Yamafumi; Takata, Minoru; Turkson, James; Li, Xiaoman Shawn; Zervos, Antonis S.

    2011-01-01

    Research highlights: → THAP5 is a DNA-binding protein and a transcriptional repressor. → THAP5 is induced in melanoma cells upon exposure to UV or treatment with cisplatin. → THAP5 induction correlates with the degree of apoptosis in melanoma cell population. → THAP5 is a pro-apoptotic protein involved in melanoma cell death. -- Abstract: THAP5 was originally isolated as a specific interactor and substrate of the mitochondrial pro-apoptotic Omi/HtrA2 protease. It is a human zinc finger protein characterized by a restricted pattern of expression and the lack of orthologs in mouse and rat. The biological function of THAP5 is unknown but our previous studies suggest it could regulate G2/M transition in kidney cells and could be involved in human cardiomyocyte cell death associated with coronary artery disease (CAD). In this report, we expanded our studies on the properties and function of THAP5 in human melanoma cells. THAP5 was expressed in primary human melanocytes as well as in all melanoma cell lines that were tested. THAP5 protein level was significantly induced by UV irradiation or cisplatin treatment, conditions known to cause DNA damage. The induction of THAP5 correlated with a significant increase in apoptotic cell death. In addition, we show that THAP5 is a nuclear protein that could recognize and bind a specific DNA motif. THAP5 could also repress the transcription of a reporter gene in a heterologous system. Our work suggests that THAP5 is a DNA-binding protein and a transcriptional repressor. Furthermore, THAP5 has a pro-apoptotic function and it was induced in melanoma cells under conditions that promoted cell death.

  15. Epigallocatechin-gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: A potential role for reducing UVB light-induced retinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Li, Chao-Peng; Yao, Jin; Tao, Zhi-Fu; Li, Xiu-Miao; Jiang, Qin, E-mail: jqin710@vip.sina.com; Yan, Biao, E-mail: yanbiao1982@hotmail.com

    2013-09-06

    Highlights: •UVB irradiation induces RPE autophagy. •EGCG treatment represses UVB-mediated autophagy. •EGCG regulates UVB-mediated autophagy through mTOR signaling pathway. •EGCG sensitizes RPE cells to UVB-induced damage in an autophagy-dependent manner. -- Abstract: Autophagy is an intracellular catabolic process involved in protein and organelle degradation via the lysosomal pathway that has been linked in the pathogenesis of age-related macular degeneration (AMD). UVB irradiation-mediated degeneration of the macular retinal pigment epithelial (RPE) cells is an important hallmark of AMD, which is along with the change in RPE autophagy. Thus, pharmacological manipulation of RPE autophagy may offer an alternative therapeutic target in AMD. Here, we found that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, plays a regulatory role in UVB irradiation-induced autophagy in RPE cells. UVB irradiation results in a marked increase in the amount of LC3-II protein in a dose-dependent manner. EGCG administration leads to a significant reduction in the formation of LC3-II and autophagosomes. mTOR signaling activation is required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation is significantly impaired by rapamycin administration. Moreover, EGCG significantly alleviates the toxic effects of UVB irradiation on RPE cells in an autophagy-dependent manner. Collectively, our study reveals a novel role of EGCG in RPE autophagy. EGCG may be exploited as a potential therapeutic reagent for the treatment of pathological conditions associated with abnormal autophagy.

  16. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  17. Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Liver Lipidomics

    Directory of Open Access Journals (Sweden)

    Zhao Li

    2017-11-01

    Full Text Available Background: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC. HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms. Methods: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS was performed. Results: Triacylglycerols (TAGs with the number of double bond (DB > 2 (except 56:5 and 56:4 TAG were significantly down-regulated; conversely, others (except 52:2 TAG were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC, phosphatidylethanolamine (PE and phosphatidylinositol (PI were altered in a certain way. Sphingomyelin (SM was up-regulated and ceramide (Cer were down-regulated in HCC tissues. Conclusions: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH, may also be effective for the treatment of HCC.

  18. Protection of the Peyer's patch-associated crypt and villus epithelium against methotrexate-induced damage is based on its distinct regulation of proliferation

    NARCIS (Netherlands)

    Renes, Ingrid B.; Verburg, Melissa; Bulsing, Nathalie P.; Ferdinandusse, Sacha; Büller, Hans A.; Dekker, Jan; Einerhand, Alexandra W. C.

    2002-01-01

    The crypt and villus epithelium associated with Peyer's patches (PPs) is largely spared from methotrexate (MTX)-induced damage, compared with the non-patch (NP) epithelium. To assess the mechanism(s) preventing damage to the PP epithelium after MTX treatment, epithelial proliferation, apoptosis, and

  19. Peritoneal carcinomatosis: an unusual presentation of fibrolamellar hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Vicente, R.; Garcia-Gutierrez, J. A.; Fernandez, A.; Santalla, F.

    2001-01-01

    Fibrolamellar hepatocellular carcinoma is an uncommon malignant tumor with characteristic clinical, radiological and histopathological features that is usually associated with a more favorable natural course and greater survival than more common variants of hepatocellular carcinoma. We describe an atypical case of a fibrolamellar hepatocellular carcinomas sowing aggressive behaviour in a 20-year-old woman. The lesion presented with massive ascites, and imaging studies revealed extensive peritoneal metastatic spread. (Author) 8 refs

  20. [Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells].

    Science.gov (United States)

    Zheng, Yongchang; Du, Shunda; Xu, Haifeng; Xu, Yiyao; Zhao, Haitao; Chi, Tianyi; Lu, Xin; Sang, Xinting; Mao, Yilei

    2014-11-18

    To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha (TNF-α)-induced hepatocellular carcinoma cells with bioinformatics tools. Published microarray dataset of TNF-α-induced HepG2, human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network. In the signal transduction network, MYC and SP1 were the key nodes of signaling transduction. Several genes from the network were closely related with cellular adhesion.Epidermal growth factor receptor (EGFR) is a possible key gene of effectively regulating cellular adhesion during the induction of TNF-α. EGFR is a possible key gene for TNF-α-induced metastasis of hepatocellular carcinoma.

  1. Diagnostic Approaches to Metastatic Hepatocellular Carcinoma of the Orbit.

    Science.gov (United States)

    Geske, Michael J; Bloomer, Michele M; Kersten, Robert C; Vagefi, M Reza

    Orbital metastasis of hepatocellular carcinoma is exceedingly rare and caries a grave prognosis. Three cases of metastatic orbital hepatocellular carcinoma in which the primary tumor was initially unknown and the diagnostic challenges encountered are presented. With hepatocellular carcinoma, open biopsy and palliative tumor debulking has an increased bleeding risk due to the highly vascular nature of the tumor and coagulopathy associated with chronic liver disease. As an alternative, fine needle aspiration biopsy should be considered for hepatocellular carcinoma with a readily accessible mass and the availability of an experienced cytopathologist.

  2. Research progress of vascular change after TACE in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kang Zhen; Xiao Enhua

    2013-01-01

    Mortality rate of hepatocellular carcinoma is high. The majority of the patients are diagnosed in advanced stage and lose surgical opportunities. Many studies have reported transcatheter arterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma, and recommended TACE as a standard treatment for hepatocellular carcinoma of Barcelona Clinical Liver Cancer staging (BCLC staging) B. However, TACE can hardly fully embolize tumor blood supply, TACE postoperative hemodynamics and angiogenesis can induce tumor recurrence and metastasis. This paper reviewed characteristics of vascular changes, mechanisms, diagnosis and treatment methods, new progress in the field of hepatocellular carcinoma after TACE. (authors)

  3. Computed tomography diagnosis of hepatocellular carcinoma rupture haemorrhage

    International Nuclear Information System (INIS)

    Zhi Weike; Jiang Bin; Liu Jinquan; Li Sixia; Zhu Zhichang

    2004-01-01

    Objective: To evaluate the diagnostic value of hepatocellular carcinoma rupture hemorrhage using Computed Tomography. Methods: Six cases diagnosed hepatocellular carcinoma rupture hemorrhage were analyzed by morphic and histologic method and investigated the key point of scan in diagnosis. Result: The correct rate of hepatocellular carcinoma rupture hemorrhage by Computed Tomography is above 83 percent, it characteristic representation is strip and would high-density shadow after enhancement. Conclusion: The characteristic representation of hepatocellular carcinoma rupture hemorrhage is attain by Computed Tomography, which provides effective operation evidences for clinical operation. (authors)

  4. Radio-embolization for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Raoul, J.L.; Edeline, J.; Pracht, M.; Boucher, E.; Rolland, Y.; Garin, E.

    2011-01-01

    Hepatocellular carcinoma is now a major public health concern. In intermediate stages (one third of hepatocellular carcinoma patients), chemo-embolization is the standard of care despite a poor tolerance and a moderate efficacy. Moreover, despite recent improvements, this technique seems in a dead end. Radio-embolization could be an excellent tool for such patients. Currently 131 I-Lipiodol, 188 Re-Lipiodol, 90 Y-glass or resin microspheres are available. More recent and promising data come from microspheres, but phase II and III studies are needed before drawing any conclusion. In the future, the combination of radio-embolization with systemic chemotherapy or targeted agents (particularly anti-angiogenic drugs) seems very promising. (authors)

  5. Clinical significance of CMTM4 expression in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Bei CH

    2017-11-01

    Full Text Available Chunhua Bei,1,* Ying Zhang,1,* Riming Wei,1 Xiaonian Zhu,1 Zhigang Wang,1 Wen Zeng,2 Qiuyue Chen,3 Shengkui Tan1 1Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, 2Department of Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, 3Department of Pathology, 181st Hospital of Chinese People’s Liberation Army, Guilin, People’s Republic of China *These authors contributed equally to this work Abstract: CMTM4 is the most conserved member of chemokine-like factor (CKLF-like MARVEL transmembrane domain-containing (CMTM family on chromosome 16q22.1, a locus that harbors a number of tumor-suppressor genes. In previous studies, CMTM4 was reported to be downregulated and exhibited tumor-suppressor activities by regulating cell growth and cell cycle in clear cell renal cell carcinoma. However, its roles in tumorigenesis of hepatocellular carcinoma (HCC remain poorly studied. This study first investigated the expression of CMTM4 in HCC, and then examined the association between the expression of CMTM4 with the clinicopathological features and prognosis of HCC patients. It was found that CMTM4 was downregulated in HCC tissues, compared with matched adjacent nontumor tissues, as detected by immunohistochemistry. In addition, Kaplan–Meier survival analysis showed that the negative expression of CMTM4 was associated with decreased overall survival rates in patients with HCC. The results of this study suggest CMTM4 plays a role as a tumor suppressor in HCC and CMTM4 negative expression is a risk factor for poor prognosis of HCC. Keywords: chemokine-like factor-like MARVEL transmembrane domain-containing 4, hepatocellular carcinoma, immunohistochemistry, prognosis

  6. Serum immunoreactive calcitonin concentration in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dugard, J; Kew, M C; Da Fonseca, M; Levin, J [University of the Witwatersrand, Johannesburg (South Africa)

    1982-08-21

    Having found raised serum calcitonin concentrations in 94% of patients with hepatocellular carcinoma when using a dextran-coated-charcoal radio-immunoassay, we have now repeated the study, using a double-antibody radio-immunoassay, in 102 further patients with hepatocellular carcinoma and 35 matched controls. Serum immunoreactive calcitonin concentrations (iCT) in the controls ranged from 10 to 310 pg/ml (mean 154,6 pg/ml). Values in the tumour patients ranged from 10 to 1,650 pg/ml (mean 302,6 pg/ml). The mean figures were significantly higher in the tumour patients (P smaller than 0,001), 35.5% of them having values above 310 pg/ml. In 65 of the patients serum iCT concentrations were also determined by dextran-coated-charcoal radio-immunoassay. Values ranged from 10 to 10780 pg/ml (mean 2,179 pg/ml). If 1,000 pg/ml is taken as the upper limit of normal, 69% of the patients had raised iCT concentrations. There was a good correlation (r=0,67; P smaller than 0,001) between serum iCT values measured with both methods in 50 patients. If measured by the double-antibody radio-immunoassay method, the serum calcitonin value is not useful as a marker for hepatocellular carcinoma.

  7. Serum immunoreactive calcitonin concentration in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Dugard, J.; Kew, M.C.; Da Fonseca, M.; Levin, J.

    1982-01-01

    Having found raised serum calcitonin concentrations is 94% of patients with hepatocellular carcinoma when using a dextran-coated-charcoal radio-immunoassay, we have now repeated the study, using a double-antibody radio-immunoassay, in 102 further patients with hepatocellular carcinoma and 35 matched controls. Serum immunoreactive calcitonin concentrations (iCT) in the controls ranged from 10 to 310 pg/ml (mean 154,6 pg/ml). Values in the tumour patients ranged from 10 to 1 650 pg/ml (mean 302,6 pg/ml). The mean figures were significantly higher in the tumour patients (P smaller than 0,001), 35,5% of them having values above 310 pg/ml. In 65 of the patients serum iCT concentrations were also determined by dextran-coated-charcoal radio-immunoassay. Values ranged from 10 to 10780 pg/ml (mean 2 179 pg/ml). If 1 000 pg/ml is taken as the upper limit of normal, 69% of the patients had raised iCT concentrations. There was a good correlation (r=0,67; P smaller than 0,001) between serum iCT values measured with both methods in 50 patients. If measured by the double-antibody radio-immunoassay method, the serum calcitonin value is not useful as a marker for hepatocellular carcinoma

  8. Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells.

    Science.gov (United States)

    Carreras Puigvert, Jordi; von Stechow, Louise; Siddappa, Ramakrishnaiah; Pines, Alex; Bahjat, Mahnoush; Haazen, Lizette C J M; Olsen, Jesper V; Vrieling, Harry; Meerman, John H N; Mullenders, Leon H F; van de Water, Bob; Danen, Erik H J

    2013-01-22

    In pluripotent stem cells, DNA damage triggers loss of pluripotency and apoptosis as a safeguard to exclude damaged DNA from the lineage. An intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNA interference screen targeting all kinases, phosphatases, and transcription factors with global transcriptomics and phosphoproteomics to map the DDR in mouse embryonic stem cells treated with the DNA cross-linker cisplatin. Networks derived from canonical pathways shared in all three data sets were implicated in DNA damage repair, cell cycle and survival, and differentiation. Experimental probing of these networks identified a mode of DNA damage-induced Wnt signaling that limited apoptosis. Silencing or deleting the p53 gene demonstrated that genotoxic stress elicited Wnt signaling in a p53-independent manner. Instead, this response occurred through reduced abundance of Csnk1a1 (CK1α), a kinase that inhibits β-catenin. Together, our findings reveal a balance between p53-mediated elimination of stem cells (through loss of pluripotency and apoptosis) and Wnt signaling that attenuates this response to tune the outcome of the DDR.

  9. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    International Nuclear Information System (INIS)

    Seo, J.M.; Lee, S.J.; Kim, S.H.; Park, C.K.; Ha, S.Y.

    2012-01-01

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  10. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  11. Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Qianzheng; Battu, Aruna; Ray, Alo; Wani, Gulzar; Qian, Jiang; He, Jinshan; Wang, Qi-en [Department of Radiology, The Ohio State University, Columbus, OH 43210 (United States); Wani, Altaf A., E-mail: wani.2@osu.edu [Department of Radiology, The Ohio State University, Columbus, OH 43210 (United States); Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210 (United States); James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210 (United States)

    2015-06-15

    Highlights: • HDAC1 and HDAC2 co-localize with UV radiation-induced DNA damage sites. • HDAC1 translocation to chromatin is dependent on DDB2 function. • HDAC1 and HDAC2 are involved in H3K56Ac deacetylation. • H3K56Ac deacetylation requires DDB1 and DDB2 but not XPA or XPC functions. • HDAC1/2 depletion decreases XPC ubiquitination and local γH2AX accumulation. - Abstract: Acetylated histone H3 lysine 56 (H3K56Ac) is one of the reversible histone post-translational modifications (PTMs) responsive to DNA damage. We previously described a biphasic decrease and increase of epigenetic mark H3K56Ac in response to ultraviolet radiation (UVR)-induced DNA damage. Here, we report a new function of UV damaged DNA-binding protein (DDB) in deacetylation of H3K56Ac through specific histone deacetylases (HDACs). We show that simultaneous depletion of HDAC1/2 compromises the deacetylation of H3K56Ac, while depletion of HDAC1 or HDAC2 alone has no effect on H3K56Ac. The H3K56Ac deacetylation does not require functional nucleotide excision repair (NER) factors XPA and XPC, but depends on the function of upstream factors DDB1 and DDB2. UVR enhances the association of DDB2 with HDAC1 and, enforced DDB2 expression leads to translocation of HDAC1 to UVR-damaged chromatin. HDAC1 and HDAC2 are recruited to UVR-induced DNA damage spots, which are visualized by anti-XPC immunofluorescence. Dual HDAC1/2 depletion decreases XPC ubiquitination, but does not affect the recruitment of DDB2 to DNA damage. By contrast, the local accumulation of γH2AX at UVR-induced DNA damage spots was compromised upon HDAC1 as well as dual HDAC1/2 depletions. Additionally, UVR-induced ATM activation decreased in H12899 cells expressing H3K56Ac-mimicing H3K56Q. These results revealed a novel role of DDB in H3K56Ac deacetylation during early step of NER and the existence of active functional cross-talk between DDB-mediated damage recognition and H3K56Ac deacetylation.

  12. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Oliveri, Roberto S; Wetterslev, Jørn; Gluud, Christian

    2011-01-01

    Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC.......Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC....

  13. Selective angiography in fifty patients with primary hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Shou-Zhong, Wang; Xing-Rong, Chen; Gong-Xian, Wang

    1983-06-01

    Selective angiography is of great importance in the diagnosis of primary hepatocellular carcinoma. It offers information on the findings, multicentricity, localisation, extension, and type of growth. This paper discusses angiography from the methodical point of view, the findings to be obtained, the types of hepatocellular carcinoma, and the diagnostic efficiency of selective angiography in the evaluation of this type of tumour.

  14. Orbital Metastasis of Hepatocellular Carcinoma: A Case Report ...

    African Journals Online (AJOL)

    Background: Hepatocellular carcinoma is one of the commonest malignancies in Nigeria, however metastasis to the orbit is a rare presentation. Objective: To present a rare case of orbital metastasis of hepatocellular carcinoma. Case Report: A 25-year-old man presented with a 3-month history of pain, progressive swelling ...

  15. Chitosan nanoparticles from marine squid protect liver cells against N-diethylnitrosoamine-induced hepatocellular carcinoma.

    Science.gov (United States)

    Subhapradha, Namasivayam; Shanmugam, Vairamani; Shanmugam, Annaian

    2017-09-01

    Rationale of this study was framed to investigate the protective effect and anti-cancer property of nanoparticles based on chitosan isolated from squid, Sepioteuthis lessoniana, on hepatic cells in N-Nitrosodiethylamine-induced hepatocellular carcinoma in rats. The results conferred that the chitosan nanoparticle supplementation had a protective effect on liver cells by reducing the levels of marker enzymes and bilirubin and thus increasing the albumin levels. The level of reduced glutathione, ascorbic acid and α-tocopherol significantly increased in both post- and pre-treatment with chitosan nanoparticles. The levels of antioxidant enzymes were enhanced and lipid peroxidation products were diminished while treating nitrosodiethylamine-induced hepatocellular carcinoma with chitosan nanoparticles. Supplementation of chitosan nanoparticles had potent anti-hyperlipidemic property that was evidenced by monitoring the serum lipid levels and its components. Animals pre-treated with chitosan nanoparticles along with nitrosodiethylamine showed a significant reduction in the total cholesterol and triglycerides levels with increase in the levels of phospholipids and free fatty acids. Chitosan nanoparticles treated rats showed significant increment in high-density lipoprotein cholesterol and reduction in low-density lipoprotein and very low-density lipoprotein cholesterol when compared with levels in nitrosodiethylamine-induced hepatocellular carcinoma. Nitrosodiethylamine-induced carcinoma changes on circulation and hepatic antioxidant defense mechanism were regulated by chitosan nanoparticles, concluding that the chitosan nanoparticles have a potent protective effect on liver cells which might be due to its robust antioxidant and anti-lipidemic property. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Koudelkova, Petra; Costina, Victor; Weber, Gerhard; Dooley, Steven; Findeisen, Peter; Winter, Peter; Agarwal, Rahul; Schlangen, Karin; Mikulits, Wolfgang

    2017-10-10

    The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the "real-time" detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell-cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient's survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells.

  17. Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Petra Koudelkova

    2017-10-01

    Full Text Available The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC. The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the “real-time” detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell–cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient’s survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells.

  18. Act No. 225 of 17 March 1979 containing regulations on third party liability for damage caused by nuclear incidents; Nuclear Incidents (Third Party Liability) Act

    International Nuclear Information System (INIS)

    1979-01-01

    This Act on nuclear third party liability provides that the maximum amount of liability of the operator of a nuclear installation in the Netherlands is set at 100 million guilders in accordance with the Paris Convention; it also implements the Brussels Supplementary Convention's additional compensation mechanism. The new Act further provides that if damage is suffered on the Netherlands' territory as a result of a nuclear incident for which compensation is payable pursuant to the Brussels Convention or to the Act, and that the funds available for this purpose are insufficient to secure compensation of such damage to an amount of one thousand million guilders, the State shall make available the public funds needed to compensate such damage up to that amount. (NEA) [fr

  19. Metastases of Hepatocellular Carcinoma Misdiagnosed as Isolated Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Greco, Assunta; De Masi, Roberto; Orlando, Stefania; Metrangolo, Antonio; Zecca, Vittorio; Morciano, Giancarlo; De Donno, Antonella; Bagordo, Francesco; Piccinni, Giancarlo

    At present, cardiac metastasis of hepatocellular carcinoma is rarely mentioned in the literature. We report a hepatocellular carcinoma patient with cardiac metastasis misdiagnosed as hypertrophic cardiomyopathy in 2011. Two years later, on presentation of syncope, an abnormal ventricular septal size was recorded by ultrasound scan, and was subsequently shown by magnetic resonance imaging to be a tumour lesion. A myocardial biopsy confirmed infiltration of hepatocellular carcinoma. This observation underlines the risk of hepatocellular carcinoma cardiac metastasis, manifested in its infiltrative form as hypertrophic cardiomyopathy. In conclusion, we suggest that the ultrasound appearance of hypertrophic cardiomyopathy in hepatocellular carcinoma patients should be seen as a "red flag" and recommend the introduction of magnetic resonance imaging assessment of transplant candidates.

  20. Molecular Mechanisms Underlying Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Christian Trepo

    2009-11-01

    Full Text Available Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.

  1. A Study on the Effect of Neurogenesis and Regulation of GSK3β/PP2A Expression in Acupuncture Treatment of Neural Functional Damage Caused by Focal Ischemia in MCAO Rats

    Directory of Open Access Journals (Sweden)

    Ding Luo

    2014-01-01

    Full Text Available 170 SD rats were randomly divided to five groups. Rats in model group, no-acupuncture group, and acupuncture group were subjected to MCAO surgery. Acupuncture group received 3 consecutive acupuncture treatments at a parameter that deep in 2 mm towards apex nasi and thrust/lifted at 3 times per second for 1 minute, while model group and no-acupuncture group were no-intervention control groups. Serious neural functional damage and sharp decrease of cerebral blood flow, obvious infarction volume, increased nestin mRNA expression, and immunopositive cells population (nestin+, BrdU+ and nestin/BrdU+ were found in MCAO rats which had not been observed in normal group and sham-operated group. However, the damage was attenuated by rat’s “self-healing” capacity 3 days after MCAO. And the “self-healing” capacity can be strengthen by acupuncture treatment through increasing cerebral blood flow, neurogenesis, and regulation of gene transcription or GSK-3β and PP2A expression. In conclusion, the present study indicates that the underlying mechanism of acupuncture treatment on neural functional damage caused by focal ischemia injury is a multiple interaction which may involve improved cerebral blood supply, neurogenesis, and regulation of gene transcription or GSK-3β and PP2A expression in MCAO rats.

  2. Elevated serum levels of Chromogranin A in hepatocellular carcinoma.

    Science.gov (United States)

    Biondi, Antonio; Malaguarnera, Giulia; Vacante, Marco; Berretta, Massimiliano; D'Agata, Velia; Malaguarnera, Michele; Basile, Francesco; Drago, Filippo; Bertino, Gaetano

    2012-01-01

    During the past three decades, the incidence of hepatocellular carcinoma in the United States has tripled. The neuroendocrine character has been observed in some tumor cells within some hepatocellular carcinoma nodules and elevated serum chromogranin A also been reported in patients with hepatocellular carcinoma. The aim of this work was to investigate the role of serum concentration of chromogranin A in patients with hepatocellular carcinoma at different stages. The study population consisted of 96 patients (63 males and 33 females age range 52-84) at their first hospital admission for hepatocellular carcinoma. The control group consisted of 35 volunteers (20 males and 15 females age range 50-80). The hepatocellular carcinoma patients were stratified according the Barcelona-Clinic Liver Cancer classification. Venous blood samples were collected before treatment from each patients before surgery, centrifuged to obtain serum samples and stored at -80° C until assayed. The chromogranin A serum levels were elevated (> 100 ng/ml) in 72/96 patients with hepatocellular carcinoma. The serum levels of chromogranin A were significantly correlated (p<0.05) with alpha-fetoprotein. In comparison with controls, the hepatocellular carcinoma patients showed a significant increase (p<0.001) vs controls. The chromogranin A levels in the Barcelona staging of hepatocellular carcinoma was higher in stage D compared to stage C (p<0.01), to stage B (p<0.001), and to stage A (p<0.001). Molecular markers, such as chromogranin A, could be very useful tools for hepatocellular carcinoma diagnosis. However the molecular classification should be incorporated into a staging scheme, which effectively separated patients into groups with homogeneous prognosis and response to treatment, and thus serves to aid in the selection of appropriate therapy.

  3. CT diagnosis of rare histological variant of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Li Huaibo; Feng Zhipeng; Duan Shaoyin; Zhaugn Xiangrong

    2009-01-01

    Objective: To explore and understand the CT findings of 5 rare histological variants of hepatocellular carcinoma. Methods: CT findings of 31 cases of rare histological variants confirmed by surgery and pathology were analyzed retrospectively. Results: 13 cases were clear cell hepatocellular carcinoma. 3 cases of them showed patchy fat density in plain scans. Enhanced CT showed features of 'fast in fast out' which was similar to the common hepatocellular carcinoma. 4 cases belonged to sclerosis hepatocellular carcinoma. They appeared as heterogeneous, slowly enhancement on arterial phase images, and delay enhancement on portal venous phase and delay phase images. 9 cases belonged to mixed hepatocellular carcinoma. 5 cases of them showed inhomogeneous enhancement and 4 without enhancement during arterial phase, 3 cases showed delay enhancement and 4 without during portal venous and delay phase. 3 cases were fibrolamellar hepatocellular carcinoma. All showed obvious and fastly enhancement on arterial phase images, subsided slowly on the portal venous and delay phase images, showing features of 'fast in slow out', no enhancement was seen in the central scar. Shrinkage phenomenon on the surface of liver could be seen on the CT plain scans in sclerosis, mixed and fibrolamellar hepatocellular carcinoma. 2 cases were the type of dense hepatocellular carcinoma. The surrounding part in the 2 cases were slightly enhanced, while the most part of the center were not enhanced similar to necrosis. Conclusion: The CT findings of rate histological variant of hepatocellular carcinoma are characteristic. Analyzing the CT plain and enhancement finding is helpful to the diagnosis of these types of hepatocellular carcinoma. (authors)

  4. Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

    Science.gov (United States)

    Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

    2014-05-01

    Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. F-box protein FBXO31 is a dedicated checkpoint protein to facilitate cell cycle arrest through activation of regulators in radiation induced DNA damage

    International Nuclear Information System (INIS)

    Santra, Manas Kumar

    2017-01-01

    In response to radiation-induced DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Previous study showed that induction of G1 arrest in response to radiation induced DNA damage is minimally a two-step process: a fast p53-independent initiation of G1 arrest mediated by cyclin D1 proteolysis and a slower maintenance of arrest resulting from increased p53 stability. We elucidated the molecular mechanism of slow and fast response of radiation induced DDR. We showed that FBXO31, a member of F-box family proteins, plays important role in DDR induced by ionizing radiation. We show that FBXO31 is responsible for promoting MDM2 degradation following radiation. FBXO31 interacts with and directs the degradation of MDM2 in ATM dependent phosphorylation of MDM2. FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage

  6. The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage

    DEFF Research Database (Denmark)

    Lafuente-Barquero, Juan; Luke-Glaser, Sarah; Graf, Marco

    2017-01-01

    of Fanconi anemia protein M (FANCM), is required for cell viability in the absence of RNase H enzymes. The integrity of the Mph1 helicase domain is crucial to prevent the accumulation of RNA-DNA hybrids and RNA-DNA hybrid-dependent DNA damage, as determined by Rad52 foci. Mph1 forms foci when RNA-DNA hybrids...

  7. Evaluation of Photoelectron Therapy Effect on Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    bahram Mofid

    2007-10-01

    Full Text Available Mofid B1, Navabpoor M2, Alizadeh Azimi M3 1. Assistant professor, Department of Radiotherapy, Faculty of Para-Medicine, Shahid Beheshti University of medical sciences 2. Instructor, Department of Technology of radiology, Faculty of Para-Medicine, Shahid Beheshti University of medical sciences Abstract Background: Photoelectron therapy method has been usad successfully, on the body phantom, cancer cells culture and animals. In this method, drugs containing x-Ray opaque factors–with high atomic numbers–are injected into the patient’s vein. After appropriate drug accumulation, about at least ten percent of the total injected amounts, 200kev. up to 300kev. of localized x-Ray beams is radiated to the site of the tumor. The Ethic Committee of Shahid Beheshti University of Medical Education and Health Services authorized the implementation of this new cancer treatment method, initially only on the group of patients who suffered from hepato-cellular carcinoma. Hepato cellular carcinoma is one of the most current malignancies of liver. In some cases, in addition to surgery, several approaches exist to come near the aim of predominating hepato-cellular carcinoma such as chemotherapy, current Radiation Therapy, Radio-Frequency application (RF, Trans-Artepical Chemo Embolization, (TACE, and Percutaneous Ethanol Injection (PEI. The effectiveness of the above-mentioned methods is about 10%-47%, applied alone or along side each other. Materials and methods: This study was a clinical-trial one. In this study, first, lipiodol (an x-ray opaque material with a high atomic number was transferred into the main vessel terminating to the tumor by angio-catheterization. Then,200kev. up to 250kev. of localized x-ray was radiated to the site of the tumor in one session. The drug volume was proportionally selected to the volume of the tumor, and the irradiation intensity was between 400 to 600cent.Gy. the beam energy absorption capacity of this drug is as times as

  8. A qualitative signature for early diagnosis of hepatocellular carcinoma based on relative expression orderings.

    Science.gov (United States)

    Ao, Lu; Zhang, Zimei; Guan, Qingzhou; Guo, Yating; Guo, You; Zhang, Jiahui; Lv, Xingwei; Huang, Haiyan; Zhang, Huarong; Wang, Xianlong; Guo, Zheng

    2018-04-23

    Currently, using biopsy specimens to confirm suspicious liver lesions of early hepatocellular carcinoma are not entirely reliable because of insufficient sampling amount and inaccurate sampling location. It is necessary to develop a signature to aid early hepatocellular carcinoma diagnosis using biopsy specimens even when the sampling location is inaccurate. Based on the within-sample relative expression orderings of gene pairs, we identified a simple qualitative signature to distinguish both hepatocellular carcinoma and adjacent non-tumour tissues from cirrhosis tissues of non-hepatocellular carcinoma patients. A signature consisting of 19 gene pairs was identified in the training data sets and validated in 2 large collections of samples from biopsy and surgical resection specimens. For biopsy specimens, 95.7% of 141 hepatocellular carcinoma tissues and all (100%) of 108 cirrhosis tissues of non-hepatocellular carcinoma patients were correctly classified. Especially, all (100%) of 60 hepatocellular carcinoma adjacent normal tissues and 77.5% of 80 hepatocellular carcinoma adjacent cirrhosis tissues were classified to hepatocellular carcinoma. For surgical resection specimens, 99.7% of 733 hepatocellular carcinoma specimens were correctly classified to hepatocellular carcinoma, while 96.1% of 254 hepatocellular carcinoma adjacent cirrhosis tissues and 95.9% of 538 hepatocellular carcinoma adjacent normal tissues were classified to hepatocellular carcinoma. In contrast, 17.0% of 47 cirrhosis from non-hepatocellular carcinoma patients waiting for liver transplantation were classified to hepatocellular carcinoma, indicating that some patients with long-lasting cirrhosis could have already gained hepatocellular carcinoma characteristics. The signature can distinguish both hepatocellular carcinoma tissues and tumour-adjacent tissues from cirrhosis tissues of non-hepatocellular carcinoma patients even using inaccurately sampled biopsy specimens, which can aid early

  9. Effect of acetylcysteine on prothrombin index in paracetamol poisoning without hepatocellular injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Knudsen, Tore Tveit; Dalhoff, Kim

    2002-01-01

    Acetylcysteine treatment reduces liver damage after paracetamol overdose, but can affect the prothrombin index, which is used to assess the progress of overdose patients. We aimed to assess retrospectively the effect of intravenous acetylcysteine on the prothrombin index in patients with paraceta......Acetylcysteine treatment reduces liver damage after paracetamol overdose, but can affect the prothrombin index, which is used to assess the progress of overdose patients. We aimed to assess retrospectively the effect of intravenous acetylcysteine on the prothrombin index in patients...... with paracetamol poisoning without signs of hepatocellular injury. Prothrombin index had been recorded before, and serially during, acetylcysteine treatment in 87 patients. After initiation of treatment, prothrombin index decreased (mean 0.33, 95% CI 0.29-0.38) in all patients, and was strongly associated...... with the start of acetylcysteine infusion. In patients with uncomplicated paracetamol poisoning, a fall in this index might be misinterpreted as a sign of liver failure, leading to prolonged treatment time....

  10. Hepatocellular carcinoma: treatment with transcatheter arterial chemoembolization

    International Nuclear Information System (INIS)

    Acunas, Buelent; Rozanes, Izzet

    1999-01-01

    This article presents a review of the literature regarding the use of transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). There have been two different approaches to the treatment: (a) percutaneous tumor ablation methods which can be divided into injectable and thermal methods; percutaneous ethanol injection (PEI) is the most widely used method, and (b) TACE. PEI is the treatment of choice for single HCCs smaller or equal to 3 cm in size. For patients with large HCCs combined TACE and PEI is probably the most effective nonsurgical treatment. In the presence of multiple HCC nodules, TACE remains the treatment of choice

  11. Hepatocellular carcinoma directly invading the duodenum

    International Nuclear Information System (INIS)

    Mohamed, Abdelrehman O.; Joshi, Sandhya; Czechowski, Janusz; Branicki, Frank

    2005-01-01

    Recurrent gastrointestinal bleeding from hepatocellular carcinoma (HCC) invading the duodenum is very rare. We present a case of 50-year-old male who was admitted with a history of recurrent upper gastrointestinal tract (UGIT) bleeding, weight loss and anemia. The patient was known to have a chronic hepatitis C. Endoscopic examination showed grade-2 non-bleeding esophageal varices, and a large ulcerated duodenal mass partially obstructing the duodenal bulb outlet and causing recurrent UGIT bleeding. Pathological evaluation of the mass revealed HCC. (author)

  12. Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage

    Directory of Open Access Journals (Sweden)

    Laila Mohamed Fadda

    2018-02-01

    Full Text Available The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc, alone or in combination with Melatonin (Melat against cardiac damage induced by sodium nitrite (Sod nit, as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p., followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.. Treatment with Sod nit significantly decreased hemoglobin (Hb levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70 and markers of cardiac injury, including troponin T (Trop. T, creatine kinase-MB (CK-MB, tumor necrosis factor-α (TNF α, and C-reactive protein (CRP in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF, the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. In Conclusion: The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.

  13. Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer

    International Nuclear Information System (INIS)

    Singh, Bhupendra; Chatterjee, Anwesha; Ronghe, Amruta M; Bhat, Nimee K; Bhat, Hari K

    2013-01-01

    Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis. Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2. The expression of OGG1 was suppressed in mammary tissues and in mammary tumors of rats treated with E2. Expression of NRF2 was also significantly suppressed in E2-treated mammary tissues and in mammary tumors. Vitamin C or BHA treatment prevented E2-mediated decrease in OGG1 and NRF2 levels in the mammary tissues. Chromatin immunoprecipitation analysis confirmed that antioxidant-mediated induction of OGG1 was through increased direct binding of NRF2 to the promoter region of OGG1. Studies using silencer RNA confirmed the role of OGG1 in inhibition of oxidative DNA damage. Our studies suggest that antioxidants Vit C and BHA provide protection against oxidative DNA damage and E2-induced mammary carcinogenesis, at least in part, through NRF2-mediated induction of OGG1

  14. The evolutionary scenario of hepatocellular carcinoma in Italy: an update.

    Science.gov (United States)

    Bucci, Laura; Garuti, Francesca; Lenzi, Barbara; Pecorelli, Anna; Farinati, Fabio; Giannini, Edoardo G; Granito, Alessandro; Ciccarese, Francesca; Rapaccini, Gian Lodovico; Di Marco, Maria; Caturelli, Eugenio; Zoli, Marco; Borzio, Franco; Sacco, Rodolfo; Cammà, Calogero; Virdone, Roberto; Marra, Fabio; Felder, Martina; Morisco, Filomena; Benvegnù, Luisa; Gasbarrini, Antonio; Svegliati-Baroni, Gianluca; Foschi, Francesco Giuseppe; Missale, Gabriele; Masotto, Alberto; Nardone, Gerardo; Colecchia, Antonio; Bernardi, Mauro; Trevisani, Franco

    2017-02-01

    Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of aetiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centres from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). The main results were as follows: (i) progressive patient aging; (ii) progressive expansion of non-viral cases and, namely, of "metabolic" hepatocellular carcinomas; (iii) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semi-annual) surveillance programme; (iv) favourable cancer stage migration; (v) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early- or intermediate-stage hepatocellular carcinoma. During the last 15 years several aetiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was owing both to the wider use of semi-annual surveillance, expanding the proportion of tumours that qualified for curative treatments, and to the improved outcome of loco-regional treatments. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. FoxM1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by targeting Snai1

    OpenAIRE

    Yu, Chun-Peng; Yu, Shui; Shi, Lei; Wang, Song; Li, Zi-Xiang; Wang, Yan-Hua; Sun, Cheng-Jian; Liang, Jun

    2017-01-01

    Forkhead box protein M1 (FoxM1) is aberrantly expressed in several types of human malignancy, and serves an important role in tumor metastasis. Epithelial-mesenchymal transition (EMT) of cancer cells has been associated cancer metastasis; however, the implication of FoxM1 in EMT and its putative roles in the regulation of cancer metastasis remain to be elucidated. In the present study, the expression of FoxM1, Snai1 and E-cadherin in hepatocellular carcinoma (HCC) cell lines with various meta...

  16. Evaluation of transcatheter therapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Yamada, Toshihiko

    1990-01-01

    The author proposed improvement of the criteria for the effects of transcatheter therapy for hepatocellular carcinoma. 104 patients were treated by transcatheter therapy. Their responses were determined by the usual criteria. Next, they were classified and evaluated in 3 groups, with the area of lipiodol deposition on CT for over 4 weeks regarded as nacrosis. The result was determined, and its relationship to prognosis was studied in light of the repeated therapy. By the usual criteria, only 10% of patients were judged as PR, and there were no differences between therapies. Many of the NC cases had low AFP levels with therapy. At the initial therapy, the ratio of cases with low AFP levels was higher and the survival time was longer in the A group. So the A group was judged as most effective. Clinically, 10 patients were considered most benefitted by therapy. They were considered the A group, but all were judged as NC. Considering the effects of repeated therapy, 10 patients with NC were judged as the A-max group. Prognosis was poor in patients of the B-max and C-max groups. These results indicate that judgement by the usual criteria was inconsistent with clinical condition. It was improved by regarding the area of lipiodol deposition on CT for over 4 weeks as necrosis. Estimations of effects and prognosis were made more accurate by considering repeated therapy. Thus, the proposed improvement of the criteria by CT is more useful to estimate transcatheter therapy of the hepatocellular carcinoma. (author)

  17. Radiological imagings of small hepatocellular carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Miyake, Hidetoshi; Hayashi, Kuniaki; Futagawa, Sakae; Matsunaga, Naofumi; Maeda, Tohru [Nagasaki Univ. (Japan). School of Medicine

    1984-08-01

    Forty three cases of small hepatocellular carcinoma (measuring less than 3 cm in diameter on imaging modalities) were detected during a period of four years and two months. There were two cases in which hepatoma measured 1 cm in diameter, twenty four cases between 1 and 2 cm, and seventeen cases between 2 and 3 cm. The relative role of each modality and AFP value in the detection of these tumors was evaluated. The detection rate of small hepatocellular carcinoma by liver scintigraphy, ultrasonography (US), computed tomography (CT) and angiography was 8%, 74%, 70% and 95%, respectively. The sensitivity of serum AFP value was 67% (either measuring more than 200ng/ml or showing a tendency of steady rising even if below the level of 200ng/ml). Most hepatomas less than 2 cm in size were hypoechoic on US, and those above 2 cm in size were hyperechoic with peripheral sonolucency (halo). Almost all cases were described as low density area on both plain and enhancement CT. Angiography was the best method for detecting small hepatomas. It may be recommended to perform angiography on every patient with liver cirrhosis at the time of diagnosis of this disease. Periodic examinations by AFP, US and CT should be done if the angiography was negative. Evaluation by US in every three months and by CT in every twelve months may be appropriate.

  18. Skeletal metastases from primary hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kim, So Sun; Huh, Jin Do; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duk; Chang, Hee Kyung; Huh, Man Ha

    1988-01-01

    In order to detect and to evaluate the frequency, the distribution, and the radiological findings of skeletal metastases from hepatocellular carcinoma, the authors retrospectively analyzed radiographic, scintigraphic, and CT findings of 257 patients with hepatocellular carcinoma. The results were as follows: 1. Skeletal metastases were demonstrated in 21 patients (8.2%). 2. Frequent symptoms were pain, limitation of motion, paralysis, and mass. In nine of them the initial symptoms were due to skeletal metastases. 3. The common sites of metastases were spine (13 cases), ribs (8 cases), pelvis (8 cases) and femur (6 cases). Humerus, skull and sternum were also frequently involved. 4. Plain film findings were purely osteolytic in all cases and pathologic fractures were noted in 5 cases. 5. The lesions appear expansible in 7 cases, and 4 of them showed associated soft tissue masses on CT scans. 6. Bone scans were performed in 13 cases of them and showed increased radiotracer uptake in all. 7. Angiographic studies of 3 cases showed hypervascularity of the metastatic lesions as well as the primary hepatic tumor.

  19. Imaging findings of mimickers of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Tae Kyoung Kim

    2015-12-01

    Full Text Available Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis.

  20. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Rui; Zhang, Haiyang; Zhang, Yan; Li, Shuang; Wang, Xinyi; Wang, Xia; Wang, Cheng; Liu, Bin; Zen, Ke; Zhang, Chen-Yu; Zhang, Chunni; Ba, Yi

    2017-04-01

    Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor

  1. Metastatic hepatocellular carcinoma on the mandible: a case report

    International Nuclear Information System (INIS)

    Kim, Jin Soo; Kim, Jae Duk

    2005-01-01

    Hepatocellular carcinoma is one of the most common cancer worldwide, primarily affecting those in regions with a high prevalence of viral hepatitis. However, the metastasis of hepatocellular carcinoma to the oral cavity is a rare phenomenon. This report presents a case of metastatic hepatocellular carcinoma in the left mandibular angle and ramus region of a 62-year-old man. Panoramic radiograph revealed an ill-defined radiolucent lesion extending from the retained root of the mandibular left second molar into the ascending ramus. The lesion had irregular and ill-defined margins.

  2. Radiation damage

    CERN Document Server

    Heijne, Erik H M; CERN. Geneva

    1998-01-01

    a) Radiation damage in organic materials. This series of lectures will give an overview of radiation effects on materials and components frequently used in accelerator engineering and experiments. Basic degradation phenomena will be presented for organic materials with comprehensive damage threshold doses for commonly used rubbers, thermoplastics, thermosets and composite materials. Some indications will be given for glass, scintillators and optical fibres. b) Radiation effects in semiconductor materials and devices. The major part of the time will be devoted to treat radiation effects in semiconductor sensors and the associated electronics, in particular displacement damage, interface and single event phenomena. Evaluation methods and practical aspects will be shown. Strategies will be developed for the survival of the materials under the expected environmental conditions of the LHC machine and detectors. I will describe profound revolution in our understanding of black holes and their relation to quantum me...

  3. Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Chen Chang-Jie

    2010-10-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored. Methods Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR and protein (Western blot levels. The phosphorylation status of cyclin-dependent kinases (CDKs and retinoblastoma (Rb protein was also examined using Western blot analysis. Results Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G1 and G2/M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1, pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27. Conclusion Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC.

  4. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features

    OpenAIRE

    Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

    2013-01-01

    Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independen...

  5. Conditions for a safe boiler operation. Contempt of guilty regulations creates high damage potential; Bedingungen fuer sicheren Kesselbetrieb. Missachtung geltender Vorschriften birgt hohes Schadenpotenzial

    Energy Technology Data Exchange (ETDEWEB)

    Selbach, H.J. [Froeling Heiz- und Trinkwassersysteme GmbH, Overath (Germany)

    2004-07-01

    Operational disturbances and damages should not occure in boilers. However sometimes it happens that even high grade components have an outage after a short service time. The causes, shown in this article, are to be searched within the planning- or installation phase as feedwater quality and erosive combustion air. (GL) [German] Eine Kesselanlage ist ein Wirtschaftsgut. Betriebsstoerungen oder Schaeden duerfen moeglichst nicht vorkommen. Trotzdem passiert es, dass selbst hochwertige Anlagen schon nach kurzer Betriebszeit ausfallen. Die Ursachen hierfuer sind oft in der Planung oder Installation sowie der Qualitaet von Fuellwasser und Verbrennungsluft begruendet. (orig.)

  6. Post-Translational Regulation of Polycystin-2 Protein Expression as a Novel Mechanism of Cholangiocyte Reaction and Repair from Biliary Damage

    Science.gov (United States)

    Spirli, Carlo; Villani, Ambra; Mariotti, Valeria; Fabris, Luca; Fiorotto, Romina; Strazzabosco, Mario

    2015-01-01

    Polycystin-2 (PC2 /TRPP2), a member of the transient receptor potential channels (TRP) family, is a non-selective calcium channel. Mutations in PC2/TRPP2 are associated with Polycystic Liver Diseases. PC2-defective cholangiocytes shows increased production of cAMP, PKA-dependent activation of the ERK1/2 pathway, HIF1α-mediated VEGF production, and stimulation of cyst growth and progression. Activation of the ERK/HIF1α/VEGF pathway in cholangiocytes plays a key role during repair from biliary damage. We hypothesized that PC2 levels are modulated during biliary damage/repair, resulting in activation of the ERK/HIF1α/VEGF pathway. Results PC2 protein expression, but not its gene expression, was significantly reduced in mouse livers with biliary damage (Mdr2−/−-KO, bile duct ligation, DDC-treatment). Treatment of colangiocytes with pro-inflammatory cytokines, nitric oxide (NO) donors and ER stressors), increased ERK1/2 phosphorylation, HIF1α transcriptional activity, secretion of VEGF, VEGFR2 phosphorylation and downregulated PC2 protein expression without affecting PC2 gene expression. Expression of Herp and NEK, ubiquitin-like proteins that promote proteosomal PC2 degradation was increased. Pre-treatment with the proteasome inhibitor MG-132 restored the expression of PC2 in cells treated with cytokines but not in cells treated with NO donors or with ER stressors. In these conditions, PC2 degradation was instead inhibited by interfering with the autophagy pathway. Treatment of DDC-mice and of Mdr2−/−-mice with the proteasome inhibitor bortezomib, restored PC2 expression and significantly reduced the ductular reaction, fibrosis and p-ERK1/2. In conclusion, in response to biliary damage, PC2 expression is modulated post-translationally by the proteasome or the autophagy pathways. PC2-dowregulation is associated with activation of ERK1/2 and increase of HIF1α-mediated VEGF secretion. Treatments able to restore PC2 expression and to reduce ductular reaction

  7. Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

    International Nuclear Information System (INIS)

    Wu Xiaofeng; Fan Jia; Wang Xiaoying; Zhou Jian; Qiu Shuangjian; Yu Yao; Liu Yinkun; Tang Zhaoyou

    2007-01-01

    CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment

  8. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Yu-Chi Su

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients.

  9. Immunization With AFP + GM CSF Plasmid Prime and AFP Adenoviral Vector Boost in Patients With Hepatocellular Carcinoma

    Science.gov (United States)

    2015-12-01

    Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult; Cancer of Liver; Cancer of the Liver; Cancer, Hepatocellular; Hepatic Cancer; Hepatic Neoplasms; Hepatocellular Cancer; Liver Cancer; Neoplasms, Hepatic; Neoplasms, Liver

  10. Is gut the "motor" for producing hepatocellular dysfunction after trauma and hemorrhagic shock?

    Science.gov (United States)

    Wang, P; Ba, Z F; Cioffi, W G; Bland, K I; Chaudry, I H

    1998-02-01

    Although studies suggest that the gut may be the "motor" responsible for producing sepsis and multiple organ failure after injury, it is not known whether enterectomy prior to the onset of hemorrhage alters proinflammatory cytokines TNF and IL-6 and, if so, whether hepatocellular dysfunction and damage are prevented or attenuated under such conditions. Under methoxyflurane anesthesia, an enterectomy in the rat was performed by excision of the duodenum, jejunum, and ileum. The rats were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of shed blood with Ringer's lactate over 1 h. At 1.5 h after the completion of resuscitation, hepatocellular function [i.e., the maximal velocity (Vmax) and transport efficiency (Km) of indocyanine green (ICG) clearance] was assessed by an in vivo ICG clearance technique. Blood samples were taken for the measurement of TNF, IL-6, and liver enzymes (i.e., SGPT and SGOT). Cardiac output and microvascular blood flow were determined by ICG dilution and laser Doppler flowmetry, respectively. The increase in circulating levels of TNF but not IL-6 was prevented by enterectomy prior to hemorrhage. The reduced Vmax and K(m) and elevated SGPT and SGOT following hemorrhage and resuscitation, however, were not significantly affected by prior enterectomy. Moreover, enterectomy before hemorrhage further reduced hepatic perfusion. Since enterectomy prior to the onset of hemorrhage does not prevent or attenuate the reduced ICG clearance and elevated liver enzymes despite downregulation of TNF production, it appears that the small intestine does not play a significant role in producing hepatocellular dysfunction and injury following trauma and hemorrhagic shock.

  11. Administration of progesterone after trauma and hemorrhagic shock prevents hepatocellular injury.

    Science.gov (United States)

    Kuebler, Joachim F; Yokoyama, Yukihiro; Jarrar, Doraid; Toth, Balazs; Rue, Loring W; Bland, Kirby I; Wang, Ping; Chaudry, Irshad H

    2003-07-01

    Administration of a single dose of progesterone following trauma and hemorrhage in progesterone-deficient rats would ameliorate the inflammatory response and hepatocellular damage. A university laboratory. Ovariectomized female Sprague-Dawley rats (250-350 g; Charles River Laboratories, Wilmington, Mass) underwent a 5-cm midline laparotomy (ie, induction of soft tissue trauma), were bled to a mean arterial blood pressure of 35 mm Hg for about 90 minutes, and then were resuscitated using Ringer lactate solution. Progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously at the end of resuscitation. In additional animals, Kupffer cells were isolated following trauma, hemorrhage, and resuscitation and treated in vitro with progesterone, lipopolysaccharide, or both. Six hours following resuscitation, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) levels and liver myeloperoxidase activity were determined. Hepatocellular function (maximum velocity of indocyanine green clearance [Vmax] and the efficiency of the active transport or Michaelis-Menten constant [Km]) and plasma levels of transaminases were measured 20 hours after resuscitation. Kupffer cell IL-6 and TNF-alpha production were assessed. Plasma levels of TNF-alpha, IL-6, aspartate aminotransferase, and alanine aminotransferase, as well as hepatic myeloperoxidase activity were increased, whereas indocyanine green clearance was depressed in vehicle-treated rats following trauma-hemorrhage. Animals treated with progesterone showed significantly reduced levels of the TNF-alpha, IL-6, and transaminases as well as reduced myeloperoxidase activity in the liver. Progesterone-treated animals showed increased Vmax and Kmax values for indocyanine green. In vitro treatment of Kupffer cells with progesterone decreased TNF-alpha production but did not affect the production of IL-6. Progesterone administration following trauma-hemorrhage ameliorates the proinflammatory response

  12. Copper exposure induces toxicity to the antioxidant system via the destruction of Nrf2/ARE signaling and caspase-3-regulated DNA damage in fish muscle: Amelioration by myo-inositol

    International Nuclear Information System (INIS)

    Jiang, Wei-Dan; Liu, Yang; Jiang, Jun; Wu, Pei; Feng, Lin; Zhou, Xiao-Qiu

    2015-01-01

    time that Cu exposure caused oxidative damage to the muscle by decreasing the antioxidant enzyme activities via the down-regulation of the expression of genes related to the disruption of the Nrf2/ARE signaling, and this down-regulation was partially caused by caspase-3-regulated DNA fragmentation. Finally, MI protects fish against Cu toxicity

  13. Copper exposure induces toxicity to the antioxidant system via the destruction of Nrf2/ARE signaling and caspase-3-regulated DNA damage in fish muscle: Amelioration by myo-inositol

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Wei-Dan; Liu, Yang [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Jiang, Jun [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Wu, Pei [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Feng, Lin, E-mail: fenglin@sicau.edu.cn [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Zhou, Xiao-Qiu, E-mail: zhouxq@sicau.edu.cn [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China)

    2015-02-15

    time that Cu exposure caused oxidative damage to the muscle by decreasing the antioxidant enzyme activities via the down-regulation of the expression of genes related to the disruption of the Nrf2/ARE signaling, and this down-regulation was partially caused by caspase-3-regulated DNA fragmentation. Finally, MI protects fish against Cu toxicity.

  14. Tort Damages

    NARCIS (Netherlands)

    L.T. Visscher (Louis)

    2008-01-01

    textabstractAbstract: In this Chapter, I provide an overview of Law and Economics literature regarding tort damages. Where necessary, attention is also spent to rules of tort liability. Both types of rules provide behavioral incentives to both injurers and victims, with respect to their level of

  15. Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-{kappa}{beta} and myosin light-chain kinase pathways

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying [Department of Anesthesia, Critical Care Medicine and Emergency Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, People' s Republic of China (China); Li, Jianguo, E-mail: 2010lijianguo@sina.cn [Department of Anesthesia, Critical Care Medicine and Emergency Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, People' s Republic of China (China)

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer Carbachol reduced the lipopolysaccharide-induced intestinal barrier breakdown. Black-Right-Pointing-Pointer Carbachol ameliorated the lipopolysaccharide-induced ileal tight junction damage. Black-Right-Pointing-Pointer Carbachol prevented the LPS-induced NF-{kappa}{beta} and myosin light-chain kinase activation. Black-Right-Pointing-Pointer Carbachol exerted its beneficial effects in an {alpha}7 nicotinic receptor-dependent manner. -- Abstract: Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-{kappa}{beta}) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the {alpha}7 nicotinic acetylcholine receptor ({alpha}7nAchR) antagonist {alpha}-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-{kappa}{beta} and MLCK pathways in an {alpha}7nAchR-dependent manner.

  16. Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice

    Directory of Open Access Journals (Sweden)

    Po-Yuan Wu

    2017-10-01

    Full Text Available Chronic ultraviolet (UV exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin’s antiphotodamage and antiphotoinflammation activities.

  17. Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice.

    Science.gov (United States)

    Wu, Po-Yuan; Lyu, Jia-Ling; Liu, Yi-Jung; Chien, Ting-Yi; Hsu, Hao-Cheng; Wen, Kuo-Ching; Chiang, Hsiu-Mei

    2017-10-10

    Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs) activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values) and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin's antiphotodamage and antiphotoinflammation activities.

  18. Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

    Directory of Open Access Journals (Sweden)

    Raúl Enrique Cuevas-Durán

    2017-11-01

    Full Text Available Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co and Rosmarinus officinalis (Ro extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a sham; (b vehicle-treated myocardial infarction (MI (MI-V; (c Ro extract-treated myocardial infarction (MI-Ro; (d Co extract-treated myocardial infarction (MI-Co; or (e Ro+Co-treated myocardial infarction (MI-Ro+Co. Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1, increased vasodilators agents (angiotensin 1–7 and bradikinin and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators.

  19. PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Wang, Jiajun; Shao, Miaomiao; Liu, Min; Peng, Peike; Li, Lili; Wu, Weicheng; Wang, Lan; Duan, Fangfang; Zhang, Mingming; Song, Shushu; Jia, Dongwei; Ruan, Yuanyuan; Gu, Jianxin

    2015-01-01

    Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα, but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment. - Highlights: • PKCα promotes the generation of ROS in hepatocellular carcinoma. • PKCα induces ROS production by up-regulating DUOX2 at post-transcriptional level. • DUOX2 is required for PKCα-induced AKT/MAPK activation and tumor progression in HCC. • The expression of PKCα is positively correlated with DUOX2 in HCC

  20. Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.

    Science.gov (United States)

    Shi, Sally Yu; Luk, Cynthia T; Schroer, Stephanie A; Kim, Min Jeong; Dodington, David W; Sivasubramaniyam, Tharini; Lin, Lauren; Cai, Erica P; Lu, Shun-Yan; Wagner, Kay-Uwe; Bazinet, Richard P; Woo, Minna

    2017-03-03

    Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis per se promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline-deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiajun; Shao, Miaomiao; Liu, Min; Peng, Peike; Li, Lili; Wu, Weicheng; Wang, Lan [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai (China); Duan, Fangfang [Institute of Biomedical Science, Fudan University, Shanghai (China); Zhang, Mingming; Song, Shushu [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai (China); Ruan, Yuanyuan, E-mail: yuanyuanruan@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai (China); Institute of Biomedical Science, Fudan University, Shanghai (China)

    2015-08-07

    Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα, but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment. - Highlights: • PKCα promotes the generation of ROS in hepatocellular carcinoma. • PKCα induces ROS production by up-regulating DUOX2 at post-transcriptional level. • DUOX2 is required for PKCα-induced AKT/MAPK activation and tumor progression in HCC. • The expression of PKCα is positively correlated with DUOX2 in HCC.

  2. PGK1 Drives Hepatocellular Carcinoma Metastasis by Enhancing Metabolic Process.

    Science.gov (United States)

    Xie, Huijun; Tong, Guihui; Zhang, Yupei; Liang, Shu; Tang, Kairui; Yang, Qinhe

    2017-07-27

    During the proliferation and metastasis, the tumor cells prefer glycolysis (Warburg effect), but its exact mechanism remains largely unknown. In this study, we demonstrated that phosphoglycerate kinase 1 (PGK1) is an important enzyme in the pathway of metabolic glycolysis. We observed a significant overexpression of PGK1 in hepatocellular carcinoma tissues, and a correlation between PGK1 expression and poor survival of hepatocellular carcinoma patients. Also, the depletion of PGK1 dramatically reduced cancer cell proliferation and metastasis, indicating an oncogenic role of PGK1 in liver cancer progression. Further experiments showed that PGK1 played an important role in MYC -induced metabolic reprogramming, which led to an enhanced Warburg effect. Our results revealed a new effect of PGK1, which can provide a new treatment strategy for hepatocellular carcinoma, as PGK1 is used to indicate the prognosis of hepatocellular carcinoma (HCC).

  3. Spontaneous rupture of adrenal metastasis from hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Chae Hun; Kim, Hyun Jin; Park, Soo Youn; Hwang, Seong Su; Choi, Hyun Joo [St. Vincent Hospital, Suwon (Korea, Republic of)

    2007-03-15

    Rupture of adrenal tumor from various primary origins is a rather rare event. We report here on a ruptured adrenal metastasis from hepatocellular carcinoma, and this ruptured metastasis was observed at the time of the initial diagnosis.

  4. Imaging and embolization of hepatocellular carcinoma supplied by gonadal artery

    International Nuclear Information System (INIS)

    Wu Hongping; Wang Junjie; Lu Yang; You Kaizhi

    2010-01-01

    Objective: To evaluate radiology and embolization for hepatocellular carcinoma supplied by gonadal artery. Methods: The medical records of 3 patients with hepatocellular carcinoma supplied by gonadal artery from August 2002 to September 2008 were reviewed. The demography, gonadal artery location, modus operandi, imaging features of liver cancer and prognosis were retrospectively analyzed. Results: Anatomic variation of gonadal artery occurred with the gonadal artery arising from the upper abdominal aorta in 1 patient and from the middle suprarenal artery in 2 patients. The blood supply of the hepatocellular carcinoma derived from the gonadal artery in all 3 patients. No complications occurred in the 6-month follow-up after embolization. Conclusion: Hepatocellular carcinoma may be supplied by gonadal artery with anomalous origin. This anatomic variant can be readily demonstrated by imaging to guide embolization. (authors)

  5. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integratio...

  6. Vitamin C and protection of DNA, proteins and lipids from oxidative damage: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006

    DEFF Research Database (Denmark)

    Sjödin, Anders Mikael

    2017-01-01

    Following an application from Specialised Nutrition Europe (formerly IDACE), submitted for authorisation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of France, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked...

  7. Vitamin E and protection of DNA, proteins and lipids from oxidative damage: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006

    DEFF Research Database (Denmark)

    Sjödin, Anders Mikael

    2016-01-01

    Following an application from Specialised Nutrition Europe (formerly IDACE), submitted for authorisation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of France, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked...

  8. Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1

    DEFF Research Database (Denmark)

    Yang, Jenq-Lin; Tadokoro, Takashi; Keijzers, Guido

    2010-01-01

    inhibitor (KN-93) blocked the ability of glutamate to induce CREB phosphorylation and APE1 expression. Selective depletion of CREB using RNA interference prevented glutamate-induced up-regulation of APE1. Thus, glutamate receptor stimulation triggers Ca(2+)- and mitochondrial reactive oxygen species...

  9. The role of micro-RNAs in hepatocellular carcinoma: from molecular biology to treatment.

    Science.gov (United States)

    D'Anzeo, Marco; Faloppi, Luca; Scartozzi, Mario; Giampieri, Riccardo; Bianconi, Maristella; Del Prete, Michela; Silvestris, Nicola; Cascinu, Stefano

    2014-05-19

    Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC.

  10. Diagnosis of small hepatocellular carcinoma by incremental dynamic CT

    International Nuclear Information System (INIS)

    Uchida, Masafumi; Kumabe, Tsutomu; Edamitsu, Osamu

    1993-01-01

    Thirty cases of pathologically confirmed small hepatocellular carcinoma were examined by Incremental Dynamic CT (ICT). ICT scanned the whole liver with single-breath-hold technique; therefore, effective early contrast enhancement could be obtained for diagnosis. Among the 30 tumors, 26 were detected. The detection rate was 87%. A high detection rate was obtained in tumors more than 20 mm in diameter. Twenty-two of 26 tumors could be diagnosed correctly. ICT examination was useful for detection of small hepatocellular carcinoma. (author)

  11. Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

    OpenAIRE

    Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. La...

  12. Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Lildballe, Dorte Launholt; Nguyen, Khoa Tran; Poulsen, Steen Seier

    2011-01-01

    No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker.......No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker....

  13. Hepatocellular Carcinoma: An Unusual Complication of Longstanding Wilson Disease.

    Science.gov (United States)

    Gunjan, Deepak; Shalimar; Nadda, Neeti; Kedia, Saurabh; Nayak, Baibaswata; Paul, Shashi B; Gamanagatti, Shivanand Ramachandra; Acharya, Subrat K

    2017-06-01

    Wilson disease is caused by the accumulation of copper in the liver, brain or other organs, due to the mutation in ATP7B gene, which encodes protein that helps in excretion of copper in the bile canaliculus. Clinical presentation varies from asymptomatic elevation of transaminases to cirrhosis with decompensation. Hepatocellular carcinoma is a known complication of cirrhosis, but a rare occurrence in Wilson disease. We present a case of neurological Wilson disease, who later developed decompensated cirrhosis and hepatocellular carcinoma.

  14. The Relationship Between Intestinal Iron Absorption and Hepatic Parenchymal Cell Damage

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mok Hyun; Hahn, Shin Suck [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1971-09-15

    Since the iron balance is maintained by regulated intestinal absorption rather than regulated excretion, there have been many reports concerning the factors which may influence the intestinal iron absorption. As the liver is the largest iron storage organ of the body, any hepatocellular damage may result in disturbances in iron metabolism, e,g., frequent co-existence of haemochromatosis and liver cirrhosis, or elevated serum iron level and increased iron absorption rate in patients with infectious hepatitis or cirrhosis. In one effort to demonstrate the influence of hepatocellular damage on intestinal iron absorption, the iron absorption rate was measured in the rabbits whose livers were injured by a single subcutaneous injection of carbon tetrachloride (doses ranging from 0.15 to 0.5 cc per kg of body weight) or by a single irradiation of 2, 000 to 16, 000 rads with Co on the liver locally. A single oral dose of 1muCi of Fe-citrate with 0.5 mg of ferrous citrate was fed in the fasting state, 24 hours after hepatic damage had been induced, without any reducing or chelating agents, and stool was collected for one week thereafter. Serum iron levels, together with conventional liver function teats, were measured at 24, 48, 72, 120 and 168 hours after liver damage had been induced. All animals were sacrificed upon the completing of the one week's test period and tissue specimens were prepared for H-E and Gomori's iron stain. Following are the results. 1. Normal iron absorption rate of the rabbit was 41.72+-3.61% when 0.5 mg of iron was given in the fasting state, as measured by subtracting the amount recovered in stool collected for 7 days from the amount given. The test period of 7 days is adequate, for only 1% of the iron given was excreted thereafter. 2. The intestinal iron absorption rate and serum iron level were significantly increased when the animal was poisoned by a single subcutaneous injection of 0.15 cc, per kg. of body weight of carbon tetrachloride or

  15. The Relationship Between Intestinal Iron Absorption and Hepatic Parenchymal Cell Damage

    International Nuclear Information System (INIS)

    Kim, Mok Hyun; Hahn, Shin Suck

    1971-01-01

    Since the iron balance is maintained by regulated intestinal absorption rather than regulated excretion, there have been many reports concerning the factors which may influence the intestinal iron absorption. As the liver is the largest iron storage organ of the body, any hepatocellular damage may result in disturbances in iron metabolism, e,g., frequent co-existence of haemochromatosis and liver cirrhosis, or elevated serum iron level and increased iron absorption rate in patients with infectious hepatitis or cirrhosis. In one effort to demonstrate the influence of hepatocellular damage on intestinal iron absorption, the iron absorption rate was measured in the rabbits whose livers were injured by a single subcutaneous injection of carbon tetrachloride (doses ranging from 0.15 to 0.5 cc per kg of body weight) or by a single irradiation of 2, 000 to 16, 000 rads with Co on the liver locally. A single oral dose of 1μCi of Fe-citrate with 0.5 mg of ferrous citrate was fed in the fasting state, 24 hours after hepatic damage had been induced, without any reducing or chelating agents, and stool was collected for one week thereafter. Serum iron levels, together with conventional liver function teats, were measured at 24, 48, 72, 120 and 168 hours after liver damage had been induced. All animals were sacrificed upon the completing of the one week's test period and tissue specimens were prepared for H-E and Gomori's iron stain. Following are the results. 1. Normal iron absorption rate of the rabbit was 41.72±3.61% when 0.5 mg of iron was given in the fasting state, as measured by subtracting the amount recovered in stool collected for 7 days from the amount given. The test period of 7 days is adequate, for only 1% of the iron given was excreted thereafter. 2. The intestinal iron absorption rate and serum iron level were significantly increased when the animal was poisoned by a single subcutaneous injection of 0.15 cc, per kg. of body weight of carbon tetrachloride or

  16. Effect of smoking on survival of patients with hepatocellular carcinoma.

    Science.gov (United States)

    Kolly, Philippe; Knöpfli, Marina; Dufour, Jean-François

    2017-11-01

    Lifestyle factors such as smoking, obesity and physical activity have gained interest in the field of hepatocellular carcinoma. These factors play a significant role in the development of hepatocellular carcinoma. Several studies revealed the impact of tobacco consumption on the development of hepatocellular carcinoma and its synergistic effects with viral etiologies (hepatitis B and C). The effects of smoking on survival in patients with a diagnosed hepatocellular carcinoma have not yet been investigated in a Western cohort where hepatitis C infection is a major risk factor. Using data from a prospective cohort of patients with hepatocellular carcinoma who were followed at the University Hospital of Bern, Switzerland, survival was compared by Kaplan-Meier analysis in smokers and nonsmokers, and multivariate Cox regression was applied to control for confounding variables. Of 238 eligible hepatocellular carcinoma patients, 64 were smokers at the time of inclusion and 174 were nonsmokers. Smokers had a significant worse overall survival than nonsmokers (hazard ratio 1.77, 95% confidence interval: 1.22-2.58, P=.003). Analysis of patients according to their underlying liver disease, revealed that smoking, and not nonsmoking, affected survival of hepatitis B virus and C virus-infected patients only. In this subgroup, smoking was an independent predictor for survival (hazard ratio 2.99, 95% confidence interval: 1.7-5.23, Phepatocellular carcinoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma.

    Science.gov (United States)

    Burra, Patrizia; Zanetto, Alberto; Germani, Giacomo

    2018-02-09

    Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.

  18. BIOCHEMICAL NUTRITIONAL PROFILE OF LIVER CIRRHOSIS PATIENTS WITH HEPATOCELLULAR CARCINOMA

    Directory of Open Access Journals (Sweden)

    Gabriela Zanatta PORT

    2014-03-01

    Full Text Available Context Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. Objective The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. Methods Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. Results The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides, protein (albumin, creatinine and uric acid, iron (transferrin, iron and ferritin saturation, hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. Conclusions Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner.

  19. Montelukast induced acute hepatocellular liver injury

    Directory of Open Access Journals (Sweden)

    Harugeri A

    2009-01-01

    Full Text Available A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM and Naranjo′s algorithm was ′probable′. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.

  20. Evaluation of CT in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nakao, Norio; Miura, Yukio; Ohnishi, Mitsunori; Kamikon-ya, Norihiko; Sakamoto, Yoshisato; Miura, Takashi; Sakamoto, Kiyoshi; Takayasu, Yoshio

    1985-06-01

    In order to evaluate the diagnostic ability of CT in hepatocellular carcinoma, four kinds of CT images were comparatively studied by the accuracy and ROC (receiver operating characteristic) curve analysis. As a result, it was clarified that CT images were evaluated more objectively by ROC curve analysis than by accuracy. The diagnostic ability of existence and differentiation of tumor in the liver were higher in order of plain CT, contrast enhanced CT (CECT), bolus CT and CT arteriography (CTA). Therefore, in an usual CT examination intended to make differential diagnosis in space occupying liver disease, bolus CT seems to be indispensable, and also CTA is essential where diagnosis is difficult even by bolus CT.

  1. Models of Hepatocellular Carcinoma and Biomarker Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Bagi, Cedo M., E-mail: cedo.bagi@pfizer.com; Andresen, Catharine J. [Global Science & Technology, PGRD, Pfizer Inc, Groton, CT 06340 (United States)

    2010-07-07

    The overwhelming need to improve preclinical models in oncology has stimulated research efforts to refine and validate robust orthotopic models that closely mimic the disease population and therefore have the potential to better predict clinical outcome with novel therapies. Sophisticated technologies including bioluminescence, contrast enhanced ultrasound imaging, positron emission tomography, computed tomography and magnetic resonance imaging have been added to existing serum- and histology-based biomarkers to assist with patient selection and the design of clinical trials. The rationale for the use of human hepatocellular carcinoma (HCC) cell lines, implementation of xenograft and orthotopic animal models and utilization of available biomarkers have been discussed, providing guidelines to facilitate preclinical research for the development of treatments for HCC patients.

  2. Embolotherapy in the management of hepatocellular carcinoma.

    Science.gov (United States)

    Mojtahedi, Alireza; Yang, Xiaoming; Goswami, Gaurav K

    2008-09-01

    Hepatocellular carcinoma (HCC) ranks fifth in frequency of cancers worldwide. The incidence of HCC in the United States is rising, primarily due to the number of patients who were infected by hepatitis in the 1960s and 1970s coupled with the rising migrant population from Asia, where hepatitis is widely prevalent. Up to 80% of the patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the option of resection or liver transplantation. The dual blood supply (arterial and portal) to the liver with predominantly arterial supply to the tumor has made embolotherapy a cornerstone in the management of inoperable HCC. The techniques have become refined not only due to the development of microcatheter angiographic capabilities, but also in the ability to deliver a wide variety of therapeutic agents to these tumors. This article reviews the fundamental principles of bland embolization, chemoembolization, and radioembolization in the management of HCC.

  3. Hepatocellular carcinoma detected by iodized oil

    International Nuclear Information System (INIS)

    Yumoto, Y.; Jinno, K.; Tokuyama, K.

    1985-01-01

    This study assesses the diagnostic value of Lipiodol (iodized oil) and computed tomography (CT) in detecting hepatocellular carcinoma (HCC). Twenty-four patients who were suspected of having HCC received injections of a small amount of Lipiodol, along with an antitumor agent, in the hepatic artery following routine celiac angiography. CT scans obtained 7-10 days after Lipiodol administration demonstrated HCC in distinct contrast to the surrounding noncancerous parenchyma. In particular, the CT-Lipiodol procedure disclosed many small HCC lesions that were not shown by celiac angiography, scintigraphy, CT with an without contrast medium enhancement, and ultrasonography. Although this procedure may miss very small or highly fibrotic lesions, it is recommended for patients suspected of having HCC and for patients for whom hepatic resection is being considered

  4. Laparoscopic RFA with splenectomy for hepatocellular carcinoma.

    Science.gov (United States)

    Hu, Kunpeng; Lei, Purun; Yao, Zhicheng; Wang, Chenhu; Wang, Qingliang; Xu, Shilei; Xiong, Zhiyong; Huang, He; Xu, Ruiyun; Deng, Meihai; Liu, Bo

    2016-07-27

    The treatment of hepatocellular carcinoma (HCC) is complicated and challenging because of the frequent presence of cirrhosis. Therefore, we propose a novel surgical approach to minimize the invasiveness and risk in patients with HCC, hypersplenism, and esophagogastric varices. This was a retrospective study carried out in 25 patients with HCC and hypersplenism and who underwent simultaneous laparoscopic-guided radio-frequency ablation and laparoscopic splenectomy with endoscopic variceal ligation. Tumor size was restricted to a single nodule of splenectomy. Laparoscopic-guided radio-frequency ablation with laparoscopic splenectomy and endoscopic variceal ligation could be an available technique for patients with HCC <3 cm, hypersplenism, and esophagogastric varices. This approach may help to minimize the surgical risks and results in a fast increase in platelet counts with an acceptable rate of complications.

  5. Superselective transcather arterial embolization for hepatocellular carcinoma with a mixture of ethanol and lipiodol

    International Nuclear Information System (INIS)

    Park, Jae Hyung; Han, Joon Koon; Choi, Byung Ihn; Han, Man Chung

    1992-01-01

    To evaluate the effectiveness of superselective transcatheter arterial embolization (STAE) for hepatocellular carcinoma (HCC) with a mixture of ethanol and Lipiodol, STAE was done in 12 male patients with HCC. There were diagnosed clinically with angiographic findings and elevated alphafetprotein levels and three were recurrent tumors after surgery. Sono-guided aspiration biopsy proved the diagnosis of hepatocellular carcinoma in another six patients. The tumor was a small single nodule (2-5cm in diameter) in 11 patients. In one patient, two nodules were found. Superselective catheterization was done using 3F Tracker catheter (Target Therapeutics USA) coaxially through 6F catheter into the feeding hepatic artery, usually the third order branch. One to four cc of 75% ethanol mixed with Lipiodol was infused under fluoroscopy immediately after injection of 2% lidocaine. Immediate angiography and CT after 2 weeks were undertaken. Complete segmental or subsegmental devascularization including feeding arteries and tumor vascularities occurred in all patients. Follow-up angiography after 6 to 15 months revealed the tumor opacified by Lipiodol. The tumor decreased in 5 cases and recurrence was found in three patients. CT taken 2 weeks after STAE showed low density halo around the tumor in 5 cases. Subsequent segmentectomy in four patients revealed total or near total necrosis of the tumor and no evidence of damage in surrounding parenchyma. STAE for HCC with a mixture of ethanol and Lipiodol is an effective and safe measure for small HCC

  6. A potential human hepatocellular carcinoma inhibitor from Bauhinia purpurea L. seeds: from purification to mechanism exploration.

    Science.gov (United States)

    Fang, Evandro Fei; Bah, Clara Shui Fern; Wong, Jack Ho; Pan, Wen Liang; Chan, Yau Sang; Ye, Xiu Juan; Ng, Tzi Bun

    2012-02-01

    A 20-kDa Kunitz-type trypsin-chymotrypsin inhibitor, Bauhinia purpurea trypsin inhibitor (BPLTI), has been isolated from the seeds of B. purpurea L. by using liquid chromatography procedures that involved ion exchange chromatography on Sp-Sepharose and Mono S and gel filtration on Superdex 75. BPLTI demonstrated protease inhibitory activities of 7226 BAEE units/mg and 65 BTEE units/mg toward trypsin and α-chymotrypsin, respectively. BPLTI was relatively thermal (0-60°C) and pH (3-10) stable and its activity could be decreased by dithiothreitol treatment. BPLTI exhibited a wide spectrum of anti-proliferative and pro-apoptotic activities especially on human hepatocellular carcinoma Hep G2 cells. However, it was devoid of a significant antiproliferative effect on immortal human hepatic WRL 68 cells. We show here that BPLTI stimulates apoptosis in Hep G2 cells, including (1) evoking DNA damage including the production of chromatin condensation and apoptotic bodies; (2) induction of cell apoptosis/necrosis; (3) mitochondrial membrane depolarization; and (4) increasing the production of cytokines. Taken together, our findings show for the first time that purified protease inhibitor from B. purpurea L. seeds is a promising candidate for the treatment of human hepatocellular carcinoma.

  7. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Sangro, Bruno; Bilbao, Jose I.; Boan, Jose; Martinez-Cuesta, Antonio; Benito, Alberto; Rodriguez, Javier; Panizo, Angel; Gil, Belen; Inarrairaegui, Mercedes; Herrero, Ignacio; Quiroga, Jorge; Prieto, Jesus

    2006-01-01

    Purpose: To investigate the antitumor effect of resin microspheres loaded with 90-yttrium against hepatocellular carcinoma and their safety in the setting of liver cirrhosis. Patients and Methods: Data from 24 consecutive patients with hepatocellular carcinoma (HCC) treated by radioembolization in the period from September 2003 to February 2005 were reviewed. Patients received no further antineoplastic therapy. A comprehensive evaluation was performed to prevent the risk of damage due to microsphere misplacing. Patients were discharged the day after microspheres injection. Results: Serious liver toxicity observed among cirrhotic patients in a first period was subsequently prevented by modifying the selection criteria and the method for calculating the activity to be administered. Among 21 patients evaluable for response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, a reduction in size of target lesions was observed in all but 1 patient. When considering only target lesions, disease control rate and response rate were 100% and 23.8%, respectively. However, 43% of patients progressed in the liver in the form of new lesions appearing a median time of 3 months after radioembolization. Conclusion: Our experience in these series of patients indicates that radioembolization using resin microspheres has a significant antitumor effect against HCC and that using stringent selection criteria and conservative models for calculating Radiation activity to be administered, radioembolization can be performed safely even in cirrhotic patients

  8. Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: Preliminary Observations

    Directory of Open Access Journals (Sweden)

    Marie Amougou Atsama

    2017-11-01

    Full Text Available Objectives: To determine the seroprevalence of hepatitis E virus (HEV infection in patients with chronic hepatitis and/or hepatocellular carcinoma (HCC and to assess its potential consequences for disease progression. Methods: We conducted a prospective case-control study on patients with HCC hepatitis B or C related and non-HCC patients including patients with CLD and patients without clinical evidence of liver disease. Anti-HEV IgG and IgM were tested by ELISA using commercially available kits. Liver damage was assessed by alanine aminotransferase, aspartate aminotransferase, platelets and prothrombin measurements. Results: We observed a significant anti-HEV IgG carriage in HCC patients compared to non-HCC subjects with CLD (41.8% vs 12.6%; P = 9.1 E-6; OR = 4.8, 95%CI: 2.3-10.6. HCC patients with HEV infection display more profound alterations of circulating liver enzymes, platelets count and prothrombin time than HCC patients without sero-reactivity to HEV. Conclusion: Overall, this study indicates a high prevalence of HEV infection in Cameroonian patients with CLD and HCC. These data suggest either that patients with liver tumors are more susceptible to hepeviral infection or that, in a tropical context, HEV might promote the progression of liver diseases towards tumor. Keywords: Hepatocellular carcinoma, Hepatitis E, Seroprevalence, Anti-HEV IgG, Anti-HEV IgM

  9. Spinal cord injury after conducting transcatheter arterial chemoembolization for costal metastasis of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Sang Jung Park

    2012-09-01

    Full Text Available Transcatheter arterial chemoembolization (TACE has been used widely to treat patients with unresectable hepatocellular carcinoma. However, this method can induce various adverse events caused by necrosis of the tumor itself or damage to nontumor tissues. In particular, neurologic side effects such as cerebral infarction and paraplegia, although rare, may cause severe sequelae and permanent disability. Detailed information regarding the treatment process and prognosis associated with this procedure is not yet available. We experienced a case of paraplegia that occurred after conducting TACE through the intercostal artery to treat hepatocellular carcinoma that had metastasized to the rib. In this case, TACE was attempted to relieve severe bone pain, which had persisted even after palliative radiotherapy. A sudden impairment of sensory and motor functions after TACE developed in the trunk below the level of the sternum and in both lower extremities. The patient subsequently received steroid pulse therapy along with supportive care and continuous rehabilitation. At the time of discharge the patient had recovered sufficiently to enable him to walk by himself, although some paresthesia and spasticity remained.

  10. Computed tomographic findings of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Eun, Chung Kie [Kyung Hee University College of Medicine, Seoul (Korea, Republic of)

    1982-09-15

    It is well known that CT is very useful in the evaluation of hepatocellular carcinoma. The computed tomographic findings of 56 patients diagnosed as hepatocellular carcinoma were reviewed and analyzed. The results were as follows: 1. The male to female ratio was 3 : 1 and the age ranged from 31 to 73 years with average age of 54 years. 2. Alpha-fetoprotein was positive in 19 out of 38 cases (50%). HBsAg was positive in 8 out of 33 cases (24%). 3. All lesions were seen as areas of low density except 1 case (0%) of isodensity, and 40 cases (72%) appeared to be solitary while 15 (26%) were multifocal. The low density was homogenous in 13 cases (24%) and inhomogenous in 42 cases (76%), and 18 cases out of 42 cases inhomogenous low density showed peripheal and/or central nodular enhancement. The additional findings were contour changes in 37 cases (66%), metastasis in 35 cases (63%), splenomegaly in 23 cases (42%) and ascities in 22 cases (39%). 4. In postcontrast scans, 41 cases (80%) out of 51 cases showed the change of density after contrast infusion. The presence and extent of tumors were better seen after contrast infusion in 30 cases (59%), better seen before contrast infusion in 11 cases (21%) and no significant difference before and after contrast infusion in 10 cases (20%). 5. The sites of involved lobe were right lobe in 38 cases (68%), left lobe in 5 cases (9%) and both lobes in 13 cases (23%). 6. 35 cases (63%) showed evidence of metastasis to regional lymph nodes, organ or tissues.

  11. Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells.

    Science.gov (United States)

    Dai, Rongjuan; Peng, Feng; Xiao, Xinqiang; Gong, Xing; Jiang, Yongfang; Zhang, Min; Tian, Yi; Xu, Yun; Ma, Jing; Li, Mingming; Luo, Yue; Gong, Guozhong

    2017-09-22

    The HBx protein of hepatitis B virus (HBV) is widely recognized to be a critical oncoprotein contributing to the development of HBV-related hepatocellular carcinoma (HCC). In addition, cationic amino acid transporter 1 (CAT-1) gene is a target of miR-122. In this study, we found that CAT-1 protein levels were higher in HBV-related HCC carcinomatous tissues than in para-cancerous tumor tissues, and that CAT-1 promoted HCC cell growth, proliferation, and metastasis. Moreover, HBx-induced decreases in Gld2 and miR-122 levels that contributed to the upregulation of CAT-1 in HCC. These results indicate that a Gld2/miR-122/CAT-1 pathway regulated by HBx likely participates in HBV-related hepatocellular carcinogenesis.

  12. The androgen receptor as an emerging target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Kanda T

    2015-06-01

    Full Text Available Tatsuo Kanda, Osamu Yokosuka Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan Abstract: Hepatocellular carcinoma (HCC is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase–, v-akt murine thymoma viral oncogene homolog 1–, or signal-transducer and activator of transcription–signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor , vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC. Keywords: vascular endothelial growth factor, angiogenesis, glucose-regulated protein 78 kDa, hepatocarcinogenesis, molecular targets 

  13. Pentazocine Protects SN4741 Cells Against MPP+-Induced Cell Damage via Up-Regulation of the Canonical Wnt/β-Catenin Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jiancai Wang

    2017-06-01

    Full Text Available The Wnt/β-catenin signaling pathway has been linked to many neurodegenerative diseases including Parkinson’s disease (PD. A glycoprotein named Dickkopf-1 (Dkk1 can combine with the receptor complex on cell membrane to inhibit Wnt/β-catenin signaling. Opioids, a series of compounds including morphine, fentanyl and pentazocine, have been reported to contribute to the up-regulation of Wnt/β-catenin signaling. Naloxone is an antagonist that has been used as an antidote to opioids through mu-opioid receptor. 1-methyl-4-phenylpyridinium (MPP+, which serves as a selective toxin for dopaminergic neurons, has been used to create experimental models of PD. In our study, we examined the protective effects of pentazocine against MPP+-induced cell death in the nigral dopaminergic cell line, SN4741 and tried to elucidate the molecular mechanisms underlying such protective effects. The data showed that pretreatment with pentazocine significantly rescued the SN4741 cell against MPP+. Moreover, the MPP+-exposed SN4741 cells exhibited a down-regulation of β-catenin, which could be restored by treatment with pentazocine. However, Dkk1 but not naloxonewas associated with the abrogation of protective effect of pentazocine. These results suggest that pentazocine alleviates MPP+-induced SN4741 cells apoptosis via the up-regulation of canonical Wnt/β-catenin signaling.

  14. Civil Liability for Environmental Damages

    Directory of Open Access Journals (Sweden)

    Daniela Ciochină

    2012-05-01

    Full Text Available We debated in this article the civil liability for environmental damages as stipulated in ourlegislation with reference to Community law. The theory of legal liability in environmental law is basedon the duty of all citizens to respect and protect the environment. Considering the importance ofenvironment in which we live, the liability for environmental damages is treated by the Constitution as aprinciple and a fundamental obligation. Many human activities cause environmental damages and, in linewith the principle of sustainable development, they should be avoided. However, when this is notpossible, they must be regulated (by criminal or administrative law in order to limit their adverse effectsand, according to the polluter pays principle, to internalize in advance their externalities (through taxes,insurances or other forms of financial security products. Communication aims to analyze these issues andlegal regulations dealing with the issue of liability for environmental damage.

  15. Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

    International Nuclear Information System (INIS)

    Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja; Joseph, Binoy; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Yin, Yuanqin; Roy, Ram Vinod; Lu, Jian; Zhang, Zhuo; Wang, Yitao

    2014-01-01

    Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE 2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE 2 production. • C3G inhibited

  16. Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

    Energy Technology Data Exchange (ETDEWEB)

    Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Joseph, Binoy [Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky, Lexington, KY 40536-0509 (United States); Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Yin, Yuanqin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Cancer Institute, The First Affiliated Hospital, China Medical University, Shenyang (China); Roy, Ram Vinod [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Lu, Jian [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); and others

    2014-10-01

    Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE{sub 2} and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE{sub 2} production. • C3G

  17. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice.

    Science.gov (United States)

    Dominick, Graham; Bowman, Jacqueline; Li, Xinna; Miller, Richard A; Garcia, Gonzalo G

    2017-02-01

    Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA-KO mice express high levels of two proteins involved in DNA repair, O-6-methylguanine-DNA methyltransferase (MGMT) and N-myc downstream-regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post-transcriptional mechanisms. We show that the CCR4-NOT complex, a post-transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long-lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post-transcriptional regulation involving specific alteration in the CCR4-NOT complex, whose modulation could control multiple aspects of the aging process. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. No time for candy: passionfruit (Passiflora edulis) plants down-regulate damage-induced extra floral nectar production in response to light signals of competition.

    Science.gov (United States)

    Izaguirre, Miriam M; Mazza, Carlos A; Astigueta, María S; Ciarla, Ana M; Ballaré, Carlos L

    2013-09-01

    Plant fitness is often defined by the combined effects of herbivory and competition, and plants must strike a delicate balance between their ability to capture limiting resources and defend against herbivore attack. Many plants use indirect defenses, such as volatile compounds and extra floral nectaries (EFN), to attract canopy arthropods that are natural enemies of herbivorous organisms. While recent evidence suggests that upon perception of low red to far-red (R:FR) ratios, which signal the proximity of competitors, plants down-regulate resource allocation to direct chemical defenses, it is unknown if a similar phytochrome-mediated response occurs for indirect defenses. We evaluated the interactive effects of R:FR ratio and simulated herbivory on nectar production by EFNs of passion fruit (Passiflora edulis f. flavicarpa). The activity of petiolar EFNs dramatically increased in response to simulated herbivory and hormonal treatment with methyl jasmonate (MeJA). Low R:FR ratios, which induced a classic "shade-avoidance" repertoire of increased stem elongation in P. edulis, strongly suppressed the EFN response triggered by simulated herbivory or MeJA application. Strikingly, the EFN response to wounding and light quality was localized to the branches that received the treatments. In vines like P. edulis, a local response would allow the plants to precisely adjust their light harvesting and defense phenotypes to the local conditions encountered by individual branches when foraging for resources in patchy canopies. Consistent with the emerging paradigm that phytochrome regulation of jasmonate signaling is a central modulator of adaptive phenotypic plasticity, our results demonstrate that light quality is a strong regulator of indirect defenses.

  19. Molecular Analysis of a Multistep Lung Cancer Model Induced by Chronic Inflammation Reveals Epigenetic Regulation of p16, Activation of the DNA Damage Response Pathway

    Directory of Open Access Journals (Sweden)

    David Blanco

    2007-10-01

    Full Text Available The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers, genetic alterations. We analyzed markers of DNA damage response (DDR, proliferative stress, telomeric stress: δ-H2AX, p16, p53, TERT. Lung cancer-related epigenetic, genetic alterations, including promoter hypermethylation status of p16(CDKN2A, APC, CDH13, Rassf1, Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase, p53 induction. p16 was also induced in early tumorigenic progression, was inactivated in bronchiolar dysplasias, tumors. Remarkably, lack of mutations of Ras, epidermal growth factor receptor, a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A, CDH13, APC, but not in Rassf1, Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.

  20. Using the marker CD34 as tool to discriminate adenoma versus hepatocellular

    International Nuclear Information System (INIS)

    Mohs Alfaro, Monica

    2011-01-01

    The CD34 marker is used as immunohistochemistry technique to detect and differentiate between the hepatocellular adenoma of the hepatocellular carcinoma. The liver lesions are described. The hepatic angiogenesis is explained [es

  1. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C

    DEFF Research Database (Denmark)

    Kimer, Nina; Dahl, Emilie Kristine; Gluud, Lise Lotte

    2012-01-01

    To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C.......To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C....

  2. Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Weis, Sebastian; Franke, Annegret; Mössner, Joachim

    2013-01-01

    Hepatocellular carcinoma is the fifth most common cancer worldwide. Percutaneous interventional therapies, such as radiofrequency (thermal) ablation (RFA), have been developed for early hepatocellular carcinoma. RFA competes with other interventional techniques such as percutaneous ethanol...

  3. RPA physically interacts with the human DNA glycosylase NEIL1 to regulate excision of oxidative DNA base damage in primer-template structures.

    Science.gov (United States)

    Theriot, Corey A; Hegde, Muralidhar L; Hazra, Tapas K; Mitra, Sankar

    2010-06-04

    The human DNA glycosylase NEIL1, activated during the S-phase, has been shown to excise oxidized base lesions in single-strand DNA substrates. Furthermore, our previous work demonstrating functional interaction of NEIL1 with PCNA and flap endonuclease 1 (FEN1) suggested its involvement in replication-associated repair. Here we show interaction of NEIL1 with replication protein A (RPA), the heterotrimeric single-strand DNA binding protein that is essential for replication and other DNA transactions. The NEIL1 immunocomplex isolated from human cells contains RPA, and its abundance in the complex increases after exposure to oxidative stress. NEIL1 directly interacts with the large subunit of RPA (K(d) approximately 20 nM) via the common interacting interface (residues 312-349) in NEIL1's disordered C-terminal region. RPA inhibits the base excision activity of both wild-type NEIL1 (389 residues) and its C-terminal deletion CDelta78 mutant (lacking the interaction domain) for repairing 5-hydroxyuracil (5-OHU) in a primer-template structure mimicking the DNA replication fork. This inhibition is reduced when the damage is located near the primer-template junction. Contrarily, RPA moderately stimulates wild-type NEIL1 but not the CDelta78 mutant when 5-OHU is located within the duplex region. While NEIL1 is inhibited by both RPA and Escherichia coli single-strand DNA binding protein, only inhibition by RPA is relieved by PCNA. These results showing modulation of NEIL1's activity on single-stranded DNA substrate by RPA and PCNA support NEIL1's involvement in repairing the replicating genome. Copyright 2010 Elsevier B.V. All rights reserved.

  4. Dopamine-induced SULT1A3/4 promotes EMT and cancer stemness in hepatocellular carcinoma.

    Science.gov (United States)

    Zou, Juan; Li, Hong; Huang, Qianling; Liu, Xiaomin; Qi, Xiaoxiao; Wang, Ying; Lu, Linlin; Liu, Zhongqiu

    2017-10-01

    Hepatocellular carcinoma has the second highest incidence rate among malignant cancers in China. Hepatocellular carcinoma development is complex because of the metabolism disequilibrium involving SULT1A3/4, a predominant sulfotransferase that metabolizes sulfonic xenobiotics and endogenous catecholamines. However, the correlation between SULT1A3/4 and hepatocellular carcinoma progression is unclear. By utilizing immunofluorescence and immunohistochemical analysis, we found that in nine hepatocellular carcinoma clinical specimens, SULT1A3/4 was abundantly expressed in tumor tissues compared to that in the adjacent tissues. Moreover, liver cancer cells (HepG2, MHCC97-L, and MHCC97-H) had higher basal expression of SULT1A3/4 than immortalized liver cells (L02 and Chang liver). Ultra-high-pressure liquid chromatography-tandem mass spectrometry assay results further revealed that the concentration of dopamine (a substrate of SULT1A3/4) was negatively correlated with SULT1A3/4 protein expression. As a transcriptional regulator of SULT1A3/4 in turn, dopamine was used to induce SULT1A3/4 in vitro. Interestingly, dopamine significantly induced SULT1A3/4 expression in liver cancer HepG2 cells, while decreased that in L02 cells. More importantly, the expression levels of epithelial-mesenchymal transition biomarkers (N-cadherin and vimentin) and cell stemness biomarkers (nanog, sox2, and oct3/4) considerably increased in HepG2 with dopamine-induced SULT1A3/4, whereas in L02, epithelial-mesenchymal transition and cancer stem cell-associated proteins were contrarily decreased. Furthermore, invasion and migration assays further revealed that dopamine-induced SULT1A3/4 dramatically stimulated the metastatic capacity of HepG2 cells. Our results implied that SULT1A3/4 exhibited bidirectional effect on tumor and normal hepatocytes and may thus provide a novel strategy for hepatocellular carcinoma clinical targeting. In addition, SULT1A3/4 re-expression could serve as a biomarker for

  5. Identification of the IGF-1 processing product human Ec/rodent Eb peptide in various tissues: Evidence for its differential regulation after exercise-induced muscle damage in humans.

    Science.gov (United States)

    Vassilakos, George; Philippou, Anastassios; Koutsilieris, Michael

    2017-02-01

    Insulin-like growth factor-1 (IGF-1) is a pleiotropic factor expressed in various tissues and plays a critical role in skeletal muscle physiology. Alternative splicing of the IGF-1 gene gives rise to different precursor polypeptides (isoforms) which could undergo post-translational cleavage, generating the common mature IGF-1 peptide and different carboxyl terminal extension (E-) peptides, with the fate of the latter being, so far, unknown. The objective if this study was to identify the IGF-1Ec forms or processing product(s), other than mature IGF-1, generated in different human and rodent tissues and particularly in human skeletal muscle after exercise-induced damage. Protein lysates from a wide range of human and rodent tissues were immunoblotted with a rabbit anti-human Ec polyclonal antibody raised against the last 24 amino acids of the C-terminal of the Ec peptide. This antibody can recognize the Ec peptide, both as part of IGF-1Ec and alone, and also the corresponding rodent forms, due to the high homology that the human Ec shares with the rodent Eb. We were able to confirm, for the first time, that the human Ec peptide and its rodent homologous Eb peptide are produced simultaneously with their precursor protein (pro-IGF-1Ec/Eb) in vivo, in a wide range of tissues (e.g. muscle, liver, heart). Proprotein convertase furin digestion of human muscle and liver protein lysates confirmed that the higher molecular form, pro-IGF-1Ec, can be cleaved to produce the free Ec peptide. Furthermore, initial evidence is provided that Ec peptide is differentially regulated during the process of muscle regeneration after exercise-induced damage in humans. The findings of this study possibly imply that the post-translational modification of the IGF-1Ec pro-peptide may regulate the bioavailability and activity of the processing product(s). Copyright © 2016. Published by Elsevier Ltd.

  6. Mechanism and significance of let-7 in diagnosis and treatment of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    HUO Tingting

    2017-07-01

    Full Text Available Abstract:MicroRNA (miRNA play important roles in post-transcriptional gene regulation. In recent years, miRNA has become a hot topic in the research on the development and progression of tumors, and gene targeting therapy for malignant tumors has achieved preliminary progress. As one of the first discovered miRNA, let-7 can regulate the cell cycle and angiogenesis and is involved in the proliferation, differentiation, and apoptosis of various tumor cells. Most members of the let-7 family can act as tumor suppressor gene and have low expression in various tumor tissues and high expression in the serum of patients with malignant tumors. Let-7 is closely associated with the invasion and drug resistance of hepatocellular carcinoma (HCC. The studies above show that let-7 might become a new marker for the early diagnosis of HCC and provide new targets for the treatment of HCC.

  7. Molecular mechanism for the involvement of nuclear receptor FXR in HBV-associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yong-dong Niu

    2011-08-01

    Full Text Available Farnesoid X receptor (FXR, also termed nuclear receptor NR1H4 is critically involved in the regulation of nascent bile formation and bile acid enterohepatic circulation. FXR and bile acids have been shown to play roles in liver regeneration and inflammatory responses. There is increasing evidence suggesting that FXR and the FXR signaling pathway are involved in the pathophysiology of a wide range of liver diseases, such as viral hepatitis, cirrhosis, and hepatocellular carcinoma (HCC. Here we discuss the latest discoveries of FXR functions with relevance to bile acid metabolism and HBV-associated HCC. More specifically, the goal of this review is to discuss the roles of FXR and bile acids in regulating HBV replication and how disregulation of the FXR-bile acid signaling pathway is involved in HBV-associated hepatocarcinogenesis.

  8. Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis.

    Science.gov (United States)

    An, Jun; Zhang, Zhigang; Liu, Zhiyong; Wang, Ruizhi; Hui, Dayang; Jin, Yi

    2017-12-06

    Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma. In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry. We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion. Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

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  3. Substrate stiffness promotes latent TGF-β1 activation in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Pang, Mingshu; Teng, Yao; Huang, Jianyong; Yuan, Yuan; Lin, Feng; Xiong, Chunyang

    2017-01-01

    Hepatocellular carcinoma (HCC) was usually coupled with increased stiffness of the extracellular matrix (ECM) and elevated level of transforming growth factor-β1 (TGF-β1). However, the mechanism by which substrate rigidity modulated TGF-β1 signaling transduction remained unknown. This paper investigated the molecular mechanism of how matrix stiffness regulating TGF-β1 signaling in HCC cells. By means of stiffness tunable collagen I-coated polyacrylamide (PA) gels, we found that the expressions of β1 integrin, p-FAK Y397 and p-Smad2 upregulated on stiffer gels as well as the content of TGF-β1 in culture media of HCC cells, which were inhibited by RGD blocking peptides, Y-27632 (ROCK inhibitor) or Blebbistatin (myosin II inhibitor). Cellular traction force was also significantly higher when plated on stiffer substrates but dramatically decreased after treatment with Y-27632 or Blebbistatin. Furthermore, the upregulation of p-Smad2 in the HCC cells on stiffer PA gels induced by exogenetic latent TGF-β1 was downregulated in the presence of RGD peptides. The nuclear translocation of Smad2 induced by latent TGF-β1 was inhibited by Y-27632 or Blebbistatin. Our results suggested that the extracellular matrix stiffness regulated latent TGF-β1 activation by cytoskeletal tension in HCC cells, showing that matrix stiffness was a key regulator involving the TGF-β1 activity in HCC cells. The current study presented a mechanism of how hepatocirrhosis developed into liver cancer. - Highlights: • TGF-β1 signaling pathway regulated by ECM stiffness was studied in hepatocellular carcinoma. • Matrix stiffness promoted latent TGF-β1 activation via β1 integrin-FAK-Rho GTPase pathway. • A mechanism of how hepatocirrhosis developed into liver cancer was presented.

  4. Irradiation damage

    Energy Technology Data Exchange (ETDEWEB)

    Howe, L.M

    2000-07-01

    There is considerable interest in irradiation effects in intermetallic compounds from both the applied and fundamental aspects. Initially, this interest was associated mainly with nuclear reactor programs but it now extends to the fields of ion-beam modification of metals, behaviour of amorphous materials, ion-beam processing of electronic materials, and ion-beam simulations of various kinds. The field of irradiation damage in intermetallic compounds is rapidly expanding, and no attempt will be made in this chapter to cover all of the various aspects. Instead, attention will be focused on some specific areas and, hopefully, through these, some insight will be given into the physical processes involved, the present state of our knowledge, and the challenge of obtaining more comprehensive understanding in the future. The specific areas that will be covered are: point defects in intermetallic compounds; irradiation-enhanced ordering and irradiation-induced disordering of ordered alloys; irradiation-induced amorphization.

  5. Irradiation damage

    International Nuclear Information System (INIS)

    Howe, L.M.

    2000-01-01

    There is considerable interest in irradiation effects in intermetallic compounds from both the applied and fundamental aspects. Initially, this interest was associated mainly with nuclear reactor programs but it now extends to the fields of ion-beam modification of metals, behaviour of amorphous materials, ion-beam processing of electronic materials, and ion-beam simulations of various kinds. The field of irradiation damage in intermetallic compounds is rapidly expanding, and no attempt will be made in this chapter to cover all of the various aspects. Instead, attention will be focused on some specific areas and, hopefully, through these, some insight will be given into the physical processes involved, the present state of our knowledge, and the challenge of obtaining more comprehensive understanding in the future. The specific areas that will be covered are: point defects in intermetallic compounds; irradiation-enhanced ordering and irradiation-induced disordering of ordered alloys; irradiation-induced amorphization

  6. Prognostic role of sirt1 in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Song, S.; Zhang, H.

    2014-01-01

    To determine the clinical significance of silent mating type information regulation 2 homolog 1 (SIRT1) expression in Hepatocellular Carcinoma (HCC) and its association with P53 and Yes-associated protein 2 (YAP2) expression. Study Design: Observational study. Place and Duration of Study: Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, China, from January 2000 to January 2010. Methodology: Tissue microarray technique and immunohistochemistry were conducted to detect the expression of SIRT1, P53 and YAP2 proteins in 300 self-paired HCC samples. Associations with clinicopathologic manifestations were analyzed, overall survival analysis and multivariate analysis were performed. Results: By tissue microarray technique and immunohistochemistry on 300 self-paired HCC samples, it was found that SIRT1, P53 and YAP2 were significantly overexpressed in HCC tumor tissues compared with adjacent non-tumor tissues. SIRT1 immunostaining localized both in the nucleus (145/300, 48.3%) and the cytoplasm (70/300, 23.3%), and the overexpression of nuclear SIRT1 was positively related to the overexpression of P53 and YAP2. Survival analysis showed that nuclear SIRT1, P53 and YAP2 overexpression predicted poor overall survival while cytoplasmic SIRT1 overexpression predicted longer overall survival. Multivariate analysis showed nuclear SIRT1 and P53 overexpression as independent tumor promoters while cytoplasmic SIRT1 overexpression as an independent tumor suppressor. Conclusion: SIRT1 was overexpressed in HCC and the expression was positively related to P53 and YAP2 expression. As the nuclear SIRT1 functions as a tumor promoter and cytoplasmic SIRT1 functions as a tumor suppressor, the role of SIRT1 in HCC should be reconsidered. (author)

  7. Prognostic implication of NQO1 overexpression in hepatocellular carcinoma.

    Science.gov (United States)

    Lin, Lijuan; Sun, Jie; Tan, Yan; Li, Zhenling; Kong, Fanyong; Shen, Yue; Liu, Chao; Chen, Litian

    2017-11-01

    To explore the role of NQO1 overexpression for prognostic implication in hepatocellular carcinoma (HCC), NQO1 mRNA levels were detected in HCC fresh tissue samples of HCC and nontumor tissues, respectively. One hundred fifty-six cases of HCC meeting strict follow-up criteria were selected for immunohistochemical staining of NQO1 protein. Correlations between NQO1 overexpression and clinicopathological features of HCC were evaluated using χ 2 tests, survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient 5-year survival was analyzed using Cox proportional hazards analysis. In results, the levels of NQO1 mRNA were significantly up-regulated in 14 fresh tissue samples of HCC. Immunohistochemical analysis showed that the NQO1 expression and overexpression rates were significantly higher in HCC samples compared with either adjacent nontumor tissues or normal liver tissues. NQO1 overexpression correlated to tumor size, venous infiltration and late pTNM stage of HCC. NQO1 overexpression was also related to low disease-free survival and 5-year survival rates. In the late-stage group, disease-free and 5-year survival rates of patients with NQO1 overexpression were significantly lower than those of patients without NQO1 expression. Further analysis using a Cox proportional hazards regression model revealed that NQO1 expression emerged as a significant independent hazard factor for the 5-year survival rate of patients with HCC. Therefore, NQO1 plays an important role in the progression of HCC. NQO1 may potentially be used as an independent biomarker for prognostic evaluation of HCC. Copyright © 2017. Published by Elsevier Inc.

  8. BLZF1 expression is of prognostic significance in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Run-Yue, E-mail: ry_huang@hotmail.com [Department of Rheumatology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510006 (China); Su, Shu-Guang [Department of Pathology, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou (China); Wu, Dan-Chun [Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou (China); Fu, Jia [Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060 (China); Zeng, Xing, E-mail: zengxing-china@163.com [Department of Rheumatology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510006 (China)

    2015-11-20

    BLZF1, a member of b-ZIP family, has been implicated in epigenetic regulation and Wnt/β-catenin signaling. Its expression and clinical significance in human cancers remain largely unknown. In this study, we showed that BLZF1 expression was reduced in hepatocellular carcinoma (HCC) tissues, compared to the paracarcinoma tissues, at both mRNA and protein levels. Results of immunohistochemistry revealed that BLZF1 was presented in both nuclear and cytoplasm. Decreased expression of nuclear and cytosolic BLZF1 in HCC was depicted in 68.2% and 79.2% of the 634 cases. Nuclear BLZF1 expression was significantly associated with tumor multiplicity (P = 0.048) and tumor capsule (P = 0.028), while cytosolic BLZF1 expression was correlated with serum AFP level (P = 0.017), tumor differentiation (P = 0.001) and tumor capsule (P = 0.003). Kaplan–Meier analysis indicated both nuclear and cytosolic BLZF1 expression was associated with poor overall survival. Low nuclear BLZF1 also indicated unfavorable disease-free survival and high tendency of tumor recurrence. Furthermore, multiple Cox regression analysis revealed nuclear BLZF1 as an independent factor for overall survival (Hazard Ratio (HR) = 0.827, 95% confident interval (95%CI): 0.697–0.980, P = 0.029). The prognostic value of BLZF1 was further confirmed by stratified analyses. Collectively, our data suggest BLZF1 is a novel unfavorable biomarker for prognosis of patients with HCC. - Highlights: • BLZF1 expression was much lower in HCC tissues. • Low BLZF1 expression was associated with poor outcomes in a cohort of 634 HCC patients. • Multiple Cox regression analysis indicated nuclear BLZF1 as an independent predictor for overall survival.

  9. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Mamta Kalra; Jary Mayes; Senait Assefa; Anil K Kaul; Rashmi Kaul

    2008-01-01

    The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC. 2008 The WJG Press. All rights reserved.

  10. Fas-Induced Apoptosis of Renal Cell Carcinoma is Mediated by Apoptosis Signal-Regulating Kinase 1 via Mitochondrial Damage-Dependent Caspase-8 Activation

    Directory of Open Access Journals (Sweden)

    Mohamed Hassan

    2009-01-01

    Full Text Available Renal cell carcinoma (RCC is a prototype of a chemo refractory tumour. It remains the most lethal of the common urologic cancers and is highly resistant to conventional therapy. Here, we confirmed the efficiency of anti-Fas monoclonal antibody (CH11 as alternative therapeutic approach for the treatment of RCC and investigated the molecular mechanism(s, whereby CH11 induces apoptosis of RCC cells. The present study shows an essential role for apoptosis signal-regulating kinase 1 (ASK1, together with both c-jun-N-terminal kinase (JNK and p38 pathways, and caspase-8 in this process. Furthermore, CH11-dependent induction of the ASK1–JNK/p38 pathways was found to activate the transcription factors AP-1 and ATF-2, and FADD-caspase-8-Bid signalling, resulting in the translocation of both Bax and Bak proteins, and subsequently mitochondrial dysregulation that is characterized by the loss of mitochondrial membrane potential (ΔΨm, cytochrome c release and cleavage of caspase-9, caspase-3 and PARP. Thus, the described molecular mechanisms of CH11-induced apoptosis suggest the reliability of Fas activation as an alternative therapeutic approach for the treatment of patients with advanced renal cell carcinoma.

  11. Gallic acid against hepatocellular carcinoma: An integrated scheme of the potential mechanisms of action from in vivo study.

    Science.gov (United States)

    Aglan, Hadeer A; Ahmed, Hanaa H; El-Toumy, Sayed A; Mahmoud, Nadia S

    2017-06-01

    The global burden of hepatocellular carcinoma is increasing; actually, it is estimated as 750,000 new cases annually. This study was initiated to emphasize the possibility that gallic acid could alleviate hepatocarcinogenesis in vivo. In this study, 40 rats were enrolled and distributed as follows; group 1 was set as negative control, while all of groups 2, 3, and 4 were orally received N-nitrosodiethylamine for hepatocellular carcinoma induction. Group 2 was left untreated, whereas groups 3 and 4 were orally treated with gallic acid and doxorubicin, respectively. The current data indicated that gallic acid administration in hepatocellular carcinoma bearing rats yielded significant decline in serum levels of alpha-fetoprotein, glypican-3, and signal transducer and activator of transcription 3 along with significant enhancement in serum suppressors of cytokine signaling 3 level. Also, gallic acid-treated group displayed significant downregulation in the gene expression levels of hepatic gamma glutamyl transferase and heat shock protein gp96. Intriguingly, treatment with gallic acid remarkably ameliorated the destabilization of liver tissue architecture caused by N-nitrosodiethylamine intoxication as evidenced by histopathological investigation. In conclusion, this study demonstrates that the hepatocarcinogenic effect of N-nitrosodiethylamine can be abrogated by gallic acid supplementation owing to its affinity to regulate signal transducer and activator of transcription 3 signaling pathway through its outstanding bioactivities including antioxidant, anti-inflammatory, apoptotic, and antitumor effects.

  12. Hepatocellular carcinomas supplied by inferior phrenic arteries.

    Science.gov (United States)

    Tanabe, N; Iwasaki, T; Chida, N; Suzuki, S; Akahane, T; Kobayashi, N; Ishii, M; Toyota, T

    1998-07-01

    To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). A total of 126 consecutive cases of HCC were studied by contract-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 1, 1, and 4. HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography.

  13. Diagnostic and therapeutic management of hepatocellular carcinoma

    Science.gov (United States)

    Bellissimo, Francesco; Pinzone, Marilia Rita; Cacopardo, Bruno; Nunnari, Giuseppe

    2015-01-01

    Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines. PMID:26576088

  14. Updates in the Management of Hepatocellular Carcinoma

    Science.gov (United States)

    Frenette, Catherine

    2011-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, and its increasing incidence worldwide is a cause for concern. Fortunately, advances in diagnostic and therapeutic approaches have contributed to earlier detection and treatment. As cancer epidemiology studies continue to elucidate the natural history of liver diseases, greater understanding of HCC has led to improved risk stratification and earlier enrollment of high-risk patients in cancer screening and surveillance programs. Improved survival rates among HCC patients also reflect significant advances in available treatment options. Advances in surgical techniques are pushing the boundaries of resection for localized disease, and progress in the field of transplantation has led to refinements in listing criteria and improved post-transplantation outcomes. The evolving field of locoregional therapies—including percutaneous ablation and transarterial chemoembolization—continues to provide novel therapeutic options that can be used in place of, or in addition to, surgical approaches. Recent advances in systemic multikinase inhibitor therapies have also demonstrated significant benefits for advanced-stage disease, and these therapies also show promise as adjuvant treatments for earlier-stage disease. This article provides an update on the management of HCC, with a focus on revised guidelines for screening and an in-depth discussion of emerging novel therapies. PMID:21346848

  15. Genetic alterations in hepatocellular carcinoma: An update

    Science.gov (United States)

    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

  16. Nonalcoholic fatty liver disease and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LI Liangping

    2016-03-01

    Full Text Available As the etiology of hepatocellular carcinoma (HCC has been changing, the incidence of HCC related to nonalcoholic fatty liver disease (NAFLD is gradually increasing in developed countries in Europe and America and some countries in Asia. This article introduces the close association between NAFLD and HCC, risk factors, clinicopathological features, and prevention and screening, and points out that although the incidence of NAFLD is not as high as that of hepatitis B- or hepatitis C-related HCC, there are a large absolute number of NAFLD patients, especially the high-risk patients with diabetes and obesity, or liver fibrosis/cirrhosis, due to a huge base number of NAFLD patients. NAFLD-related HCC is commonly seen in the elderly with various comorbidities and a poor prognosis. This article also points out that the prevention should focus on the effective treatment of NAFLD. The strict screening of high-risk population is the strategy for the diagnosis of early-stage HCC. At present, the sensitivity of alpha-fetoprotein is relatively low, and imaging examinations including computed tomography are the main screening methods; however, there are no measures for early warning of NAFLD-related HCC.

  17. CT findings of exophytic hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sang Jin; Cho, June Sik; Kim, Hyung Lyul; Lee, Chung Keun; Kim, Dae Hong; Rhee, Byung Chull [Chungnam National University College of Medicine, Daejeon (Korea, Republic of)

    1993-11-15

    We retrospectively evaluated the characteristic computed tomographic(CT) findings in nine patients with exohepatic hepatocellular carcinoma(HCC) pathologically prove by surgery(n=2) or percutaneous needle biopsy(n=7). The CT findings of exphepatic HCC were correlated with clinical findings and compared with those of usual HCC. Lesions were in the left lobe(n=7) and right lobe(n=2) of the liver. All lesions showed a well-marginated hypodense mass with capsular enhancement on enhanced CT scan. The patterns of capsular enhancement were complete in five and partial in four case. The portal vein thrombosis was seen only in one case. There was no difference between exohepatic HCC and usual HCC in clinical findings such as increased {alpha}-fetoprotein({alpha}-FP), positive hepatitis B surface antigen(HBsAg), and underlying liver cirrhosis. In conclusion, the CT findings of exohepatic HCC were a well-defined hyperdense mass with complete or partial capsular enhancement and these findings may be useful in differentiation from the tumors of adjacent organs.

  18. Ectopic hepatocellular carcinoma in a dog.

    Science.gov (United States)

    Burton, I R; Limpus, K; Thompson, K G; Owen, M C; Worth, A J

    2005-12-01

    A 14-year-old neutered male Bearded Collie was presented with a history of recurrent, intermittent urinary incontinence of 7 years duration. A large, firm, non-painful mass was found in the mid-abdominal region on palpation. Ultrasonography of the mass revealed a compartmentalised structure with mixed echogenicity, and which did not appear to be associated with any of the abdominal organs. Ultrasound-guided fine needle aspirates contained several clusters of epithelial cells with cytological features of hepatocytes. At exploratory laparotomy, the mass was found in the gastrosplenic ligament within the greater omentum. PATHOLOGICAL FINDINGS AND DIAGNOSIS: Histopathologically, the mass consisted of sheets of hepatocytes, but without the characteristic hepatic architecture. The cells showed moderate variation in nuclear size and were sometimes binucleate. A diagnosis of hepatocellular carcinoma (HCC) in the mesentery was made. The presence of ectopic hepatic tissue has been reported rarely in man and cats, but not in the dog. Neoplastic transformation of ectopic hepatic tissue is seen in man. This is the first report of the presentation, clinical findings and treatment of a dog with ectopic HCC.

  19. In Utero Hepatocellular Transplantation in Rats

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    Emma Muñoz-Sáez

    2013-01-01

    Full Text Available This work represents a step forward in the experimental design of an in utero hepatocellular transplantation model in rats. We focused on the enrichment optimization of isolated fetal hepatocytes suspension, arranging the surgery methodology of in utero transplantation, monitoring the biodistribution of the transplanted hepatocytes, and assessing the success of the transplants. Rat fetuses have been transplanted at the 17th embryonic day (ED17 with fetal hepatocytes isolated from rats at the end of pregnancy (ED21. We assessed possible differences between lymphocyte population, CD4 positive, CD8 positive, double-positive T-cells, and anti-inflammatory cytokines interleukins 4 and 10 (IL4 and IL10 as well. Cellular viability reached the rates of 90–95%. Transplanted groups had a limited success. Transplanted hepatocytes were not able to pass through the hematoplacental barrier. The hepatocytes injected were primarily located in the liver. There was an upward trend in the whole amount of T CD4 and T CD8 cells. There was an increased IL4 in the transplanted groups observed in the pregnant rats. The possibility to induce tolerance in fetuses with a hepatocyte transplant in utero could be a key point to avoid the immunosuppression treatments which must be undergone by transplanted patients.

  20. Repeated proton beam therapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hashimoto, Takayuki; Tokuuye, Koichi; Fukumitsu, Nobuyoshi; Igaki, Hiroshi; Hata, Masaharu; Kagei, Kenji; Sugahara, Shinji; Ohara, Kiyoshi; Matsuzaki, Yasushi; Akine, Yasuyuki

    2006-01-01

    Purpose: To retrospectively evaluate the safety and effectiveness of repeated proton beam therapy for newly developed or recurrent hepatocellular carcinoma (HCC). Methods and Materials: From June 1989 through July 2000, 225 patients with HCC underwent their first course of proton beam therapy at University of Tsukuba. Of them, 27 with 68 lesions who had undergone two or more courses were retrospectively reviewed in this study. Median interval between the first and second course was 24.5 months (range 3.3-79.8 months). Median total dose of 72 Gy in 16 fractions and 66 Gy in 16 fractions were given for the first course and the rest of the courses, respectively. Results: The 5-year survival rate and median survival period from the beginning of the first course for the 27 patients were 55.6% and 62.2 months, respectively. Five-year local control rate for the 68 lesions was 87.8%. Of the patients, 1 with Child-Pugh class B and another with class C before the last course suffered from acute hepatic failure. Conclusions: Repeated proton beam therapy for HCC is safe when the patient has a target in the peripheral region of the liver and liver function is Child-Pugh class A

  1. Hepatocellular carcinoma: a systems biology perspective

    Directory of Open Access Journals (Sweden)

    Lorenza Alice D'alessandro

    2013-02-01

    Full Text Available Hepatocellular carcinomas (HCC have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment.

  2. Hepatocellular carcinomas supplied by inferior phrenic arteries

    International Nuclear Information System (INIS)

    Tanabe, N.; Iwasaki, T.; Akahane, T.; Kobayashi, N.; Ishii, M.; Toyota, T.; Chida, N.; Suzuki, S.

    1998-01-01

    Purpose: To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). Material and Methods: A total of 126 consecutive cases of HCC were studied by contrast-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. Results: In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 7, 1, and 4. Conclusion: HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography. (orig.)

  3. Infrequent widespread microsatellite instability in hepatocellular carcinomas.

    Science.gov (United States)

    Yamamoto, H; Itoh, F; Fukushima, H; Kaneto, H; Sasaki, S; Ohmura, T; Satoh, T; Karino, Y; Endo, T; Toyota, J; Imai, K

    2000-03-01

    Widespread or high-frequency microsatellite instability (MSI) due to the defective DNA mismatch repair (MMR) occurs in the majority of hereditary non-polyposis colorectal cancer and a subset of sporadic malignant tumors. The incidence of MSI and underlying DNA MMR defects have been well characterized in gastrointestinal carcinogenesis, but not in hepatocarcinogenesis. To address the issue, we analyzed 55 Japanese hepatocellular carcinomas using several indicators of DNA MMR defects, such as microsatellite analysis, loss of heterozygosity (LOH) and mutation analysis of MMR genes, methylation of hMLH1 promoter, and frameshift mutations of mononucleotide repeat sequences within possible target genes. Mutation of beta2-microglobulin gene, which is presumably involved in MSI-positive tumor cell escape from immune surveillance was also examined. Some of these analyses were also carried out in 9 human liver cancer cell lines. None of the 3 quasi-monomorphic mononucleotide markers sensitive for MSI, BAT26, BAT25, and BAT34C4 presented shortened unstable alleles in any of the carcinoma, cirrhosis, chronic hepatitis tissues, or cell lines. LOH at MMR genes was infrequent (4.4 approximately 7.1%), and no mutations were detected. Neither hMLH1 hypermethylation nor frameshift mutation in the target genes was detected. No mutations were found in beta2-microglobulin. Widespread MSI due to the defective DNA MMR appears to play little if any part in Japanese hepatocarcinogenesis.

  4. Hepatocellular carcinomas supplied by inferior phrenic arteries

    Energy Technology Data Exchange (ETDEWEB)

    Tanabe, N.; Iwasaki, T.; Akahane, T.; Kobayashi, N.; Ishii, M.; Toyota, T. [Tohoku Univ. School of Medicine (Japan). Third Dept. of Internal Medicine; Chida, N.; Suzuki, S. [National Sendai Hospital (Japan). Dept. of Gastroenterology

    1998-07-01

    Purpose: To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). Material and Methods: A total of 126 consecutive cases of HCC were studied by contrast-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. Results: In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 7, 1, and 4. Conclusion: HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography. (orig.)

  5. Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells

    International Nuclear Information System (INIS)

    Kou, Xingrui; Zhao, Qiudong; Zhao, Xue; Li, Rong; Wei, Lixin; Wu, Mengchao; Jing, Yingying; Deng, Weijie; Sun, Kai; Han, Zhipeng; Ye, Fei; Yu, Guofeng; Fan, Qingmin; Gao, Lu

    2013-01-01

    Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved. For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells. TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation. Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway

  6. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Lulu Fan

    Full Text Available BACKGROUND: Endoplasmic reticulum stress (ER stress is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone, is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of the endoplasmic reticulum (ER stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153 in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.

  7. New Natural Pigment Fraction Isolated from Saw Palmetto: Potential for Adjuvant Therapy of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Hor-Yue Tan

    2016-08-01

    Full Text Available For the first time, we discovered a small proportion of aqueous fraction from Saw Palmetto apart from the fatty acid-rich fraction exhibited pharmacological activity. Therefore, this study aims to explore the anti-tumor potential of red pigmented aqueous fraction of Saw Palmetto, NYG on human hepatocellular carcinoma and its possible targets. Subcutaneous xenograft and orthotopic implantation models of HCC were used to evaluate the tumor inhibitory effect of NYG. Human hepatocellular carcinoma (HCC cell lines and human umbilical vein endothelial cells (HUVEC were used as in vitro model. The mRNA expression was conducted by qPCR. Protein expression was monitored by immunoblotting and immunohistochemistry. Cell migration and blood vessel formation were determined by chamber assay and tube formation assay, respectively. Significant tumor inhibition of NYG in dose-dependent manner was observed on subcutaneous xenograft and orthotopic HCC model. NYG has no direct action on cell viability or VEGF secretion of HCC cells. However, NYG reduced in vitro migration and vessel formation activities of HUVEC cells, as well as in vivo intratumoral neovascularization. NYG attenuated extracellular signal-regulated kinases (ERK activation in endothelial cells, which may be associated with the suppression of migration and tube formation of HUVEC. NYG suppressed tumor expansion of HCC via inhibiting neovascularization, and may be potential adjuvant treatment for HCC.

  8. New Natural Pigment Fraction Isolated from Saw Palmetto: Potential for Adjuvant Therapy of Hepatocellular Carcinoma.

    Science.gov (United States)

    Tan, Hor-Yue; Wang, Ning; Takahashi, Masao; Feng, Yigang; Li, Hongyun; Feng, Yibin

    2016-08-05

    For the first time, we discovered a small proportion of aqueous fraction from Saw Palmetto apart from the fatty acid-rich fraction exhibited pharmacological activity. Therefore, this study aims to explore the anti-tumor potential of red pigmented aqueous fraction of Saw Palmetto, NYG on human hepatocellular carcinoma and its possible targets. Subcutaneous xenograft and orthotopic implantation models of HCC were used to evaluate the tumor inhibitory effect of NYG. Human hepatocellular carcinoma (HCC) cell lines and human umbilical vein endothelial cells (HUVEC) were used as in vitro model. The mRNA expression was conducted by qPCR. Protein expression was monitored by immunoblotting and immunohistochemistry. Cell migration and blood vessel formation were determined by chamber assay and tube formation assay, respectively. Significant tumor inhibition of NYG in dose-dependent manner was observed on subcutaneous xenograft and orthotopic HCC model. NYG has no direct action on cell viability or VEGF secretion of HCC cells. However, NYG reduced in vitro migration and vessel formation activities of HUVEC cells, as well as in vivo intratumoral neovascularization. NYG attenuated extracellular signal-regulated kinases (ERK) activation in endothelial cells, which may be associated with the suppression of migration and tube formation of HUVEC. NYG suppressed tumor expansion of HCC via inhibiting neovascularization, and may be potential adjuvant treatment for HCC.

  9. Silencing glypican-3 expression induces apoptosis in human hepatocellular carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shiyuan [The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu (China); Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, Gansu (China); Li, Yumin, E-mail: liym@lzu.edu.cn [The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu (China); Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, Gansu (China); Chen, Wei [Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, Gansu (China); Zheng, Pengfei [The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu (China); Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, Gansu (China); Liu, Tao; He, Wenting; Zhang, Junqiang; Zeng, Xiangting [Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, Gansu (China)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer RNA interference GPC3 induces apoptosis in human hepatocellular carcinoma cell. Black-Right-Pointing-Pointer Silencing GPC3 resulted in the release of cytochrome c and activation of caspase-3. Black-Right-Pointing-Pointer GPC3 modulates the Bax/Bcl-2/cytochrome c/caspase-3 apoptotic signaling pathway. Black-Right-Pointing-Pointer Knockdown of GPC3 is a novel approach to HCC treatment. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common internal malignant tumors. Glypican-3 (GPC3) is involved in the biological and molecular events in the tumorigenesis of HCC. We used RNA interference to evaluate the molecular effects of GPC3 suppression at the translational level and demonstrated for the first time that GPC3 silencing results in a significant elevation of the Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria and the activation of caspase-3. The results suggest that GPC3 regulates cell proliferation by enhancing the resistance to apoptosis through the dysfunction of the Bax/Bcl-2/cytochrome c/caspase-3 signaling pathway and therefore plays a critical role in the tumorigenesis of HCC. Thus, the knockdown of GPC3 should be further investigated as an attractive novel approach for the targeted gene therapy of HCC.

  10. Magnetic Resonance Imaging Finding of Metastatic Hepatocellular Carcinoma in Ovary: A Case Report

    International Nuclear Information System (INIS)

    Kwak, Soon Hyuk; Cho, Bum Sang; Kang, Min Ho; Lee, Seung Young; Han, Gi Seok; Cha, Sang Hoon; Park, Kil Sun; Kim, Sung Jin; Choi, Song Yi

    2011-01-01

    Hepatocellular carcinoma is the most common primary malignant tumor of liver. Metastasis of hepatocellular carcinoma occurs in various organs, but metastasis to the ovary is extremely rare. We report MRI finding of metastatic hepatocellular carcinoma of the ovary in a 37-year-old woman who was treated hepatocellular carcinoma transarterial chemoembolization and radiofrequency ablation a year ago. Pelvic MRI revealed a mass in pelvic cavity with heterogeneous signal intensity and centripetal enhancement. Surgical excision and pathologic examination confirmed metastatic hepatocellular carcinoma in the ovary.

  11. Damaged Skylab

    Science.gov (United States)

    1973-01-01

    The Saturn V vehicle, carrying the unmarned orbital workshop for the Skylab-1 mission, lifted off successfully and all systems performed normally. Sixty-three seconds into the flight, engineers in the operation support and control center saw an unexpected telemetry indication that signalled that damages occurred on one solar array and the micrometeoroid shield during the launch. The micrometeoroid shield, a thin protective cylinder surrounding the workshop protecting it from tiny space particles and the sun's scorching heat, ripped loose from its position around the workshop. This caused the loss of one solar wing and jammed the other. Still unoccupied, the Skylab was stricken with the loss of the heat shield and sunlight beat mercilessly on the lab's sensitive skin. Internal temperatures soared, rendering the station uninhabitable, threatening foods, medicines, films, and experiments. This image, taken during a fly-around inspection by the Skylab-2 crew, shows a crippled Skylab in orbit. The crew found their home in space to be in serious shape; the heat shield gone, one solar wing gone, and the other jammed. The Marshall Space Flight Center (MSFC) developed, tested, rehearsed, and approved three repair options. These options included a parasol sunshade and a twin-pole sunshade to restore the temperature inside the workshop, and a set of metal cutting tools to free the jammed solar panel.

  12. Structural damage

    International Nuclear Information System (INIS)

    Gray, R.E.; Bruhn, R.W.

    1992-01-01

    Virtually all structures show some signs of distress due to deterioration of the building components, to changed loads, or to changed support conditions. Changed support conditions result from ground movements. In mining regions many cases of structural distress are attributed to mining without considering alternative causes. This is particularly true of coal mining since it occurs under extensive areas. Coal mining is estimated to have already undermined more than eight million acres and may eventually undermine 40 million acres in the United States. Other nonmetal and metal underground mines impact much smaller areas. Although it is sometimes difficult, even with careful study, to identify the actual cause of damage, persons responsible for underground coal mining should at least be aware of possible causes of building stress other than mine subsidence. This paper presents information on distress to structures and briefly reviews a number of causes of ground movements other than subsidence: Mass movements, dissolution, erosion, frost action, shrinking and swelling, yield into excavations and compressibility

  13. Radiation damage prediction system using damage function

    International Nuclear Information System (INIS)

    Tanaka, Yoshihisa; Mori, Seiji

    1979-01-01

    The irradiation damage analysis system using a damage function was investigated. This irradiation damage analysis system consists of the following three processes, the unfolding of a damage function, the calculation of the neutron flux spectrum of the object of damage analysis and the estimation of irradiation effect of the object of damage analysis. The damage function is calculated by applying the SAND-2 code. The ANISN and DOT3, 5 codes are used to calculate neutron flux. The neutron radiation and the allowable time of reactor operation can be estimated based on these calculations of the damage function and neutron flux. The flow diagram of the process of analyzing irradiation damage by a damage function and the flow diagram of SAND-2 code are presented, and the analytical code for estimating damage, which is determined with a damage function and a neutron spectrum, is explained. The application of the irradiation damage analysis system using a damage function was carried out to the core support structure of a fast breeder reactor for the damage estimation and the uncertainty evaluation. The fundamental analytical conditions and the analytical model for this work are presented, then the irradiation data for SUS304, the initial estimated values of a damage function, the error analysis for a damage function and the analytical results are explained concerning the computation of a damage function for 10% total elongation. Concerning the damage estimation of FBR core support structure, the standard and lower limiting values of damage, the permissible neutron flux and the allowable years of reactor operation are presented and were evaluated. (Nakai, Y.)

  14. Positive feedback regulation of a Lycium chinense-derived VDE gene by drought-induced endogenous ABA, and over-expression of this VDE gene improve drought-induced photo-damage in Arabidopsis.

    Science.gov (United States)

    Guan, Chunfeng; Ji, Jing; Zhang, Xuqiang; Li, Xiaozhou; Jin, Chao; Guan, Wenzhu; Wang, Gang

    2015-03-01

    Violaxanthin de-epoxidase (VDE) plays an important role in protecting the photosynthetic apparatus from photo-damage by dissipating excessively absorbed light energy as heat, via the conversion of violaxanthin (V) to intermediate product antheraxanthin (A) and final product zeaxanthin (Z) under light stress. We have cloned a VDE gene (LcVDE) from Lycium chinense, a deciduous woody perennial halophyte, which can grow in a large variety of soil types. The amino acid sequence of LcVDE has high homology with VDEs in other plants. Under drought stress, relative expression of LcVDE and the de-epoxidation ratio (Z+0.5A)/(V+A+Z) increased rapidly, and non-photochemical quenching (NPQ) also rose. Interestingly, these elevations induced by drought stress were reduced by the topical administration of abamine SG, a potent ABA inhibitor via inhibition of NCED in the ABA synthesis pathway. Until now, little has been done to explore the relationship between endogenous ABA and the expression of VDE genes. Since V serves as a common precursor for ABA, these data support the possible involvement of endogenous ABA in the positive feedback regulation of LcVDE gene expression in L. chinense under drought stress. Moreover, the LcVDE may be involved in modulating the level of photosynthesis damage caused by drought stress. Furthermore, the ratio of (Z+0.5A)/(V+A+Z) and NPQ increased more in transgenic Arabidopsis over-expressing LcVDE gene than the wild types under drought stress. The maximum quantum yield of primary photochemistry of PSII (Fv/Fm) in transgenic Arabidopsis decreased more slowly during the stressed period than that in wild types under the same conditions. Furthermore, transgenic Arabidopsis over-expressing LcVDE showed increased tolerance to drought stress. Copyright © 2014 Elsevier GmbH. All rights reserved.

  15. Gene replacement therapy for genetic hepatocellular jaundice.

    Science.gov (United States)

    van Dijk, Remco; Beuers, Ulrich; Bosma, Piter J

    2015-06-01

    Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.

  16. How to detect hepatocellular carcinoma in cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Janice; Robinson, Philip J. [Department of Clinical Radiology, St. James' s University Hospital, Beckett Street, Leeds LS9 7TF (United Kingdom)

    2002-09-01

    Cirrhosis predisposes to hepatocellular carcinoma (HCC) which develops by sequential steps of de-differentiation of hepatocytes from regenerative nodules via borderline (dysplastic) nodules to frankly malignant HCC. Effective treatment depends on early recognition of HCC, so the key tasks for imaging are firstly recognising the presence of a suspicious lesion, and secondly differentiating between benign, borderline and malignant nodules. Screening of high-risk cirrhotic patients with sonography and measurement of alpha fetoprotein (AFP) is helpful but will not reliably differentiate small HCC from benign or dysplastic nodules. Large HCCs can usually be recognised by their characteristic morphology on imaging, but the appearances of smaller benign and malignant nodules show considerable overlap on unenhanced sonography, CT and MRI. Increasing degrees of histological malignancy are associated with increasing arterialisation and loss of portal blood supply, so the recognition of HCC requires the use of dynamic imaging with contrast-enhanced CT or T1-weighted MRI with gadolinium enhancement. Sonography with microbubble contrast media now offers another method for detecting arterialised nodules; however, some non-malignant nodules show arterial hypervascularity and a minority of HCCs are hypovascular, so the assessment of perfusion does not conclusively distinguish benign from malignant lesions. Kupffer cell function is another attribute of liver tissue which can be explored using MRI with superparamagnetic iron oxide particles (SPIO). Experience thus far suggests that uptake of SPIO is an effective discriminator between benign and malignant nodules. The combination of SPIO with gadolinium-enhanced MRI offers the opportunity for imaging characterisation of cirrhotic nodules by cellular function as well as by blood supply, and this approach is now proposed as the examination of choice for detecting HCC in cirrhosis. (orig.)

  17. Epidemiology of hepatocellular carcinoma in India.

    Science.gov (United States)

    Acharya, Subrat K

    2014-08-01

    Indian data on epidemiology of HCC is not available. Cancer is not a reportable disease in India and the cancer registries in India are mostly urban. National cancer registry program of the Indian Council of Medical Research (ICMR) has been recently expanded to include 21 population based and 6 hospital based cancer registries. The last published registry data by ICMR available in the cancer registry website (www.ncrpindia.org) was in 2008 which provides information on various cancers from 2006 to 2008. The other source of information was the report published by International Agency for Research on Cancer (WHO). According to these available data the age adjusted incidence rate of hepatocellular carcinoma (HCC) in India for men ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 population per year. The male:female ratio for HCC in India is 4:1. The age of presentation varies from 40 to 70 years. According to a study conducted by verbal autopsy in 1.1 million homes representing the whole country, the age standardized mortality rate for HCC in India for men is 6.8/100,000 and for women is 5.1/100,000. According to another study the incidence of HCC in cirrhotics in India is 1.6% per year. The unpublished data from various tertiary care centers suggest that the incidence of HCC is increasing in India. There is a need for a multi-centric HCC registry under the aegis of INASL.

  18. Dichlorodiphenyltrichloroethane (DDT) and risk of hepatocellular carcinoma

    Science.gov (United States)

    Persson, E. Christina; Graubard, Barry I.; Evans, Alison A.; London, W. Thomas; Weber, Jean-Philippe; LeBlanc, Alain; Chen, Gang; Lin, Wenyao; McGlynn, Katherine A.

    2014-01-01

    Dichlorodiphenyltrichloroethane (p,p’-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p’-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p’-DDE), may also be associated with HCC in humans. To examine whether there is an association between p,p’-DDT and/or p,p’-DDE in a population at high-risk of developing HCC. A nested case-control study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. The current study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p’-DDT and p,p’-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmers) and levels of p,p’-DDT or p,p’-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression, p,p’-DDT and/or p,p’-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Overall, the highest quintile of p,p’-DDT was associated with an increased risk of HCC, OR= 2.96 95% CI; 1.19–7.40. There were no statistically significant associations with p,p’-DDE. Overall, these results suggest that recent exposure to p,p’-DDT may increase risk of HCC. PMID:22290210

  19. Targeting cancer stem cells in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    He AR

    2014-12-01

    Full Text Available Aiwu Ruth He,1 Daniel C Smith,1 Lopa Mishra2 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The poor outcome of patients with hepatocellular carcinoma (HCC is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs. Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with

  20. Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Chi, Kwan-Hwa; Liao, Chao-Sheng; Chang, Chih-Chia; Ko, Hui-Ling; Tsang, Yuk-Wah; Yang, Kuo-Ching; Mehta, Minesh P.

    2010-01-01

    Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial α-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had ≥2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had ≥50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had ≥Grade 2 elevation of liver enzymes, and 15 had ≥Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

  1. Hemodynamic characteristics of early stage hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kudo, Masatoshi; Tomita, Shusuke; Tochio, Hitoshi

    1992-01-01

    Hemodynamic characteristics were studied by using in vivo vascular imaging techniques in 17 resected early stage hepatocellular carcinoma (e-HCC) by comparing them with 49 resected advanced HCCs (ad-HCC) less than 3 cm in diameter. In this study, e-HCC was defined as the nodule being uniformly composed of well-differentiated HCC or adenomatous hyperplastic nodule containing well-differentiated HCC foci within the nodule. In vivo vascular imaging techniques are as follows; US angiography with intraarterial CO 2 microbubbles were performed to assess the tumor arterial vascularity, and CT during arterial portography (CTAP) was performed to assess the portal perfusion within the nodule. Of 17 e-HCC nodules 5 were hypervascular, 5 were isovascular, 4 were hypovascular, and 3 were vascular spot in hypovascular pattern in contrast to 49 ad-HCC nodules, 43 of which were hypervascular and 6 were isovascular. Of 14 e-HCCs, 9 nodules showed perfusion defect and 5 did not on CTAP, whereas all 37 ad-HCCs on which CTAP was performed, showed perfusion defect. Forty-one percent (7/17) of e-HCC showed fatty metamorphosis in contrast to 8% (4/49) of ad-HCC. In conclusion, hemodynamic characteristics of e-HCC are summarized as follows. (1) Arterial tumor neovascularization is relatively low. (2) Portal perfusion is present in some of e-HCC cases. (3) Hypoperfusion state both from arterial and portal supply is present in some of e-HCC cases. (4) Vascular spot in hypovascular pattern is characteristic arterial pattern in AH containing HCC foci. (5) Fatty metamorphosis may be related with hypoperfusion state of the nodule in e-HCC. (author)

  2. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triple-negative breast cancer

    International Nuclear Information System (INIS)

    Kala, Rishabh; Shah, Harsh N.; Martin, Samantha L.; Tollefsbol, Trygve O.

    2015-01-01

    Nutrition is believed to be a primary contributor in regulating gene expression by affecting epigenetic pathways such as DNA methylation and histone modification. Resveratrol and pterostilbene are phytoalexins produced by plants as part of their defense system. These two bioactive compounds when used alone have been shown to alter genetic and epigenetic profiles of tumor cells, but the concentrations employed in various studies often far exceed physiologically achievable doses. Triple-negative breast cancer (TNBC) is an often fatal condition that may be prevented or treated through novel dietary-based approaches. HCC1806 and MDA-MB-157 breast cancer cells were used as TNBC cell lines in this study. MCF10A cells were used as control breast epithelial cells to determine the safety of this dietary regimen. CompuSyn software was used to determine the combination index (CI) for drug combinations. Combinatorial resveratrol and pterostilbene administered at close to physiologically relevant doses resulted in synergistic (CI <1) growth inhibition of TNBCs. SIRT1, a type III histone deacetylase (HDAC), was down-regulated in response to this combinatorial treatment. We further explored the effects of this novel combinatorial approach on DNA damage response by monitoring γ-H2AX and telomerase expression. With combination of these two compounds there was a significant decrease in these two proteins which might further resulted in significant growth inhibition, apoptosis and cell cycle arrest in HCC1806 and MDA-MB-157 breast cancer cells, while there was no significant effect on cellular viability, colony forming potential, morphology or apoptosis in control MCF10A breast epithelial cells. SIRT1 knockdown reproduced the effects of combinatorial resveratrol and pterostilbene-induced SIRT1 down-regulation through inhibition of both telomerase activity and γ-H2AX expression in HCC1806 breast cancer cells. As a part of the repair mechanisms and role of SIRT1 in recruiting DNMTs

  3. P0525 : N-Acetylated alpha smooth muscle actin levels are increased in hepatic fibrosis but decreased in hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Nielsen, M.J.; Nielsen, Signe Holm; Hansen, N.U.B.

    2015-01-01

    Alpha Smooth Muscle Actin (a-SMA) is upregulated together with extracellular matrix (ECM) during activation of Hepatic Stellate Cells (HSCs) in fibrosis. Histone deacetylase (HDAC) remove acetylations and regulate the expression of genes, which is associated with cancers. There is a close...... relationship between cirrhosis and hepatocellular carcinoma (HCC), and markers enabling identification of patients in risk of developing HCC with cirrhosis is a major unmet clinical need. We developed an ELISA for the assessment of acetylated a-SMA (Aca- SMA) in serum. The objective was to investigate...

  4. CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.

    Science.gov (United States)

    Tang, Juan; Guo, Yun-Shan; Yu, Xiao-Ling; Huang, Wan; Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

    2015-10-27

    Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

  5. Involvement of miR-485-5p in hepatocellular carcinoma progression targeting EMMPRIN.

    Science.gov (United States)

    Sun, Xiangjun; Liu, Yonglei; Li, Ming; Wang, Mingchun; Wang, Yutong

    2015-05-01

    EMMPRIN plays important roles in cancer development, which includes EMMPRIN 1, 2, 3, and 4 isoforms. EMMPRIN2 is the main component in human cancers, but its regulation by miRNAs is still unclear. In this study, we will investigate the mechanism of EMMPRIN regulation in hepatocellular carcinoma (HCC) by miRNAs. Through RT-PCR, we found that EMMPRIN2 was the main isoform in HCC cells. EMMPRIN2 was down-regulated significantly by predicted miRNAs and miR-485-5p was one of the miRNA that regulated EMMPRIN in HCC cell lines. It was verified that EMMPRIN was a target gene of miR-485-5p by using luciferase analysis assay. We found that miR-485-5p was significantly downregulated in HCC tissues and that its expression was inversely correlated with the TNM stage and metastasis in HCC samples. Results of cellular functions in HCC showed that miR-485-5p could inhibit cell proliferation and metastasis. Additionally, miR-485-5p overexpression suppressed HCC growth in vivo by down-regulation of EMMPRIN. Our study for the first time demonstrated that miR-485-5p represses HCC invasive and metastatic capacities by targeting EMMPRIN expression. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Quantitative proteome analysis reveals the correlation between endocytosis-associated proteins and hepatocellular carcinoma dedifferentiation.

    Science.gov (United States)

    Naboulsi, Wael; Bracht, Thilo; Megger, Dominik A; Reis, Henning; Ahrens, Maike; Turewicz, Michael; Eisenacher, Martin; Tautges, Stephanie; Canbay, Ali E; Meyer, Helmut E; Weber, Frank; Baba, Hideo A; Sitek, Barbara

    2016-11-01

    The majority of poorly differentiated hepatocellular carcinomas (HCCs) develop from well-differentiated tumors. Endocytosis is a cellular function which is likely to take part in this development due to its important role in regulating the abundances of vital signaling receptors. Here, we aimed to investigate the abundance of endocytosis-associated proteins in HCCs with various differentiation grades. Therefore, we analyzed 36 tissue specimens from HCC patients via LC-MS/MS-based label-free quantitative proteomics including 19 HCC tissue samples with different degrees of histological grades and corresponding non-tumorous tissue controls. As a result, 277 proteins were differentially regulated between well-differentiated tumors and controls. In moderately and poorly differentiated tumors, 278 and 1181 proteins, respectively, were significantly differentially regulated compared to non-tumorous tissue. We explored the regulated proteins based on their functions and identified thirty endocytosis-associated proteins, mostly overexpressed in poorly differentiated tumors. These included proteins that have been shown to be up-regulated in HCC like clathrin heavy chain-1 (CLTC) as well as unknown proteins, such as secretory carrier-associated membrane protein 3 (SCAMP3). The abundances of SCAMP3 and CLTC were immunohistochemically examined in tissue sections of 84 HCC patients. We demonstrate the novel association of several endocytosis-associated proteins, in particular, SCAMP3 with HCC progression. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Updated Vertical Extent of Collision Damage

    DEFF Research Database (Denmark)

    Tagg, R.; Bartzis, P.; Papanikolaou, P.

    2002-01-01

    The probabilistic distribution of the vertical extent of collision damage is an important and somewhat controversial component of the proposed IMO harmonized damage stability regulations for cargo and passenger ships. The only pre-existing vertical distribution, currently used in the international...

  8. Liver resection for non-cirrhotic hepatocellular carcinoma in south ...

    African Journals Online (AJOL)

    Background. We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. Methods. We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur ...

  9. Scintigraphic demonstration of a metastasizing hepato-cellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Heintz, P; Gratz, K F; Schwarzrock, R; Schober, O; Neuhaus, P; Creutzig, H

    1986-01-01

    Adenomas and hepato cellular carcinomas cannot be differentiated by nuclear medicine: both exhibit masked radiodrug trapping at reduced perfusion. Two patients revealed specific accumulation in extrahepatic foci unknown before; hence, the diagnosis of a metastasizing hepatocellular carcinoma had to be verified. One case is demonstrated in full detail. (orig./SHA).

  10. Infection of hepatitis C virus genotypes in hepatocellular carcinoma ...

    African Journals Online (AJOL)

    The aim of this retrospective study was to investigate the infection of hepatitis C virus (HCV) genotypes in hepatocellular carcinoma (HCC) patients from rural areas of Faisalabad region. Among 179 HCC subjects, men and women were 51 and 49%, respectively. All samples positive for HCV RNA by qualitative PCR were ...

  11. Hepatitis viruses and hepatocellular carcinoma | Kew | South African ...

    African Journals Online (AJOL)

    Animal models - other members of the hepadnavirus family (to which HBV belongs) that also cause HCC in their respective animal hosts, and transgenic mice into which sequences of HBV DNA have been inserted - are proving useful in elucidating putative mechanisms of HBV-related hepatocellular carcinogenesis, but no ...

  12. Magnetic Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy

    DEFF Research Database (Denmark)

    Ungureanu, Bogdan Silviu; Teodorescu, Cristian-Mihail; Săftoiu, Adrian

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results...

  13. Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

    NARCIS (Netherlands)

    Fages, Anne; Duarte-Salles, Talita; Stepien, Magdalena; Ferrari, Pietro; Fedirko, Veronika; Pontoizeau, Clement; Trichopoulou, Antonia; Aleksandrova, Krasimira; Tjonneland, Anne; Olsen, Anja; Clavel-Chapelon, Franoise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Kaaks, Rudolf; Kuhn, Tilman; Floegel, Anna; Boeing, Heiner; Lagiou, Pagona; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.; Weiderpass, Elisabete; Agudo, Antonio; Molina-Montes, Esther; Maria Huerta, Jose; Ardanaz, Eva; Dorronsoro, Miren; Sjoberg, Klas; Ohlsson, Bodil; Khaw, Kay-Tee; Wareham, Nick; Travis, Ruth C.; Schmidt, Julie A.; Cross, Amanda; Gunter, Marc; Riboli, Elio; Scalbert, Augustin; Romieu, Isabelle; Elena-Herrmann, Benedicte; Jenab, Mazda

    2015-01-01

    Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is

  14. Cutaneous features seen in primary liver cell (Hepatocellular ...

    African Journals Online (AJOL)

    Primary liver cell carcinoma (PLCC), predominantly hepatocellular carcinoma is a killer. In the southwestern region of Nigeria it occupies the second position, behind prostate cancer in males. Females account for about a third of diagnosed cases. Children are not spared. Over 80 % of PLCC cases present to the hospital at ...

  15. Chemopreventive effect of corosolic acid in human hepatocellular ...

    African Journals Online (AJOL)

    Anticancer effects of corosolic acid have been demonstrated earlier in human cervix adenocarcinoma and osteosarcoma cells, but the exact underlying molecular mechanisms have not been studied. Hence, an attempt was made to identify the anticancer mechanism of corosolic acid in human hepatocellular carcinoma cells ...

  16. Clinical utility of imaging for evaluation of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Murakami T

    2014-07-01

    Full Text Available Takamichi Murakami,1 Masakatsu Tsurusaki,1 Tomoko Hyodo,1 Yasuharu Imai2 1Department of Radiology, Kinki University Faculty of Medicine, 2Department of Hepatology and Gastroenterology, Ikeda Municipal Hospital, Osaka, Japan Abstract: The hemodynamics of a hepatocellular nodule is the most important imaging parameter used to characterize various hepatocellular nodules in liver cirrhosis, because sequential changes occur in the feeding vessels and hemodynamic status during hepatocarcinogenesis. Therefore, the imaging criteria for hepatocellular carcinoma (HCC are also usually based on vascular findings, eg, early arterial uptake followed by washout in the portal venous and equilibrium phases. Contrast-enhanced ultrasonography, dynamic multidetector-row computed tomography (MDCT, and dynamic magnetic resonance (MR imaging with gadopentetate dimeglumine (Gd-DTPA are useful for detecting hypervascular HCC on the basis of vascular criteria but are not as useful for hypovascular HCC. Contrast-enhanced MR imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA, a hepatocyte-specific MR contrast agent, is superior to dynamic MDCT and dynamic MR imaging with Gd-DTPA in detecting both hypervascular and hypovascular HCC. Moreover, Gd-EOB-DTPA-enhanced MR imaging can display each histologically differentiated HCC as hypointense relative to the liver parenchyma. 18F-fluorodeoxyglucose positron emission tomography imaging might not be suitable for the screening and detection of HCC, given its lower diagnostic performance. However, this technique plays an important role in determining whether HCC has spread beyond the liver. Keywords: hepatocellular carcinoma, evaluation, imaging, clinical utility

  17. Chronic hepatitis C presenting with a diagnosis of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Hallager, Sofie; Weis, Nina

    2014-01-01

    Chronic hepatitis C (CHC) affects around 16,000 individuals in Denmark of whom about 50% are diagnosed. In the presence of CHC and cirrhosis the annual risk of hepatocellular carcinoma (HCC) is 1-5%. We report on two patients who presented with disseminated HCC at the time of CHC diagnosis...

  18. Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity.

    Science.gov (United States)

    Zhu, Xiaosan; Dai, Yichen; Chen, Zhangxin; Xie, Junpei; Zeng, Wei; Lin, Yuanyuan

    2013-01-01

    Overexpression of Pokemon, which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including hepatocellular carcinoma (HCC). Pokemon is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of Pokemon knockdown on the regulation of HCC growth. POK shRNA suppressed the expression of Pokemon protein in HepG2 cells compared to the negative control vector-transfected HCC cells. Pokemon knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. AKT activation and the expression of various cell cycle-related genes were inhibited following Pokemon knockdown. These data demonstrate that Pokemon may play a role in HCC progression, suggesting that inhibition of Pokemon expression using Pokemon shRNA should be further evaluated as a novel target for the control of HCC.

  19. Non-coding RNAs: New therapeutic targets and opportunities for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yu Cuiyun

    2016-02-01

    Full Text Available Non-coding RNAs (ncRNA are RNA molecules without protein coding functions owing to the lack of an open reading frame (ORF. Based on the length, ncRNAs can be divided into long and short ncRNAs; short ncRNAs include miRNAs and piRNAs. Hepatocellular carcinoma (HCC is among the most frequent forms of cancer worldwide and its incidence is increasing rapidly. Studies have found that ncRNAs are likely to play a crucial role in a variety of biological processes including the pathogenesis and progression of HCC. In this review, we summarized the regulation mechanism and biological functions of ncRNAs in HCC with respect to its application in HCC diagnosis, therapy and prognosis.

  20. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells.

    Science.gov (United States)

    Bai, Tao; Wang, Shuai; Zhao, Yipu; Zhu, Rongtao; Wang, Weijie; Sun, Yuling

    2017-09-30

    Ferroptosis is a novel form of cell death, which is characterized by accumulation of reactive oxygen species (ROS). Sigma 1 receptor (S1R) has been suggested to function in oxidative stress metabolism. Both erastin and sorafenib significantly induced S1R protein expression. Haloperidol strongly promoted erastin- and sorafenib-induced cell death, which was blocked by ferrostatin-1 but not ZVAD-FMK or necrosulfonamide. During ferroptosis, haloperidol substantially increased the cellular levels of Fe 2+ , GSH and lipid peroxidation. Furthermore, several ferroptosis-related protein targets were up-regulated in the absence of haloperidol. Thus, Our study identified an association between haloperidol and ferroptosis for the first time. Our analyses of a combination of drugs may provide a novel strategy of hepatocellular carcinoma (HCC) therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Natural resource damage assessments: The second generation

    International Nuclear Information System (INIS)

    Luthi, R.; Burlington, L.; Reinharz, E.; Shutler, S.

    1993-01-01

    The Damage Assessment Regulations Team (DART), Office of General Counsel, National Oceanic and Atmospheric Administration (NOAA), has focused on developing natural resource damage assessment regulations for oil pollution in navigable waters. These procedures may lower the transaction costs of assessments, encourage joint cooperative assessments, simplify most assessments and provide technical guidance for conducting assessments. DART is developing regulations for the assessment of damages due to injuries related to oil spills under the Oil pollution Act of 1990. These regulations will involve coordination, restoration and economic valuation. NOAA encourages federal, state, tribal and foreign trustees, to develop prespill plans. Coordination with response agencies assures protection of important natural resources. The regulations provide an open record, which becomes the basis for judicial review. Various methods being developed to assess damages for injuries to natural resources include: compensation formulas for spills under 50,000 gallons of oil, the Type A model, expedited damage assessment (EDA) procedures, and comprehensive damage assessment (CDA) procedures which can be used for spills of various sizes. These procedures provide trustees with a choice for assessing natural resource damages to each oil spill. NOAA is emphasizing the importance of restoration. Restoration plans will define project goals and objectives, establish procedures and methods for site restoration, and define the approach based on sound science. Finally, numerous economic methods are identified to calculate the lost or diminished use as passive use of the affected resources

  2. Autophagy in DNA Damage Response

    Directory of Open Access Journals (Sweden)

    Piotr Czarny

    2015-01-01

    Full Text Available DNA damage response (DDR involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, although it is suggested that it involves the inhibition of mammalian target of rapamycin complex 1 (mTORC1. mTORC1 represses autophagy via phosphorylation of the ULK1/2–Atg13–FIP200 complex thus preventing maturation of pre-autophagosomal structures. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly(ADPribose polymerase 1 (PARP-1, Mre11–Rad50–Nbs1 (MRN complex or FOXO3, which activate repressors of mTORC1. SQSTM1/p62 is one of the proteins whose levels are regulated via autophagic degradation. Inhibition of autophagy by knockout of FIP200 results in upregulation of SQSTM1/p62, enhanced DNA damage and less efficient damage repair. Mitophagy, one form of autophagy involved in the selective degradation of mitochondria, may also play role in DDR. It degrades abnormal mitochondria and can either repress or activate apoptosis, but the exact mechanism remains unknown. There is a need to clarify the role of autophagy in DDR, as this process may possess several important biomedical applications, involving also cancer therapy.

  3. Specific diagnosis of hepatocellular carcinoma by delayed hepatobiliary imaging

    International Nuclear Information System (INIS)

    Hasegawa, Y.; Nakano, S.; Ibuka, K.

    1986-01-01

    For assessment of the value of delayed hepatobiliary imaging with technetium 99m (/sup 99m/Tc)-(Sn)-N-pyridoxyl-5-methyltryptophan (/sup 99m/Tc-PMT) for specific diagnosis of hepatocellular carcinoma, 88 patients with various malignant and benign liver diseases (49 with hepatocellular carcinoma, 4 with cholangiocellular carcinoma, 10 with metastatic liver carcinoma, 2 with liver cysts, 2 with liver hemangioma, 1 with liver abscess, 2 with intrahepatic lithiasis, 12 with liver cirrhosis, and 6 with chronic hepatitis) were studied. In 20 (41%) of the 49 patients with hepatocellular carcinoma, greater uptake of /sup 99m/Tc-PMT by the tumor than by the surrounding liver tissue was seen in delayed hepatobiliary images, whereas in eight patients (16%), equilibrated uptake was seen. No increased uptake of the radioisotope by hepatic lesions was seen in 21 patients with localized liver diseases other than hepatoma. Moreover, in 18 patients with diffuse liver diseases, no focal accumulation of the radioisotope was seen in delayed /sup 99m/Tc-PMT images. In addition, of 28 patients with hepatocellular carcinoma in whom the serum alpha-fetoprotein level showed little or no increase, 12 showed increased uptake of /sup 99m/Tc-PMT by the tumor. In assessing delayed /sup 99m/Tc-PMT images, however, it was necessary to consider following complications: accumulation of tracer in obstructed and dilated biliary trees; retention of radioactivity in nonneoplastic liver tissues; difficulties in evaluating /sup 99m/Tc-PMT uptake by small hepatic tumors; overlapping of radioactivity in the gut and gallbladder in delayed /sup 99m/Tc-PMT images of tumors. This study indicates that delayed /sup 99m/Tc-PMT images can be useful in the diagnosis of hepatocellular carcinoma

  4. Screening for hepatocellular carcinoma by Egyptian physicians

    Institute of Scientific and Technical Information of China (English)

    Sahar; M; Hassany; Ehab; F; Abdou; Moustafa; Mohamed; El; Taher; Afaf; Adel; Abdeltwab; Hubert; E; Blum

    2015-01-01

    AIM: To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma(HCC). METHODS: The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts:(1) personal information regarding the physician(name, age, specialty and type of health care setting); and(2) professional experience in the care of patients at risk for HCC development(screening, knowledge about the cause and natural course of liver diseases and HCC risk). RESULTS: Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus(HCV) genotype as risk factor for HCC development(P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis(P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health(MOH) doctors consider HCV infection as the leading cause of HCC in Egypt(P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening(P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo(P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation.CONCLUSION: In Egypt, physicians

  5. Hepatic protection and anticancer activity of curcuma: a potential chemopreventive strategy against hepatocellular carcinoma.

    Science.gov (United States)

    Li, Yan; Shi, Xue; Zhang, Jingwen; Zhang, Xiang; Martin, Robert C G

    2014-02-01

    Malignant transformation of hepatocellular carcinoma (HCC) occurs through repetitive liver injury in a context of inflammation and oxidative DNA damage. A spectrum of natural sesquiterpenoids from curcuma oil has displayed antioxidant, anti-inflammatory and anti-carcinogenic properties. The aim of the study was to investigate the hepatoprotective and anti-HCC effects of curcuma oil in vivo and in vitro. Mice were pretreated with curcuma oil (100 mg/kg) for 3 days, then treated with Concanavalin A (30 mg/kg). The hepatic tissue was evaluated for histology, CD4+ cell, interferon-γ, apoptosis, lipid peroxidation, 8-hydroxy-deoxyguanosine and MnSOD. C57L/J mice were treated with curcuma oil and 107 Hepa1-6 cells directly inoculated into liver lobes. The effects of curcuma oil on cell growth and cell death were evaluated. In addition, MnSOD, HSP60, catalase, NF-κB and caspase-3 were also investigated in the Hepa1-6 cells treated with curcuma oil. Pretreatment with curcuma oil significantly attenuates inflammation and oxidative damage by Concanavalin A. Treatment with curcuma oil can decrease the incidence of HCC. Curcuma oil inhibits cell growth and induces cell death in Hepa1-6 cells. Curcuma protected mice with hepatic injury from inflammatory and oxidative stress. Curcuma oil can inhibit hepatoma cell growth in vivo and in vitro.

  6. Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression

    Energy Technology Data Exchange (ETDEWEB)

    Gonsebatt, M.E. [UNAM, Ciudad Universitaria, Dept. Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Mexico (Mexico); Razo, L.M. del; Sanchez-Pena, L.C. [Seccion de Toxicologia, CINVESTAV, Mexico (Mexico); Cerbon, M.A. [Facultad de Quimica, UNAM, Departamento de Biologia, Mexico (Mexico); Zuniga, O.; Ramirez, P. [Facultad de Estudios Superiores Cuautitlan, UNAM, Laboratorio de Toxicologia Celular, Coordinacion General de Estudios de Posgrado e Investigacion, Cuautitlan Izcalli, Estado de Mexico (Mexico)

    2007-09-15

    Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 {mu}M of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function. (orig.)

  7. Lipid droplet-associated proteins in alcoholic liver disease: a potential linkage with hepatocellular damage

    OpenAIRE

    Ikura, Yoshihiro; Caldwell, Stephen H

    2015-01-01

    Steatosis is a characteristic morphological change of alcoholic liver disease, but its pathologic significance is still obscure. Regardless of cell types, intracellular lipid droplets are coated with a phospholipid monolayer, on which many kinds of lipid droplet-associated proteins are present. These proteins, such as the perilipin family of proteins and the cell death inducing DNA fragmentation factor (DFF) 45-like effectors, are recognized to play important roles in lipid metabolism in the ...

  8. Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

    Directory of Open Access Journals (Sweden)

    Franziska Paech

    2017-06-01

    Full Text Available Tyrosine kinase inhibitors (TKIs are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis, all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism, imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib, and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.

  9. ADAM10/17-Dependent Release of Soluble c-Met Correlates with Hepatocellular Damage

    Czech Academy of Sciences Publication Activity Database

    Chalupský, Karel; Kanchev, Ivan; Žbodáková, Olga; Buryová, Halka; Jiroušková, Markéta; Kořínek, Vladimír; Gregor, Martin; Sedláček, Radislav

    2013-01-01

    Roč. 59, č. 2 (2013), s. 76-78 ISSN 0015-5500 R&D Projects: GA ČR GAP305/10/2143; GA ČR GAP303/10/2044; GA AV ČR IAA500520812 Institutional support: RVO:68378050 Keywords : c-Met * HGF * shedding * ADAM metalloproteinase * liver Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.778, year: 2013

  10. The second generation of natural resource damage assessments: Lessons learned?

    International Nuclear Information System (INIS)

    Luthi, R.B.; Burlington, L.B.; Reinharz, E.; Shutler, S.K.

    1993-01-01

    The Damage Assessment Regulations Team (DART), under the Office of General Counsel of the National Oceanic and Atmospheric Administration (NOAA), has centered its efforts on developing natural resource damage assessment regulations for oil pollution in navigable waters. These procedures will likely lower the costs associated with damage assessments, encourage joint cooperative assessments and simplify most assessments. The DART team of NOAA is developing new regulations for the assessment of damages due to injuries related to oil spills under the Oil Pollution Act of 1990. These regulations will involve coordination, restoration, and economic valuation. Various methods are currently being developed to assess damages for injuries to natural resources. The proposed means include: compensation tables for spills under 50,000 gallons, Type A model, expedited damage assessment (EDA) procedures, and comprehensive procedures. They are being developed to provide trustees with a choice for assessing natural resource damages for each oil spill

  11. A control study of TACE using high-dosed and routine-dosed iodized oil as a treatment of large hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Zhou Junmin; Zhan Jincheng; Zhang Zhenming

    2005-01-01

    Objective: To investigate the side effects and curative effect in high-dosed lipiodol-transcatheter arterial chemoembolization as a treatment of large hepatocellular carcinoma. Methods: 79 patients with unresectable hepatocellular carcinoma were treated by TACE, and divided into 2 groups. In group A, 39 patients with the tumor sized 7-18cm in diameter, routine-dosed, 10-20ml lipiodol was given in TACE. 40 patients were enrolled in the high-dosed group B, who were given more than 20ml iodized oil in TACE. Results: The First to third year survival rate of group A was 66.7%, 33.3%, 0% respectively,while in group B it was 75%, 45%, 7.5% respectively. The effective rate was 71.7% in Group A and 87.5% in Group B. There was a significant difference between both groups. There was no significant difference of critical side effects and liver function damage between group A and B. Conclusion: High-dosed lipiodol chemoembolization as a treatment of unresectable hepatocellular carcinoma is superior to the routine TACE, especially when the tumor is large and the liver function reserve is good. (authors)

  12. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

    Science.gov (United States)

    Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

    2013-12-01

    Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of

  13. SERUM LEPTIN LEVENS AND HEPATOCELLULAR CARCINOMA: REVIEW ARTICLE.

    Science.gov (United States)

    Andrighetto, Luiza Vitelo; Poziomyck, Aline Kirjner

    2016-01-01

    Hepatocellular carcinoma is one of the most frequent types of malignant tumors in the world. There is growing evidence of the relationship between it development and obesity. The mechanism that links obesity to cancer is still not fully understood; however, it is essential to the understanding the adipose tissue in metabolic changes related to obesity and hepatocellular carcinoma. To review the influence of serum leptin levels in patients with hepatocelular carcinoma. Systematic review of the literature based on the methodology of the Cochrane Institute. The search for articles was in the database: Science Direct, Scielo, Medline, Lilacs e Pubmed. The key words used were hepatocellular carcinoma, leptin, adipokine. After evaluation of individual studies, were selected seven studies. The results previously studied are still inconsistent and contradictory, and leptin can be effectively involved in the occurrence and development of hepatocellular carcinoma. Therefore, it is necessary to develop prospective, well-designed and conducted focusing on the role and specific mechanisms of this hormone in patients with hepatocellular carcinoma, so that new correlations can be properly supported. O carcinoma hepatocelular é um dos tipos mais frequentes de tumores malignos no mundo. Há crescentes evidências da relação entre o seu desenvolvimento e a obesidade. O mecanismo que os relaciona ainda não é completamente entendido. Entretanto é essencial a compreensão do tecido adiposo nas alterações metabólicas relacionadas à obesidade e ao câncer. Revisar a influência dos níveis séricos de leptina em pacientes com carcinoma hepatocelular. Trata-se de revisão bibliográfica baseada na metodologia do Instituto Cochrane; a busca de dados foi realizada na base de dados Science Direct, Scielo, Medline, Lilacs e Pubmed, empregando as seguintes descritores: hepatocellular carcinoma, leptin, adipokine. Após avaliação individual dos artigos selecionaram-se sete estudos

  14. Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion.

    Science.gov (United States)

    Ng, Lui; Tung-Ping Poon, Ronnie; Yau, Simon; Chow, Ariel; Lam, Colin; Li, Hung-Sing; Chung-Cheung Yau, Thomas; Law, Wai-Lun; Pang, Roberta

    2013-08-01

    Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelial-mesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, β-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs. Copyright © 2013 by the

  15. Quantitative Proteomics Reveals the Regulatory Networks of Circular RNA CDR1as in Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Yang, Xue; Xiong, Qian; Wu, Ying; Li, Siting; Ge, Feng

    2017-10-06

    Circular RNAs (circRNAs), a class of widespread endogenous RNAs, play crucial roles in diverse biological processes and are potential biomarkers in diverse human diseases and cancers. Cerebellar-degeneration-related protein 1 antisense RNA (CDR1as), an oncogenic circRNA, is involved in human tumorigenesis and is dysregulated in hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CDR1as functions in HCC remain unclear. Here we explored the functions of CDR1as and searched for CDR1as-regulated proteins in HCC cells. A quantitative proteomics strategy was employed to globally identify CDR1as-regulated proteins in HCC cells. In total, we identified 330 differentially expressed proteins (DEPs) upon enhanced CDR1as expression in HepG2 cells, indicating that they could be proteins regulated by CDR1as. Bioinformatic analysis revealed that many DEPs were involved in cell proliferation and the cell cycle. Further functional studies of epidermal growth factor receptor (EGFR) found that CDR1as exerts its effects on cell proliferation at least in part through the regulation of EGFR expression. We further confirmed that CDR1as could inhibit the expression of microRNA-7 (miR-7). EGFR is a validated target of miR-7; therefore, CDR1as may exert its function by regulating EGFR expression via targeting miR-7 in HCC cells. Taken together, we revealed novel functions and underlying mechanisms of CDR1as in HCC cells. This study serves as the first proteome-wide analysis of a circRNA-regulated protein in cells and provides a reliable and highly efficient method for globally identifying circRNA-regulated proteins.

  16. Clinical and laboratory features of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Andrés Cárdenas

    2007-02-01

    Full Text Available

    The clinical presentation of hepatocellular carcinoma (HCC differs between patients in developing countries (African and Chinese populations from those in industrialized countries. In industrialized countries, HCC co-exists with symptomatic cirrhosis in 80% of cases and clinical manifestations are usually related to those of the underlying disease. On the other hand, patients from developing countries have HCC and cirrhosis in approximately 40% of cases. Underlying cirrhosis in many cases is not advanced and does not produce any symptoms or associated symptoms are masked by those of the tumor (right upper quadrant pain, mass in the upper abdomen, weight loss and weakness. In a subset of patients, there are no clinical manifestations as HCC may occur in the context of hepatitis B infection without cirrhosis.

    Clinical Manifestations

    In Western countries, nearly 35% percent of patients with HCC are asymptomatic. Some of the most common clinical manifestations include: abdominal pain (53-58% of patients, especially in epigastrium or right upper quadrant, abdominal mass (30%, weight loss, malaise, anorexia, cachexia, jaundice or fever.

    Physical Exam

    Physical findings vary with the stage of disease. The patient may exhibit slight or moderate wasting when first seen. In patients with cirrhosis, typical stigmata of chronic liver disease may be present. In advanced stages of HCC the liver may be enlarged and there is significant tenderness. An arterial bruit may be heard over the liver

  17. The evaluation of p,p′-DDT exposure on cell adhesion of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Jin, Xiaoting; Chen, Meilan; Song, Li; Li, Hanqing; Li, Zhuoyu

    2014-01-01

    Graphical abstract: - Highlights: • Low doses p,p′-DDT exposure disrupts cell–cell adhesion and cell–matrix adhesion in HepG2 cells. • Both oxidative stress and JAK/STAT3 pathway are activated in p,p′-DDT-treated HepG2 cells. • The stimulation of JAK/STAT3 pathway is mediated by oxidative stress. • p,p′-DDT regulates adhesion molecules via the JAK/STAT3 pathway. • p,p′-DDT stimulates JAK/STAT3 signal pathway and disrupts the expressions of cell adhesion molecules in nude mice models. - Abstract: Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p′-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p′-DDT, exposing HepG2 cells for 6 days, decreased cell–cell adhesion and elevated cell–matrix adhesion. Strikingly, p,p′-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p′-DDT-induced effects. p,p′-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p′-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p′-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p′-DDT profoundly promotes the adhesion process by decreasing cell–cell adhesion and inducing cell

  18. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis

    International Nuclear Information System (INIS)

    Srisuttee, Ratakorn; Koh, Sang Seok; Malilas, Waraporn; Moon, Jeong; Cho, Il-Rae; Jhun, Byung Hak; Horio, Yoshiyuki; Chung, Young-Hwa

    2012-01-01

    Highlights: ► Up-regulation of SIRT1 protein and activity sensitizes Hep3B-HBX cells to oxidative stress-induced apoptosis. ► Nuclear localization of SIRT1 is not required for oxidation-induced apoptosis. ► Ectopic expression and enhanced activity of SIRT1 attenuate JNK phosphorylation. ► Inhibition of SIRT1 activity restores resistance to oxidation-induced apoptosis through JNK activation. -- Abstract: We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of β-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

  19. 7 CFR 160.78 - Loss or damage of standards.

    Science.gov (United States)

    2010-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) NAVAL STORES REGULATIONS AND.... The cost of making necessary repairs to any duplicates, or of replacing those damaged beyond repair...

  20. Diagnostic imaging and interventional radiology of hepatocellular carcinoma: A multicenter study on 290 cases

    International Nuclear Information System (INIS)

    Dalla Palma, Ludovico; Puzzi Mucelli, Roberto; Sponza, Massimo; De Santis, Mario; Gandini, Giovanni; Matricardi, Luigi; Rossi, Cristina

    1997-01-01

    The authors report of a multicenter study on the diagnosis and interventional therapy of hepatocellular carcinoma (HCC).The first aim -diagnostic - was to evaluate the sensitivity of 4 imaging techniques, namely ultrasonography (US), Computed Tomography (CT), digital arteriography (DSA) and Lipiodol CT (LCT), in hepatocellular carcinoma detection. The accuracy of these techniques was also investigated in tumor staging, which is important for treatment planning.The second aim - treatment - consisted in assessing the therapeutic efficacy of intraarterial chemoembolization (CEAT) versus percutaneous ethanol injection (PEI) in non advanced hepatocellular carcinoma and of intraarterial chemoembolization versus no treatment (NT) in advanced hepatocellular carcinoma. Treatment efficacy was evaluated with the following randomized protocols

  1. Nucleotide sequence, organization and expression of rdgA and rdgB genes that regulate pectin lyase production in the plant pathogenic bacterium Erwinia carotovora subsp. carotovora in response to DNA-damaging agents.

    Science.gov (United States)

    Liu, Y; Chatterjee, A; Chatterjee, A K

    1994-12-01

    In most soft-rotting Erwinia spp., including E. carotovora subsp. carotovora strain 71 (Ecc71), production of the plant cell wall degrading enzyme pectin lyase (Pnl) is activated by DNA-damaging agents such as mitomycin C (MC). Induction of Pnl production in Ecc71 requires a functional recA gene and the rdg locus. DNA sequencing and RNA analyses revealed that the rdg locus contains two regulatory genes, rdgA and rdgB, in separate transcriptional units. There is high homology between RdgA and repressors of lambdoid phages, specially phi 80. RdgB, however, has significant homology with transcriptional activators of Mu phage. Both RdgA and RdgB are also predicted to possess helix-turn-helix motifs. By replacing the rdgB promoter with the IPTG-inducible tac promoter, we have determined that rdgB by itself can activate Pnl production in Escherichia coli. However, deletion analysis of rdg+ DNA indicated that, when driven by their native promoters, functions of both rdgA and rdgB are required for the induction of pnlA expression by MC treatment. While rdgB transcription occurs only after MC treatment, a substantial level of rdgA mRNA is detected in the absence of MC treatment. Moreover, upon induction with MC, a new rdgA mRNA species, initiated from a different start site, is produced at a high level. Thus, the two closely linked rdgA and rdgB genes, required for the regulation of Pnl production, are expressed differently in Ecc71.

  2. 7 CFR 51.1911 - Damaged.

    Science.gov (United States)

    2010-01-01

    ... Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE REGULATIONS AND STANDARDS UNDER THE AGRICULTURAL MARKETING ACT OF 1946... the fruit. Such scars damage the tomato when they are rough or deep, or when channels extend into the...

  3. Damage analysis: damage function development and application

    International Nuclear Information System (INIS)

    Simons, R.L.; Odette, G.R.

    1975-01-01

    The derivation and application of damage functions, including recent developments for the U.S. LMFBR and CTR programs, is reviewed. A primary application of damage functions is in predicting component life expectancies; i.e., the fluence required in a service spectrum to attain a specified design property change. An important part of the analysis is the estimation of the uncertainty in such fluence limit predictions. The status of standardizing the procedures for the derivation and application of damage functions is discussed. Improvements in several areas of damage function development are needed before standardization can be completed. These include increasing the quantity and quality of the data used in the analysis, determining the limitations of the analysis due to the presence of multiple damage mechanisms, and finally, testing of damage function predictions against data obtained from material surveillance programs in operating thermal and fast reactors. 23 references. (auth)

  4. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances

    Science.gov (United States)

    Dhanasekaran, Renumathy; Bandoh, Salome; Roberts, Lewis R.

    2016-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development. PMID:27239288

  5. CTP synthase forms the cytoophidium in human hepatocellular carcinoma.

    Science.gov (United States)

    Chang, Chia-Chun; Jeng, Yung-Ming; Peng, Min; Keppeke, Gerson Dierley; Sung, Li-Ying; Liu, Ji-Long

    2017-12-15

    CTP synthase (CTPS) can aggregate into an intracellular macrostructure, the cytoophidium, in various organisms including human cells. Previous studies have shown that assembly of human CTPS cytoophidia may be correlated with the cellular metabolic status, and is able to promote the activity of CTPS. A correlation between the cytoophidium and cancer metabolism has been proposed but not yet been revealed. In the current study we provide clear evidence of the presence of CTPS cytoophidia in various human cancers and some non-cancerous tissues. Moreover, among 203 tissue samples of hepatocellular carcinoma, 56 (28%) samples exhibited many cytoophidia, whereas no cytoophidia were detected in adjacent non-cancerous hepatocytes for all samples. Our findings suggest that the CTPS cytoophidium may participate in the adaptive metabolism of human hepatocellular carcinoma. Copyright © 2017. Published by Elsevier Inc.

  6. Hepatocellular carcinoma: Implications for Asia-Pacific Oncology Nurses

    Directory of Open Access Journals (Sweden)

    Deborah A Boyle

    2017-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a prominent malignancy in the Asia-Pacific region. Despite considerable knowledge about it's scope and nature this malignancy remains incurable. This manuscript reviews the epidemiology of this cancer, its pathogenesis, risk factors, potential prevention, surveillance, treatment, and the oncology nurses' role relative to this malignancy. A literature search from the past decade was performed using the PubMed and CINAHL databases using the search terms “hepatocellular carcinoma,” “Asia,” and “nursing issues”. Themes such as etiology, prevention, treatment, and prognosis were included in this synthesis which has particular relevance to oncology nurses within the Asia-Pacific region.

  7. Serological diagnosis of hepatocellular carcinoma: challenges and opportunities

    Directory of Open Access Journals (Sweden)

    LU Fengmin

    2017-07-01

    Full Text Available Serological markers have the features of noninvasiveness and simple operation and thus have become a research hotspot in the diagnosis of hepatocellular carcinoma. This article briefly introduces the role of the conventional serological marker alpha-fetoprotein (AFP in assisting the diagnosis and predicting the prognosis of HBV-related liver cancer, as well as the clinical value of new markers such as alpha-fetoprotein-L3 and abnormal prothrombin/des-γ-carboxy prothrombin. Based on literature review, the possibility of serum Golgi protein 73 used for laboratory auxiliary diagnosis of hepatocellular carcinoma has been denied. The results of the author′s experiment suggest that serum GP73 measurement can be used as a laboratory diagnostic index for progressive liver fibrosis and liver cirrhosis.

  8. Efficacy of intrahepatic absolute alcohol in unrespectable hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Farooqi, J.I.; Hameed, K.; Khan, I.U.; Shah, S.

    2001-01-01

    To determine efficacy of intrahepatic absolute alcohol injection in researchable hepatocellular carcinoma. A randomized, controlled, experimental and interventional clinical trial. Gastroenterology Department, PGMI, Hayatabad Medical Complex, Peshawar during the period from June, 1998 to June, 2000. Thirty patients were treated by percutaneous, intrahepatic absolute alcohol injection sin repeated sessions, 33 patients were not given or treated with alcohol to serve as control. Both the groups were comparable for age, sex and other baseline characteristics. Absolute alcohol therapy significantly improved quality of life of patients, reduced the tumor size and mortality as well as showed significantly better results regarding survival (P< 0.05) than the patients of control group. We conclude that absolute alcohol is a beneficial and safe palliative treatment measure in advanced hepatocellular carcinoma (HCC). (author)

  9. Case report combined hepatocellular and cholangiocarcinoma with sarcomatous transformation.

    Science.gov (United States)

    Boonsakan, Paisarn; Thangnapakorn, Orathai; Tapaneeyakorn, Jiemjit; Kositchaiwat, Sawit; Bunyaratvej, Sukhum

    2007-03-01

    Combined hepatocellular and cholangiocarcinoma with sarcomatous transformation was first recognized in Ramathibodi Hospital in 2005. This variant of carcinoma has been increasingly reported particularly from Asian countries. Dedifferentiation of the epithelial component to various sarcomatous components is likely the underlying mechanism. The causative factors of hepatocarcinogenesis in Thailand include chronic viral hepatitis B or C, exposures to aflatoxin B1 and nitrosamine(s) and occasionally some certain nodular hepatocellular lesions due to arterial hyperperfusion. It is suggested that the recent change of the Thai peoples' life style to an increased consumption of fast foods containing food preservatives especially nitrate or nitrite, the nitrosamine precursor may allow heavy exposure(s) to the chemical carcinogen(s) i.e. nitrosamine(s) leading to sarcomatous transformation of the carcinoma.

  10. Cerebrovascular accidents associated with sorafenib in hepatocellular carcinoma.

    Science.gov (United States)

    Saif, Muhammad W; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered.

  11. Simple Sugar Intake and Hepatocellular Carcinoma: Epidemiological and Mechanistic Insight

    Directory of Open Access Journals (Sweden)

    Juan Carlos Laguna

    2014-12-01

    Full Text Available Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved.

  12. Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Chaohui, E-mail: zuochaohui@vip.sina.com [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Qiu, Xiaoxin [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Liu, Nianli; Yang, Darong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Xia, Man [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Liu, Jingshi [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Wang, Xiaohong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); and others

    2015-05-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.

  13. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Granito A

    2015-04-01

    Full Text Available Alessandro Granito,1 Elena Guidetti,1 Laura Gramantieri2,3 1Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy; 2Dipartimento dell'Apparato Digerente, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3Centro di Ricerca Biomedica Applicata (CRBA, Azienda Ospedaliero-Universitaria Policlinico S Orsola-Malpighi e Università di Bologna, Bologna, Italy Abstract: c-MET is the membrane receptor for hepatocyte growth factor (HGF, also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC. In particular, c-MET amplification is a rare event, accounting for 4%–5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC. Keywords: hepatocellular carcinoma, c-MET, clinical trials

  14. Hepatitis B virus X promotes hepatocellular carcinoma development via nuclear protein 1 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Bak, Yesol; Shin, Hye-jun; Bak, In seon [Disease Model Research Laboratory, Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon (Korea, Republic of); Yoon, Do-young [Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul (Korea, Republic of); Yu, Dae-Yeul, E-mail: dyyu10@kribb.re.kr [Disease Model Research Laboratory, Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon (Korea, Republic of)

    2015-10-30

    Hepatocellular carcinoma (HCC) is one of the most common malignancies and chronic hepatitis B virus (HBV) infection is a major risk factor for HCC. Hepatitis B virus X (HBx) protein relates to trigger oncogenesis. HBx has oncogenic properties with a hyperproliferative response to HCC. Nuclear protein 1 (NUPR1) is a stress-response protein, frequently upregulated in several cancers. Recent data revealed that NUPR1 is involved in tumor progression, but its function in HCC is not revealed yet. Here we report HBx can induce NUPR1 in patients, mice, and HCC cell lines. In an HBx transgenic mouse model, we found that HBx overexpression upregulates NUPR1 expression consistently with tumor progression. Further, in cultured HBV positive cells, HBx knockdown induces downregulation of NUPR1. Smad4 is a representative transcription factor, regulated by HBx, and we showed that HBx upregulates NUPR1 by Smad4 dependent way. We found that NUPR1 can inhibit cell death and induce vasculogenic mimicry in HCC cell lines. Moreover, NUPR1 silencing in HepG2-HBx showed reduced cell motility. These results suggest that HBx can modulate NUPR1 expression through the Smad4 pathway and NUPR1 has a role in hepatocellular carcinoma progression. - Highlights: • NUPR1 is overexpressed in HBx transgenic mouse and HCC patients. • NUPR1 inactivation hampers the HBx induced growth, VM formation, and migration of HepG2 cells in vitro. • NUPR1 has a role for survival of HCC and mechanistically NUPR1 is activated by HBx-Smad4 axis.

  15. Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Wu M

    2018-05-01

    Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

  16. Bioinformatics functional analysis of let-7a, miR-34a, and miR-199a/b reveals novel insights into immune system pathways and cancer hallmarks for hepatocellular carcinoma.

    Science.gov (United States)

    Soliman, Bangly; Salem, Ahmed; Ghazy, Mohamed; Abu-Shahba, Nourhan; El Hefnawi, Mahmoud

    2018-05-01

    Let-7a, miR-34a, and miR-199 a/b have gained a great attention as master regulators for cellular processes. In particular, these three micro-RNAs act as potential onco-suppressors for hepatocellular carcinoma. Bioinformatics can reveal the functionality of these micro-RNAs through target prediction and functional annotation analysis. In the current study, in silico analysis using innovative servers (miRror Suite, DAVID, miRGator V3.0, GeneTrail) has demonstrated the combinatorial and the individual target genes of these micro-RNAs and further explored their roles in hepatocellular carcinoma progression. There were 87 common target messenger RNAs (p ≤ 0.05) that were predicted to be regulated by the three micro-RNAs using miRror 2.0 target prediction tool. In addition, the functional enrichment analysis of these targets that was performed by DAVID functional annotation and REACTOME tools revealed two major immune-related pathways, eight hepatocellular carcinoma hallmarks-linked pathways, and two pathways that mediate interconnected processes between immune system and hepatocellular carcinoma hallmarks. Moreover, protein-protein interaction network for the predicted common targets was obtained by using STRING database. The individual analysis of target genes and pathways for the three micro-RNAs of interest using miRGator V3.0 and GeneTrail servers revealed some novel predicted target oncogenes such as SOX4, which we validated experimentally, in addition to some regulated pathways of immune system and hepatocarcinogenesis such as insulin signaling pathway and adipocytokine signaling pathway. In general, our results demonstrate that let-7a, miR-34a, and miR-199 a/b have novel interactions in different immune system pathways and major hepatocellular carcinoma hallmarks. Thus, our findings shed more light on the roles of these miRNAs as cancer silencers.

  17. Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum

    International Nuclear Information System (INIS)

    Gao, Hua-Jun; Chen, Ya-Jing; Zuo, Duo; Xiao, Ming-Ming; Li, Ying; Guo, Hua; Zhang, Ning; Chen, Rui-Bing

    2015-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. Lectin affinity chromatography (LAC) was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography (LC) separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain (FGG), FOS-like antigen 2 (FOSL2), and α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase B (MGAT5B) were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC

  18. Characterization of the oncogenic function of centromere protein F in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Yongdong; Liu, Lulu; Zeng, Tingting; Zhu, Ying-Hui [State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou (China); Li, Jiangchao [Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou (China); Chen, Leilei [Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong (China); Li, Yan; Yuan, Yun-Fei [State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou (China); Ma, Stephanie, E-mail: stefma@hku.hk [Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong (China); State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong (China); Guan, Xin-Yuan, E-mail: xyguan@hkucc.hku.hk [State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou (China); Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong (China); State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong (China)

    2013-07-12

    Highlights: •Overexpression of CENPF is frequently detected in HCC. •Upregulation of CENPF serves as an independent prognosis factor in HCC patients. •CENPF functions as an oncogene in HCC by promoting cell G2/M transition. -- Abstract: Centromere protein F (CENPF) is an essential nuclear protein associated with the centromere-kinetochore complex and plays a critical role in chromosome segregation during mitosis. Up-regulation of CENPF expression has previously been detected in several solid tumors. In this study, we aim to study the expression and functional role of CENPF in hepatocellular carcinoma (HCC). We found CENPF was frequently overexpressed in HCC as compared with non-tumor tissue. Up-regulated CENPF expression in HCC was positively correlated with serum AFP, venous invasion, advanced differentiation stage and a shorter overall survival. Cox regression analysis found that overexpression of CENPF was an independent prognosis factor in HCC. Functional studies found that silencing CENPF could decrease the ability of the cells to proliferate, form colonies and induce tumor formation in nude mice. Silencing CENPF also resulted in the cell cycle arrest at G2/M checkpoint by down-regulating cell cycle proteins cdc2 and cyclin B1. Our data suggest that CENPF is frequently overexpressed in HCC and plays a critical role in driving HCC tumorigenesis.

  19. OCT4 increases BIRC5 and CCND1 expression and promotes cancer progression in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Cao, Lu; Wu, Mengchao; Zhang, Ying; Su, Changqing; Li, Chunguang; Shen, Shuwen; Yan, Yan; Ji, Weidan; Wang, Jinghan; Qian, Haihua; Jiang, Xiaoqing; Li, Zhigang

    2013-01-01

    OCT4 and BIRC5 are preferentially expressed in human cancer cells and mediate cancer cell survival and tumor maintenance. However, the molecular mechanism that regulates OCT4 and BIRC5 expression is not well characterized. By manipulating OCT4 and BIRC5 expression in hepatocellular carcinoma (HCC) cell lines, the regulatory mechanism of OCT4 on BIRC5 and CCND1 were investigated. Increasing or decreasing OCT4 expression could enhance or suppress BIRC5 expression, respectively, by regulating the activity of BIRC5 promoter. Because there is no binding site for OCT4 within BIRC5 promoter, the effect of OCT4 on BIRC5 promoter is indirect. An octamer motif for OCT4 in the CCND1 promoter has directly and partly participated in the regulation of CCND1 promoter activity, suggesting that OCT4 also could upregulated the expression of CCND1. Co-suppression of OCT4 and BIRC5 induced cancer cell apoptosis and cell cycle arrest, thereby efficiently inhibiting the proliferative activity of cancer cells and suppressing the growth of HCC xenogrfts in nude mice. OCT4 can upregula