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Sample records for cancer invasion proliferation

  1. Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

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    Ji, S.Q.; Cao, J. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Zhang, Q.Y.; Li, Y.Y. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China); Yan, Y.Q. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Yu, F.X. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China)

    2013-09-27

    To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

  2. Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin

    Institute of Scientific and Technical Information of China (English)

    Yu Liu; Bao-An Liu

    2011-01-01

    AIM: To investigate the contribution of periostin in nicotine-promoted gastric cancer cell proliferation, survival, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). METHODS: Gastric cancer cells were treated with nicotine and periostin protein expression was determined by immunoblotting. Periostin mRNA in gastric cancer cells was silenced using small interfering RNA (siRNA) techniques and periostin gene expression was evaluated by quantitative reverse transcription-polymerase chain reaction. Gastric cancer cells transfected with control or periostin siRNA plasmid were compared in terms of cell proliferation using the methylthiazolyldiphenyl-tetrazolium bromide assay. Cell apoptosis was compared using annexin V-fluoresceine isothiocyanate and propidium iodine double staining. Tumor invasion was determined using the Boyden chamber invasion assay, and the EMT marker Snail expression was evaluated by immunoblotting. RESULTS: Nicotine upregulated periostin in gastric cancer cells through a COX-2 dependent pathway, which was blocked by the COX-2-specific inhibitor NS398. Periostin mRNA expression was decreased by ~87.2% by siRNA in gastric cancer cells, and stable periostinsilenced cells were obtained by G418 screening. Periostin- silenced gastric cancer cells exhibited reduced cell proliferation, elevated sensitivity to chemotherapy with 5-fluorouracil, and decreased cell invasion and Snail expression (P < 0.05). CONCLUSION: Periostin is a nicotine target gene in gastric cancer and plays a role in gastric cancer cell growth, invasion, drug resistance, and EMT facilitated by nicotine.

  3. Effects of Src on Proliferation and Invasion of Lung Cancer Cells

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    Rui ZHENG

    2011-04-01

    Full Text Available Background and objective It has been proven that Src played pivotal roles in carcinogenesis, cancer progression and metastasis. The aim of this study is to explore the roles of Src phosphorylation on lung cancer cells. Methods Western blot and immunoprecipitation was used to detect the expression and phosphorylation of Src in lung cancer cells. MTT and Boyden chamber assay was used to examine the effects of inhibition of Src phosphorylation on proliferation and invasion of lung cancer cells in vitro, respectively. Results pp60src was expressed in all lung cancer cell lines in this study. All 5 non-small cell lung cancer (NSCLC cell lines had increased autophosphorylated tyrosine-418, while nearly no phosphorylated Src in small cell lung cancer SBC5 cell line was detected. The effect of inhibition of Src tyrosine kinase on cell proliferation varied among the lung cancer cell lines. Submicromolar Src tyrosine kinase inhibitor (≤1 μM remarkably suppressed the proliferation of PC-9 and A549 cells in a dose dependent manner (P < 0.05, while the same concentration of Src tyrosine kinase inhibitor had no significant effect on proliferation of H226, PC14PE6 and RERFLCOK cells. Invasiveness of lung cancer cells was significantly suppressed by Src tyrosine kinase in a dose-dependent manner (P < 0.05. Conclusion Phosphorylation of Src, but not over-expression, plays a pivotal role in proliferation and invasion of NSCLC cell lines in vitro.

  4. NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis.

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    Yan-fei Liu

    Full Text Available Gastric cancer is one of the most common malignancies and has a high rate of metastasis. We hypothesize that NME2 (Nucleoside Diphosphate Kinase 2, which has previously been considered as an anti-metastatic gene, plays a role in the invasiveness of gastric cancer cells. Using a tissue chip technology and immunohistochemistry, we demonstrated that NME2 expression was associated with levels of differentiation of gastric cancer cells and their metastasis into the lymph nodes. When the NME2 gene product was over-expressed by ;in vitro stable transfection, cells from BGC823 and MKN45 gastric cancer cell lines had reduced rates of proliferation, migration, and invasion through the collagen matrix, suggesting an inhibitory activity of NME2 in the propagation and invasion of gastric cancer. NME2 could, therefore, severe as a risk marker for gastric cancer invasiveness and a potential new target for gene therapy to enhance or induce NME2 expression.

  5. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells

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    Zhao, Bing; HU, MENGCAI

    2013-01-01

    Gallic acid is a trihydroxybenzoic acid, also known as 3,4,5-trihydroxybenzoic acid, which is present in plants worldwide, including Chinese medicinal herbs. Gallic acid has been shown to have cytotoxic effects in certain cancer cells, without damaging normal cells. The objective of the present study was to determine whether gallic acid is able to inhibit human cervical cancer cell viability, proliferation and invasion and suppress cervical cancer cell-mediated angiogenesis. Treatment of HeLa...

  6. Astrocyte elevated gene-1 induces breast cancer proliferation and invasion through upregulating HER2/neu expression

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    ZHANG Xin; ZHANG Ning; ZHANG Mei-xin

    2011-01-01

    Background Astrocyte elevated gene-1 (AEG-1),primarily identified as a late response gene induced by HIV-1 infection,plays multiple roles in the process of oncogenesis.This novel gene has been demonstrated to be involved in the several potent carcinogenic pathways,including PI3K/Akt pathway,nuclear factor (NF)-KB pathway,and Wnt/β-catenin pathway.Although the function of AEG-1 has been intensively investigated in recent years,the molecular mechanism underlying its oncogenic role is largely unknown.The aim of this research was to explore the potential function of AEG-1 in breast cancer development and progression.Methods AEG-1 was ectopically overexpressed in breast cancer MCF-7 cells and its biological effects on the proliferation and invasion of MCF-7 cells were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and invasion assays.The expression of HER2/neu,a crucial oncogene involving in breast cancer carcinogenesis,was also determined.Results Overexpression of the AEG-1 promoted the proliferation and invasion ability of breast cancer cells,and upregulated the expression of HER2/neu,a crucial oncogene involving in breast cancer carcinogenesis.Conclusion AEG-1 might facilitate the proliferation and invasion of breast cancer cells by upregulating HER2/neu expression,which provides a potential target for breast cancer therapy.

  7. PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation, Migration and Invasion.

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    Yang, Lei; Zhu, Jia; Huang, Hua; Yang, Qichang; Cai, Jing; Wang, Qiuhong; Zhu, Junya; Shao, Mengting; Xiao, Jinzhang; Cao, Jie; Gu, Xiaodan; Zhang, Shusen; Wang, Yingying

    2015-01-01

    PFTK1, also known as PFTAIRE1, CDK14, is a novel member of Cdc2-related serine/threonine protein kinases. Recent studies show that PFTK1 is highly expressed in several malignant tumors such as hepatocellular carcinoma, esophageal cancer, breast cancer, and involved in regulation of cell cycle, tumors proliferation, migration, and invasion that further influence the prognosis of tumors. However, the expression and physiological significance of PFTK1 in gastric cancer remain unclear. In this study, we analyzed the expression and clinical significance of PFTK1 by Western blot in 8 paired fresh gastric cancer tissues, nontumorous gastric mucosal tissues and immunohistochemistry on 161 paraffinembedded slices. High PFTK1 expression was correlated with the tumor grade, lymph node invasion as well as Ki-67. Through Cell Counting Kit (CCK)-8 assay, flow cytometry, colony formation, wound healing and transwell assays, the vitro studies demonstrated that PFTK1 overexpression promoted proliferation, migration and invasion of gastric cancer cells, while PFTK1 knockdown led to the opposite results. Our findings for the first time supported that PFTK1 might play an important role in the regulation of gastric cancer proliferation, migration and would provide a novel promising therapeutic strategy against human gastric cancer.

  8. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells.

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    Zhao, Bing; Hu, Mengcai

    2013-12-01

    Gallic acid is a trihydroxybenzoic acid, also known as 3,4,5-trihydroxybenzoic acid, which is present in plants worldwide, including Chinese medicinal herbs. Gallic acid has been shown to have cytotoxic effects in certain cancer cells, without damaging normal cells. The objective of the present study was to determine whether gallic acid is able to inhibit human cervical cancer cell viability, proliferation and invasion and suppress cervical cancer cell-mediated angiogenesis. Treatment of HeLa and HTB-35 human cancer cells with gallic acid decreased cell viability in a dose-dependent manner. BrdU proliferation and tube formation assays indicated that gallic acid significantly decreased human cervical cancer cell proliferation and tube formation in human umbilical vein endothelial cells, respectively. Additionally, gallic acid decreased HeLa and HTB-35 cell invasion in vitro. Western blot analysis demonstrated that the expression of ADAM17, EGFR, p-Akt and p-Erk was suppressed by gallic acid in the HeLa and HTB-35 cell lines. These data indicate that the suppression of ADAM17 and the downregulation of the EGFR, Akt/p-Akt and Erk/p-Erk signaling pathways may contribute to the suppression of cancer progression by Gallic acid. Gallic acid may be a valuable candidate for the treatment of cervical cancer.

  9. Afatinib inhibits proliferation and invasion and promotes apoptosis of the T24 bladder cancer cell line.

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    Tang, Yunhua; Zhang, Xiangyang; Qi, Fan; Chen, Mingfeng; Li, Yuan; Liu, Longfei; He, Wei; Li, Zhuo; Zu, Xiongbing

    2015-05-01

    Afatinib is a highly selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2). Although preclinical and clinical studies have indicated that afatinib has antitumor activity and clinical efficacy in non-small cell lung carcinoma, head and neck squamous cell carcinoma and breast cancer, there are few studies investigating its inhibitory effect on human bladder carcinoma cells. In this study, the antitumor effect of afatinib was investigated on the T24 bladder cancer cell line. The T24 bladder cancer cell line was treated with afatinib at various concentrations (0, 1, 5, 10 and 20 µmol/l). MTT assay was used to estimate the proliferation of the T24 cells; flow cytometric analysis was used to estimate the effect of afatinib on T24 cell apoptosis; cell invasion ability was assessed by a Transwell invasion assay; and western blot analysis was used to detect the expression of Bcl-2, Bax, Akt, extracellular-signal-regulated kinase (ERK)1/2, matrix metalloproteinase (MMP)-2 and MMP-9. The MTT assay demonstrated that afatinib inhibited the proliferation of T24 cells in a dose- and time-dependent manner. Flow cytometric analysis revealed that the cell apoptosis rate increased as the concentration of afatinib increased. The cell invasion assay indicated that afatinib treatment significantly inhibited the invasive behavior of T24 cells in a dose-dependent manner. Western blot analysis showed that with increasing afatinib concentrations, Bcl-2, phosphorylated (p)-ERK1/2, p-Akt, MMP-2 and MMP-9 expression levels were significantly decreased, whereas total (t)-ERK1/2 and t-Akt expression levels remained basically unchanged, and Bax expression levels were greatly increased. The results indicate that afatinib inhibits the proliferation and invasion of T24 cells in vitro and induces the apoptosis of these cells by inhibiting the EGFR signaling network.

  10. Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion

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    Nelson S. Yee

    2015-10-01

    Full Text Available The goal of this article is to provide a critical review of the transient receptor potential melastatin-subfamily member 8 (TRPM8 in cancers, with an emphasis on its roles in cellular proliferation, survival, and invasion. The TRPM8 ion channels regulate Ca²⁺ homeostasis and function as a cellular sensor and transducer of cold temperature. Accumulating evidence has demonstrated that TRPM8 is aberrantly expressed in a variety of malignant solid tumors. Clinicopathological analysis has shown that over-expression of TRPM8 correlates with tumor progression. Experimental data have revealed important roles of TRPM8 channels in cancer cells proliferation, survival, and invasion, which appear to be dependent on the cancer type. Recent reports have begun to reveal the signaling mechanisms that mediate the biological roles of TRPM8 in tumor growth and metastasis. Determining the mechanistic roles of TRPM8 in cancer is expected to elucidate the impact of thermal and chemical stimuli on the formation and progression of neoplasms. Translational research and clinical investigation of TRPM8 in malignant diseases will help exploit these ion channels as molecular biomarkers and therapeutic targets for developing precision cancer medicine.

  11. The Biological Effect of Hepsin on the Proliferation and Invasion of PC-3 Prostate Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Yong Xu; Zhiqiang Fan; Jantao Sun; Ranlu Liu; Weiming Zhao; Chunyu Wang; Ju Zhang

    2006-01-01

    OBJECTIVE Recent studies have shown that hepsin, a type of transmembrane serine protease, is highly upregulated in prostate cancer, but, little is known about its role in progression and invasion of this cancer. We constructed a hepsin-expressing plasmid and transfected it into PC-3 cells to investigate the effect of the hepsin gene on the biological behavior of the PC-3 cells.METHODS Plasmid pHepsin-IRES2 was transfected into prostate cancer PC-3 cells using Fugene6, and the cells with stable hepsin expression were screened and selected with Zeocin (600 mg/L). The hepsin mRNA level was measured by real-time PCR and the growth curve of the PC-3-transfected cells assessed using MTT and BrdU assays. A Boyden chamber was used to examine the difference in invasion and metastases between transfected and non-transfected cells.RESULTS The hepsin mRNA level in pHepsin-IRES2 transfected -PC-3 cells was significantly higher than that found in the control PC-3 cells. While the growth curve of the hepsin gene transfected PC-3 cells showed that there was no significant effect on proliferation, the invasive ability of the pHepsin-IRES2 transfected PC-3 cells, as compared with control cells, was significantly increased (P<0.05).CONCLUSION The results suggest that even though hepsin has no effect on the proliferation of prostate cancer PC-3 cells, it does promote cellular invasion and metastasis.Therefore hepsin may have a role in the development of prostate cancer.

  12. MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines

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    Viticchiè, Giuditta; Lena, Anna Maria; Latina, Alessia;

    2011-01-01

    transition and invasion of healthy tissues (usually bones). MicroRNA-203 (miR-203) is a tumor suppressor microRNA often silenced in different malignancies. Here, we show that miR-203 is downregulated in clinical primary prostatic tumors compared to normal prostate tissue, and in metastatic prostate cancer...... cell lines compared to normal epithelial prostatic cells. Overexpression of miR-203 in brain or bone metastatic prostate cell lines (DU145 and PC3) is sufficient to induce a mesenchymal to epithelial transition with inhibition of cell proliferation, migration and invasiveness. We have identified CKAP2......, LASP1, BIRC5, WASF1, ASAP1 and RUNX2 as new miR-203 direct target mRNAs involved in these events. Therefore, miR-203 could be a potentially new prognostic marker and therapeutic target in metastatic prostate cancer....

  13. Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation.

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    Jiang, Jianxiong; Dingledine, Ray

    2013-02-01

    Population studies, preclinical, and clinical trials suggest a role for cyclooxygenase-2 (COX-2, PTGS2) in tumor formation and progression. The downstream prostanoid receptor signaling pathways involved in tumorigenesis are poorly understood, although prostaglandin E2 (PGE(2)), a major COX-2 metabolite which is usually upregulated in the involved tissues, presumably plays important roles in tumor biology. Taking advantage of our recently identified novel selective antagonist for the EP2 (PTGER2) subtype of PGE(2) receptor, we demonstrated that EP2 receptor activation could promote prostate cancer cell growth and invasion in vitro, accompanied by upregulation of the tumor-promoting inflammatory cytokines, such as IL-1β and IL-6. Our results suggest the involvement of prostaglandin receptor EP2 in cancer cell proliferation and invasion possibly via its inflammatory actions, and indicate that selective blockade of the PGE(2)-EP2 signaling pathway via small molecule antagonists might represent a novel therapy for tumorigenesis.

  14. Adipose-derived mesenchymal stem cells promote cell proliferation and invasion of epithelial ovarian cancer

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    Chu, Yijing; Tang, Huijuan; Guo, Yan; Guo, Jing; Huang, Bangxing; Fang, Fang; Cai, Jing, E-mail: caijingmmm@hotmail.com; Wang, Zehua, E-mail: zehuawang@163.net

    2015-09-10

    Adipose-derived mesenchymal stem cell (ADSC) is an important component of tumor microenvironment. However, whether ADSCs have a hand in ovarian cancer progression remains unclear. In this study, we investigated the impact of human ADSCs derived from the omentum of normal donors on human epithelial ovarian cancer (EOC) cells in vitro and in vivo. Direct and indirect co-culture models including ADSCs and human EOC cell lines were established and the effects of ADSCs on EOC cell proliferation were evaluated by EdU incorporation and flow cytometry. Transwell migration assays and detection of MMPs were performed to assess the invasion activity of EOC cells in vitro. Mouse models were established by intraperitoneal injection of EOC cells with or without concomitant ADSCs to investigate the role of ADSCs in tumor progression in vivo. We found that ADSCs significantly promoted proliferation and invasion of EOC cells in both direct and indirect co-culture assays. In addition, after co-culture with ADSCs, EOC cells secreted higher levels of matrix metalloproteinases (MMPs), and inhibition of MMP2 and MMP9 partially relieved the tumor-promoting effects of ADSCs in vitro. In mouse xenograft models, we confirmed that ADSCs promoted EOC growth and metastasis and elevated the expression of MMP2 and MMP9. Our findings indicate that omental ADSCs play a promotive role during ovarian cancer progression. - Highlights: • Omental adipose derived stem cells enhanced growth and invasion properties of ovarian cancer cells. • Adipose derived stem cells promoted the growth and metastasis of ovarian cancer in mice models. • Adipose derived stem cells promoted MMPs expression and secretion of ovarian cancer cells. • Elevated MMPs mediated the tumor promoting effects of ADSCs.

  15. MTA1 promotes proliferation and invasion in human gastric cancer cells

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    Yao Y

    2015-07-01

    Full Text Available Yuan Yao,1 Shuting Feng,1 Mingming Xiao,2 Yan Li,1 Li Yang,1 Jiao Gong1 1Digestive System Department, 2Department of Pathology, The People’s Hospital of Liaoning Province, Shenyang, Liaoning, People’s Republic of China Abstract: Although metastasis-associated protein 1 (MTA1 has been widely li­nked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in gastric cancer. The aim of this study was to examine whether the MTA1 gene is associated with the process of proliferation and invasion by regulating several molecular targets in gastric cancer. MTA1 expression in 61 gastric cancer tissue and adjacent noncancerous tissues was analyzed by immunohistochemistry. The prognostic value of MTA1 for overall survival and disease-free survival was determined by Kaplan–Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Furthermore, overexpression of MTA1 in SGC7901 and BGC823 cells promoted cell cycle progression, cell adhesion, and cell invasion. Our study found that MTA1 is overexpressed in gastric cancers, which contributes to malignant cell growth by facilitating cell cycle progression through upregulation of cyclin D1 and accelerates the migration and invasion of human gastric cancer cells by regulating expression of fibronectin and MMP2/MMP9. Taken together, MTA1 was involved in the pathogenesis of gastric cancer and might be a candidate therapeutic target in gastric cancer. Keywords: cell cycle, cell adhesion, migration

  16. Overexpressed ubiquitin ligase Cullin7 in breast cancer promotes cell proliferation and invasion via down-regulating p53

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    Guo, Hongsheng [Department of Histology and Embryology, Guangdong Medical College, Dongguan 523808, Guangdong (China); Wu, Fenping [The 7th People’s Hospital of Chengdu, Chengdu 610041, Sichuan (China); Wang, Yan [The Second School of Clinical Medicine, Guangdong Medical College, Dongguan 523808, Guangdong (China); Yan, Chong [School of Pharmacy, Guangdong Medical College, Dongguan 523808, Guangdong (China); Su, Wenmei, E-mail: wenmeisutg@126.com [Oncology of Affiliated Hospital Guangdong Medical College, Zhanjiang 524000, Guangdong (China)

    2014-08-08

    Highlights: • Cullin7 is overexpressed in human breast cancer samples. • Cullin7 stimulated proliferation and invasion of breast cancer cells. • Inhibition of p53 contributes to Cullin7-induced proliferation and invasion. - Abstract: Ubiquitin ligase Cullin7 has been identified as an oncogene in some malignant diseases such as choriocarcinoma and neuroblastoma. However, the role of Cullin7 in breast cancer carcinogenesis remains unclear. In this study, we compared Cullin7 protein levels in breast cancer tissues with normal breast tissues and identified significantly higher expression of Cullin7 protein in breast cancer specimens. By overexpressing Cullin7 in breast cancer cells HCC1937, we found that Cullin7 could promote cell growth and invasion in vitro. In contrast, the cell growth and invasion was inhibited by silencing Cullin7 in breast cancer cell BT474. Moreover, we demonstrated that Cullin7 promoted breast cancer cell proliferation and invasion via down-regulating p53 expression. Thus, our study provided evidence that Cullin7 functions as a novel oncogene in breast cancer and may be a potential therapeutic target for breast cancer management.

  17. PFTK1 regulates cell proliferation, migration and invasion in epithelial ovarian cancer.

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    Zhang, Weiwei; Liu, Rong; Tang, Chunhui; Xi, Qinghua; Lu, Shumin; Chen, Wenjuan; Zhu, Lianxin; Cheng, Jialin; Chen, Yannan; Wang, Wei; Zhong, Jianxin; Deng, Yan

    2016-04-01

    PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine-protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development.

  18. 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.

  19. Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion

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    Lu, Xiao-Yu; Yan, Yan; Zhai, Yu-Jia; Bao, Qing; Doetsch, Paul W.; Deng, Xingming; Thai, Tiffany L.; Alli, Abdel A.; Eaton, Douglas C.; Shen, Bao-Zhong; Ma, He-Ping

    2017-01-01

    Recent studies indicate that the transient receptor potential canonical 6 (TRPC6) channel is highly expressed in several types of cancer cells. However, it remains unclear whether TRPC6 contributes to the malignancy of human non-small cell lung cancer (NSCLC). We used a human NSCLC A549 cell line as a model and found that pharmacological blockade or molecular knockdown of TRPC6 channel inhibited A549 cell proliferation by arresting cell cycle at the S-G2M phase and caused a significant portion of cells detached and rounded-up, but did not induce any types of cell death. Western blot and cell cycle analysis show that the detached round cells at the S-G2M phase expressed more TRPC6 than the still attached polygon cells at the G1 phase. Patch-clamp data also show that TRPC whole-cell currents in the detached cells were significantly higher than in the still attached cells. Inhibition of Ca2+-permeable TRPC6 channels significantly reduced intracellular Ca2+ in A549 cells. Interestingly, either blockade or knockdown of TRPC6 strongly reduced the invasion of this NSCLC cell line and decreased the expression of an adherent protein, fibronectin, and a tight junction protein, zonula occluden protein-1 (ZO-1). These data suggest that TRPC6-mediated elevation of intracellular Ca2+ stimulates NSCLC cell proliferation by promoting cell cycle progression and that inhibition of TRPC6 attenuates cell proliferation and invasion. Therefore, further in vivo studies may lead to a consideration of using a specific TRPC6 blocker as a complement to treat NSCLC. PMID:28030826

  20. Thymus vulgaris (thyme) inhibits proliferation, adhesion, migration, and invasion of human colorectal cancer cells.

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    Al-Menhali, Afnan; Al-Rumaihi, Aisha; Al-Mohammed, Hana; Al-Mazrooey, Hana; Al-Shamlan, Maryam; AlJassim, Meaad; Al-Korbi, Noof; Eid, Ali Hussein

    2015-01-01

    Colorectal cancer (CRC) remains one of the most common malignancies and a leading cause of cancer-related deaths. Its prognosis remains poor for patients with several grades of this disease. This underscores the need for alternative modalities, such as herbal medicines, to treat this disease. A commonly used plant that appears to be of high medicinal value is Thymus vulgaris L. However, the effects of this plant on the malignant behavior of human CRC cells remains poorly investigated. This study was undertaken to determine the anticancer efficacy of T. vulgaris extract (TVE) in CRC cells. Our results show that TVE inhibits proliferation in a concentration- and time-dependent fashion. This decreased proliferation was concomitant with increased apoptotic cell death as evidenced by increased caspase3/7 activity. Moreover, TVE also decreased adhesion to fibronectin in a concentration-dependent manner. The migratory and invasive capacities of HCT116 cells were significantly inhibited by TVE. Taken together, these data suggest that the TVE inhibits malignant phenotype of colon cancer cells. Therefore, T. vulgaris could have an anticancer effect and that some of its bioactive compounds may prove to be effective treatment modalities for human CRC.

  1. Study on the correlation of helicobacter pylori infection with proliferation, invasion and angiogenesis molecules in gastric cancer tissue

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    Sa-Mei Lv; Jian Zhang; You-Wei Wu; Jian Zhou; Li-Ping Shi

    2016-01-01

    Objective:To study the correlation of helicobacter pylori infection with proliferation, invasion and angiogenesis molecules in gastric cancer tissue.Methods: A total of 60 cases of cancer tissue samples and 60 cases of normal tissue samples more than 5 cm away from cancer tissue edge were collected for study from gastric cancer patients treated in our hospital, and according to the testing results of helicobacter pylori (Hp), gastric cancer tissue was divided into Hp-L(+) and Hp-L(-), and the levels of proliferation, invasion and angiogenesis molecules were determined.Results:Bcl-2, Survivin, KLK8, N-cadherin, Vimentin, Snail, Twist, VEGFR, COX-2 and HIF-1α protein levels in gastric cancer tissue were significantly higher than those in normal tissue, and E-cadherin protein level was significantly lower than that in normal tissue; Bcl-2, Survivin, KLK8, N-cadherin, Vimentin, Snail, Twist, VEGF, VEGFR, COX-2 and HIF-1α protein levels in Hp-L(+) gastric cancer tissue were significantly higher than those in Hp-L(-) gastric cancer tissue, and E-cadherin protein level was significantly lower than that in Hp-L(-) gastric cancer tissue.Conclusion:Helicobacter pylori infection in gastric cancer tissue can promote cancer cell proliferation, epithelial-mesenchymal transition and angiogenesis.

  2. MicroRNA-124 inhibits cellular proliferation and invasion by targeting Ets-1 in breast cancer.

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    Li, Wentao; Zang, Wenqiao; Liu, Pei; Wang, Yuanyuan; Du, Yuwen; Chen, Xiaonan; Deng, Meng; Sun, Wencong; Wang, Lei; Zhao, Guoqiang; Zhai, Baoping

    2014-11-01

    MicroRNAs (miRNAs) are small non-coding RNAs that, by targeting certain messenger RNAs (mRNAs) for translational repression or cleavage, can regulate the expression of these genes. In addition, miRNAs may also function as oncogenes and tumor-suppressor genes, as the abnormal expression of miRNAs is associated with various human tumors. However, the effects of the expression of miR-124 in breast cancer remain unclear. The present study was conducted to study the expression of miR-124 in breast cancer, paying particular attention to miR-124's relation to the proliferation, invasion, and apoptosis in breast cancer cell MCF-7 and MDA-MB-231. Real-time quantitative RT-PCR (qRT-PCR) was performed to identify miR-124 that was down-regulated in breast cancer tissues. We also showed E26 transformation specific-1 (Ets-1) and miR-124 expression levels in breast cancer tissues that were associated with lymph node metastases. With transfected synthetic miR-124 agomir into MCF-7 and MDA-MB-231, a significant reduction (P Ets-1 as a potential major target gene of miR-124, and the result showed that miR-124 can bind to putative binding sites within the Ets-1 mRNA 3' untranslated region (UTR) to reduce its expression. Based on these findings, we propose that miR-124 and Ets-1 may serve as a therapeutic agent in breast cancer.

  3. Crosstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901

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    Dan L

    2012-10-01

    Full Text Available Li Dan,1,* Ding Jian,2,* Lin Na,1 Wang Xiaozhong,1 1Digestive Department, the Union Hospital of Fujian Medical University, Fujian, People’s Republic of China; 2Digestive Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workBackground/objective: To investigate the crosstalk between epidermal growth factor receptor (EGFR and integrin-mediated signal transduction pathways in human gastric adenocarcinoma cells.Methods: EGF was used as a ligand of EGFR to stimulate the gastric adenocarcinoma cell, SGC7901. Signal molecules downstream of the integrin, FAK(Y397 and p130cas(Y410 phosphorylation, were measured by immunoprecipitation and western blot. Fibronectin (Fn was used as a ligand of integrin to stimulate the same cell line. Signal molecules downstream of EGFR and extracellular signal-regulated kinase (ERK general phosphorylation were also measured. Focal adhesion kinase (FAK small-interfering RNA was designed and transfected into SGC7901 cells to decrease the expression of FAK. Modified Boyden chambers and MTT assay were used to examine the effect of FAK inhibition on the invasiveness and proliferation of SGC7901.Results: EGF activated FAK(Y397 and p130cas(Y410 phosphorylation, while Fn activated ERK general phosphorylation. Inhibition of FAK expression decreased p130cas(Y410 phosphorylation activated by EGF and ERK general phosphorylation activated by Fn, also decreased the invasiveness and proliferation of SGC7901 cells activated by EGF or Fn.Conclusion: There is crosstalk between EGFR and integrin signal transduction. FAK may be a key cross point of the two signal pathways and acts as a potential target for human gastric cancer therapy.Keywords: gastric adenocarcinoma, epidermal growth factor receptor, integrin, focal adhesion kinase, crosstalk

  4. Effect of WFDC 2 silencing on the proliferation, motility and invasion of human serous ovarian cancer cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Ya-Fei Zhu; Guo-Lan Gao; Sheng-Bo Tang; Zhen-Dong Zhang; Qing-Shui Huang

    2013-01-01

    Objective: To investigate effect and possible mechanisms of silencing human WFDC2 (HE4) gene on biological behavior changes as cell proliferation, apoptosis, movement and invasion of human serous ovarian cancer cell line SKOV3. Methods: Lentiviral WFDC2 gene sequence of small interfering siRNA was stablely transfected into SKOV3 identified by Q-PCR and western-blot. Obtained SKOV3 stable strains with silenced HE4 were measured by proliferation, apoptosis, migration, and invasion. Results: Gene sequencing showed that the oligonucleotides were successfully inserted into the expected site. After silencing HE4 in the SKOV3, proliferation was significantly inhibited (P<0.05). G0/G1 phase was arrested by the cell cycle (P<0.01) and capacity of the migration and invasion decreased significantly (P<0.01). Slight early apoptosis ratio and no change of late apoptosis were found without change of Caspase-3 or Bcl-2 protein. Proteins involed in ERK pathway as phosphorylated protein as p-EGFR, p- ERK decreased and protease protein involved in tissue remoding as matrix metalloproteinases MMP-9, MMP-2 and cathepsin B decreased compared with control group. Conclusions: HE4 gene plays an important role in regulating proliferation, apoptosis, migration, invasion of serous ovarian cancer cells by ERK pathway and protease system. Its role in apoptosis needs to be further explored, and it may be a potential target for serous ovarian cancer.

  5. miR-1271 promotes non-small-cell lung cancer cell proliferation and invasion via targeting HOXA5

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yongfang; Xu, Lianhong; Jiang, Lixin, E-mail: jianglx66766@163.com

    2015-03-13

    MicroRNAs (miRNAs) are short, non-coding RNAs (∼22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating numerous target genes at posttranscriptional level. However, the role of microRNAs in lung cancer, particularly non-small-cell lung cancer (NSCLC), has remained elusive. In this study, two microRNAs, miR-1271 and miR-628, and their predicted target genes were identified differentially expressed in NSCLC by analyzing the miRNA and mRNA expression data from NSCLC tissues and their matching normal controls. miR-1271 and its target gene HOXA5 were selected for further investigation. CCK-8 proliferation assay showed that the cell proliferation was promoted by miR-1271 in NSCLC cells, while miR-1271 inhibitor could significantly inhibited the proliferation of NSCLC cells. Interestingly, migration and invasion assay indicated that overexpression of miR-1271 could significantly promoted the migration and invasion of NSCLC cells, whereas miR-1271 inhibitor could inhibited both cell migration and invasion of NSCLC cells. Western blot showed that miR-1271 suppressed the protein level of HOXA5, and luciferase assays confirmed that miR-1271 directly bound to the 3'untranslated region of HOXA5. This study indicated indicate that miR-1271 regulates NSCLC cell proliferation and invasion, via the down-regulation of HOXA5. Thus, miR-1271 may represent a potential therapeutic target for NSCLC intervention. - Highlights: • Overexpression of miR-1271 promoted proliferation and invasion of NSCLC cells. • miR-1271 inhibitor inhibited the proliferation and invasion of NSCLC cells. • miR-1271 targets 3′ UTR of HOXA5 in NSCLC cells. • miR-1271 negatively regulates HOXA5 in NSCLC cells.

  6. FHL2 Antagonizes Id1-Promoted Proliferation and Invasive Capacity of Human MCF-7 Breast Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Wei-dong Han; Zhi-qiang Wu; Ya-li Zhao; Yi-ling Si; Ming-zhou Guo; Xiao-bing Fu

    2010-01-01

    Objective:FHL2 was previously identified to be a novel interacting factor of Id family proteins.The aim of this study was to investigate,the effects of FHL2 on Id1-mediated transcriptional regulation activity and its oncogenic activity in human breast cancer cells.Methods:Cell transfection was performed by Superfect reagent.Id1 stably overexpressed MCF-7 cells was cloned by G418 screening.The protein level of Id1 was detected by western blot analysis.Dual relative luciferase assays were used to measure the effect of E47-mediated transcriptional activity in MCF-7 human breast cancer cells.MTT assay was used to measure cell proliferation.Transwell assay was used to measure the invasive capacity of MCF-7 cancer cells.Results:The basic helix-loop-helix(bHLH)factor E47-mediated transcription activity was markedly repressed by Id1 in MCF-7 cells.This Id1-mediated repression was effectively antagonized by FHL2 transduction.Overexpression of Id1 markedly promoted the proliferation rate and invasive capacity of MCF-7 cells; however,these effects induced by Id1 were significantly suppressed by overexpression of FHL2 in cells.Conclusion:FHL2 can inhibit the proliferation and invasiveness of human breast cancer cells by repressing the functional activity of Id1.These findings provide the basis for further investigating the functional roles of FHL2-Id1 signaling in the carcinogenesis and development of human breast cancer.

  7. MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zhan-Guo, E-mail: zhang_zhanguo@hotmail.com; Chen, Wei-Xun, E-mail: chenweixunclark@163.com; Wu, Yan-Hui, E-mail: wuyanhui84@126.com; Liang, Hui-Fang, E-mail: lianghuifang1997@126.com; Zhang, Bi-Xiang, E-mail: bixiangzhang@163.com

    2014-11-07

    Highlights: • MiR-132 is down-regulated in breast cancer tissues and cell lines. • MiR-132 directly regulates HN1 by binding its 3′ UTR. • MiR-132 shows regulatory role in proliferation, invasion, migration and metastasis. • HN1 is involved in miR-132-mediated cell behavior. • Aberrant HN1 is associated with worse overall survival of breast cancer patients. - Abstract: Accumulating evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. This study aims to investigate the role and the underlying mechanism of miR-132 in breast cancer. Here, we report that miR-132 is significantly down-regulated in breast cancer tissues and cancer cell lines. Additional study identifies HN1 as a novel direct target of miR-132. MiR-132 down-regulates HN1 expression by binding to the 3′ UTR of HN1 transcript, thereby, suppressing multiple oncogenic traits such as cancer cell proliferation, invasion, migration and metastasis in vivo and in vitro. Overexpression of HN1 restores miR-132-suppressed malignancy. Importantly, higher HN1 expression is significantly associated with worse overall survival of breast cancer patients. Taken together, our data demonstrate a critical role of miR-132 in prohibiting cell proliferation, invasion, migration and metastasis in breast cancer through direct suppression of HN1, supporting the potential utility of miR-132 as a novel therapeutic strategy against breast cancer.

  8. Effects of MicroRNA-10b on lung cancer cell proliferation and invasive metastasis and the underlying mechanism

    Institute of Scientific and Technical Information of China (English)

    Qiao-Li Su; Shuang-Qing Li; Duo-Ning Wang; Feng Liu; Bo Yuan

    2014-01-01

    Objective:To study the influence ofMicroRNA-10b on proliferation and invasion of human low metastatic lung cancer cell95-C and its mechanism.Methods:LipofectamineMicroRNA-10b eukaryotic expression plasmid was transfected into95-C.The experiment group was divided into blank control group, empty vector transfected group andMicroRNA-10b transfected group.Real time quantitativeRT-PCR was used to detect theexpression ofMicroRNA-10b and KLF4mRNA expression.Proliferations of cells were detected by cell proliferation assay, invasion of the detected the cellTranswell experiments, the expression ofKLF4 protein was detected in Western blotting cells.Results:The proliferation rate ofMicroRNA-10b plasmid transfection group increased significantly after transfection, invasion and migration ability enhancement, by comparison, there are statistically significant differences in the blank control group and negative control group(P0.05). Conclusions:MicroRNA-10b may promote proliferation and invasion of95-C cells by down regulating the expression ofKLF4 protein.

  9. miR-98 targets ITGB3 to inhibit proliferation, migration, and invasion of non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Ni R

    2015-09-01

    Full Text Available Ran Ni,1 Yongjie Huang,2 Jing Wang11Department of Respiration Medicine, 2Department of Geriatric Respiration and Sleep, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaBackground: Accumulating evidence has emphasized causative links between aberrant microRNA (miR expression patterns and cancer development. Abnormally expressed miRNA-98 (miR-98 was found in certain types of human cancers. The biological roles of miR-98 in lung cancer, however, remain largely undefined.Methods: We evaluated the expression of miR-98 in normal lung tissues, lung cancer tissues, normal human bronchial epithelial cells, and lung cancer cells using quantitative real-time polymerase chain reaction. Effect of miR-98 on proliferation of lung cancer cells was investigated using MTT assay and colony formation assay. Transwell assay was used to assess the effects of miR-98 on migration and invasion of lung cancer cells. Whether miR-98 targets the 3'-untranslated region (3'-UTR of integrin β3 (ITGB3 coding gene ITGB3 mRNA was ascertained using luciferase reporter assay. Finally, we transplanted miR-98 expressing A549 cells into nude mice to observe the effect of miR-98 on tumor growth in vivo.Results: We confirmed that miR-98 was frequently low expressed in lung cancer tissues and human lung cancer cells. Reintroduction of miR-98 into lung cancer cells inhibited cell proliferation, migration, and invasion in vitro and suppressed tumor formation in a nude mouse model. Furthermore, we identified that miR-98 exerted inhibitory roles by directly binding to 3'-UTR of ITGB3 mRNA, thus negatively regulated the expression of ITGB3. Interestingly, upon restoring the expression of ITGB3, the effect of miR-98 on cell proliferation was partially reversed.Conclusion: Our findings suggest that miR-98 prevents proliferation, migration, and invasion of lung cancer cells by directly binding to the 3'-UTR of ITGB3 mRNA and could be a

  10. miR-92a is upregulated in cervical cancer and promotes cell proliferation and invasion by targeting FBXW7

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Chuanyi [Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008 (China); Shen, Liangfang, E-mail: lfshen2008@163.com [Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008 (China); Mao, Lei; Wang, Bing; Li, Yang; Yu, Huizhi [Department of Radiation Oncology, Yueyang Second People' s Hospital, Yueyang 414000 (China)

    2015-02-27

    MicroRNAs (miRNAs) are involved in the cervical carcinogenesis and progression. In this study, we investigated the role of miR-92a in progression and invasion of cervical cancer. MiR-92a was significantly upregulated in cervical cancer tissues and cell lines. Overexpression of miR-92a led to remarkably enhanced proliferation by promoting cell cycle transition from G1 to S phase and significantly enhanced invasion of cervical cancer cells, while its knockdown significantly reversed these cellular events. Bioinformatics analysis suggested F-box and WD repeat domain-containing 7 (FBXW7) as a novel target of miR-92a, and miR-92a suppressed the expression level of FBXW7 mRNA by direct binding to its 3′-untranslated region (3′UTR). Expression of miR-92a was negatively correlated with FBXW7 in cervical cancer tissues. Furthermore, Silencing of FBXW7 counteracted the effects of miR-92a suppression, while its overexpression reversed oncogenic effects of miR-92a. Together, these findings indicate that miR-92a acts as an onco-miRNA and may contribute to the progression and invasion of cervical cancer, suggesting miR-92a as a potential novel diagnostic and therapeutic target of cervical cancer. - Highlights: • miR-92a is elevated in cervical cancer tissues and cell lines. • miR-92a promotes cervical cancer cell proliferation, cell cycle transition from G1 to S phase and invasion. • FBXW7 is a direct target of miR-92a. • FBXW7 counteracts the oncogenic effects of miR-92a on cervical cancer cells.

  11. Silencing of SOX12 by shRNA suppresses migration, invasion and proliferation of breast cancer cells

    Science.gov (United States)

    Ding, Hanzhi; Quan, Hong; Yan, Weiguo; Han, Jing

    2016-01-01

    Sex determining region Y-box protein 12 (SOX12) is essential for embryonic development and cell-fate determination. The role of SOX12 in tumorigenesis of breast cancer is not well-understood. Here, we found that SOX12 mRNA expression was up-regulated in human breast cancer tissues. To clarify the roles of SOX12 in breast cancer, we used lentiviral shRNAs to suppress its expression in two breast cancer cells with relatively higher expression of SOX12 (BT474 and MCF-7). Our findings strongly suggested that SOX12 was critical for cell migration and invasion of breast cancer cells. We found that silencing of SOX12 significantly decreased the mRNA and protein levels of MMP9 and Twist, while notably increased E-cadherin. Moreover, SOX12 knockdown significantly inhibited the proliferation of breast cancer cells in vitro and the growth of xenograft tumours in vivo. Flow cytometry analysis revealed that breast cancer cells with SOX12 knockdown showed cell cycle arrest and decreased mRNA and protein levels of proliferating cell nuclear antigen (PCNA), CDK2 and Cyclin D1. Taken together, SOX12 plays an important role in growth inhibition through cell-cycle arrest, as well as migration and invasion of breast cancer cells. PMID:27582508

  12. Constitutive expression of Wnt/β-catenin target genes promotes proliferation and invasion of liver cancer stem cells

    Science.gov (United States)

    CHEN, WEI; ZHANG, YU-WEI; LI, YANG; ZHANG, JIAN-WEN; ZHANG, TONG; FU, BIN-SHENG; ZHANG, QI; JIANG, NAN

    2016-01-01

    Wnt/β-catenin is an important signaling pathways involved in the tumorgenesis, progression and maintenance of cancer stem cells (CSCs). In the present study, the role of Wnt/β-catenin signaling in CSC-mediated tumorigenesis and invasion in liver CSCs was investigated. A small population of cancer stem-like side population (SP) cells (3.6%) from liver cancer samples were identified. The cells were highly resistant to drug treatment due to the enhanced expression of drug efflux pumps, such as ABC subfamily G member 2, multidrug resistance protein 1 and ATP-binding cassette subfamily B member 5. Furthermore, using TOPflash and reverse transcription-quantitative polymerase chain reaction analysis, Wnt/β-catenin signaling and the transcriptional regulation of Wnt/β-catenin target genes including dickkopf Wnt signaling pathway inhibitor 1, axis inhibition protein 2 and cyclin D1 were observed to be markedly upregulated in liver cancer SP cells. As a consequence, SP cells possessed infinite cell proliferation potential and the ability to generating tumor spheres. In addition, upon reducing Wnt/β-catenin signaling, the rates of proliferation, tumor sphere formation and tumor invasion of SP cells were markedly reduced. Therefore, these data suggest that Wnt/β-catenin signaling is a potential therapeutic target to reduce CSC-mediated tumorigenicity and invasion in liver cancer. PMID:26956539

  13. Effects of HMGA2 on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells

    Institute of Scientific and Technical Information of China (English)

    Yan-Ni Xi; Xiao-Yan Xin; Hong-Mei Ye

    2014-01-01

    Objective: To analyze effects of high mobility group AT-hook 2 (HMGA2) on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Methods:Three methods were applied to observe the effect on HMGA2 expression in ovarian cancer cells and ovarian epithelial cells. Results: After the application of siRNA-HMGA2, number of T29A2-cell clones was decreased, there was significant difference compared with the negative control Block-iT. After application of let-7c, number of T29A2+ cell clones was decreased significantly, however, after the application of Anti-let-7, the number of clones restored, and there was no significant difference compared with the negative control group. After interference, the number of T29A2- cells which passed through Matrigel polycarbonate membrane were significantly lower than the negative control group. After the treatment of siRNA-HMGA2, let-7c and sh-HMGA2 respectively, growth and proliferation of T29A2-, T29A2+ and SKOV3 were slower, and the phenomenon was most obvious in SKOV3. Stable interference of HMGA2 induced mesenchymal-epithelial changes in the morphology of SKOV3-sh-HMGA2. Conclusions: HMGA2 can promote malignant transformation of ovarian cancer cells, enhance cell invasion and metastasis, and promote cell growth and proliferation of ovarian cancer cells, which can cause ovarian cancer to progress rapidly and affect the quality of life.

  14. Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro.

    Science.gov (United States)

    Xu, Y J; Li, S Y; Cheng, Q; Chen, W K; Wang, S L; Ren, Y; Miao, C H

    2016-02-01

    Tumour cell proliferation, invasion and apoptosis are crucial steps in tumour metastasis. We evaluated the effect of serum from patients undergoing colon cancer surgery receiving thoracic epidural and propofol anaesthesia on colon cancer cell biology. Patients were randomly assigned to receive propofol anaesthesia with a concomitant thoracic epidural (PEA, n = 20) or sevoflurane anaesthesia with opioid analgesia (SGA, n = 20). Venous blood was obtained before induction of anaesthesia and 24 hours postoperatively. The LoVo colon cancer cells were cultured with patient serum from both groups and the effects on proliferation, invasion and apoptosis were measured. Twenty-four hours after surgery, the absorbance value of LoVo cells at 10% serum concentration from PEA was decreased when compared with SGA (0.302 (0.026) vs 0.391 (0.066), p = 0.005). The inhibitory rate of LoVo cells at 10% serum concentration from PEA was higher than that from SGA (p = 0.004) 24 h after surgery. The number of invasive LoVo cells at 10% serum concentration from PEA was reduced when compared with SGA (44 (4) vs 62 (4), p < 0.001). Exposure of LoVo cells to postoperative serum from patients receiving PEA led to a higher luminescence ratio (apoptosis) than those receiving SGA (0.36 (0.04) vs 0.27 (0.05), p < 0.001). Serum from patients receiving PEA for colon cancer surgery inhibited proliferation and invasion of LoVo cells and induced apoptosis in vitro more than that from patients receiving SGA. Anaesthetic technique might influence the serum milieu in a way that affects cancer cell biology and, thereby, tumour metastastasis.

  15. Matrine reduces the proliferation and invasion of colorectal cancer cells via reducing the activity of p38 signaling pathway.

    Science.gov (United States)

    Ren, Hongtao; Zhang, Shuqun; Ma, Hongbing; Wang, Yali; Liu, Di; Wang, Xijing; Wang, Zhongwei

    2014-12-01

    Matrine has been used in anti-inflammatory and anti-cancer therapies for a long time. However, the anti-metastatic effect and related mechanism(s) in colorectal cancer (CRC) are still unclear. In this study, we investigated whether the administration of matrine could inhibit the proliferation, motility, and invasion of human CRC cells via regulating p38 signaling pathway. Results showed that matrine inhibited migration and invasion of CRC cells in vitro and in vivo. Additionally, after being treated with matrine for 24 h, the expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 as well as proteinase activity in CRC cells were reduced in a dose-dependent manner. Moreover, matrine reduced the phosphorylation level of p38 obviously. Combined treatment with p38 inhibitor (SB203580) and matrine resulted in a synergistic reduction of invasion as well as MMP-2/-9 expression in CRC cells. It was also found that matrine inhibited the proliferation and metastasis of CRC tumor in vivo. In conclusion, p38 signaling pathway may involve in matrine's inhibitory effects on migration and invasion of CRC cells by reducing the expression of MMP-2/-9, suggesting that matrine may be a potential therapeutic agent for CRC.

  16. Correlation of survivin, p53 and Ki-67 in laryngeal cancer Hep-2 cell proliferation and invasion

    Institute of Scientific and Technical Information of China (English)

    Shi-Geng Pei; Ju-Xiang Wang; Xue-Ling Wang; Qing-Jun Zhang; Hong Zhang

    2015-01-01

    Objective:To investigate the mechanism of survivin, p53 and Ki-67 on Hep-2 human laryngeal cancer endothelial cell proliferation and invasion.Methods:Laryngeal squamous cell carcinoma and paracancerous normal tissues were collected, total RNA was extracted from tissues,survivin,p53and Ki-67gene mRNA expression levels in laryngeal cancer and the adjacent tissues were detected by Real-time PCR. Human laryngeal cancer Hep-2 epithelial cells were selected,survivin gene was overexpressed, and cell proliferation was detected by MTT.p53 andKi-67gene expression changes in overexpressedsurvivin gene were detected by Western blot. Changes in Hep-2 cell invasive ability were studied whensurvivin was overexpressed as detected by Transwell invasion assay.Results: In the adjacent tissues, survivin,p53andKi-67 gene relative expression levels were 1.72 ± 0.9, 13.7 ± 5.7 and 5.7 ± 1.3, respectively; while in cancer tissues, gene relative expression levels were 53.7 ± 8.3, 66.7 ± 5.2 and 61.0 ± 3.1, respectively, which was significantly increased. As detected by MTT, relative cell survival rate within 12 h ofsurvivinoverexpression were: load control group, (88.5±1.6)%; overexpressed group, (90.3±1.9)%. Transwell invasion assay results indicated that overexpressedsurvivincould significantly increase the relative survival rate of cells. Conclusions:Expressions ofp53,Ki67 and survivin are increased in cancer; and there is a positive correlation betweensurvivin, p53andKi67 expressions in laryngeal carcinoma.

  17. CCL21/CCR7 enhances the proliferation, migration, and invasion of human bladder cancer T24 cells.

    Directory of Open Access Journals (Sweden)

    Miao Mo

    Full Text Available To investigate the effects of CCL21/CCR7 on the proliferation, migration, and invasion of T24 cells and the possible associated mechanisms: expression of MMP-2 and MMP-9, and regulation of BCL-2 and BAX proteins.T24 cells received corresponding treatments including vehicle control, antibody (20 ng/mL CCR7 antibody and 50 ng/ml CCL21, and 50, 100, and 200 ng/ml CCL21. Proliferation was evaluated by MTT assay; cell migration and invasion were assayed using a transwell chamber. Cell apoptosis was induced by Adriamycin (ADM. The rate of cell apoptosis was examined by flow cytometry using annexin V-FITC/PI staining. Western-blot was used to analyze MMP-2 and MMP-9 and BCL-2 and BAX proteins.CCL21 promoted T24 cell proliferation in concentration-dependent manner with that 200 ng/mL induced the largest amount of proliferation. Significant differences of cell migration were found between CCL21treatment groups and the control group in both the migration and invasion studies (P < 0.001 for all. The expressions of MMP-2 and MMP-9 proteins were significantly increased after CCL21 treatment (p < 0.05 for all. Protein expression of Bcl-21 follows an ascending trend while the expression of Bax follows a descending trend as the concentration of CCL21 increases. No difference was found between the control group and antibody group for all assessments.CCL21/CCR7 promoted T24 cell proliferation and enhanced its migration and invasion via the increased expression of MMP-2 and MMP-9. CCL21/CCR7 had antiapoptotic activities on T24 cells via regulation of Bcl-2 and Bax proteins. CCL21/CCR7 may promote bladder cancer development and metastasis.

  18. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  19. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.

  20. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    Directory of Open Access Journals (Sweden)

    Jing Y

    2016-03-01

    Full Text Available Yue Jing,1 Gang Wang,1 Ying Ge,1 Minjie Xu,1 Shuainan Tang,1 Zhunan Gong1,2 1Center for New Drug Research and Development, 2Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, People’s Republic of China Abstract: Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl-l-proline methyl ester (AA-PMe, a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1. AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27 cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. Keywords: Asiatic acid derivatives, gastric cancer cells, anti-tumor effect, cytotoxicity, apoptosis, cell cycle arrest, migration, invasion, mobility 

  1. Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

    Science.gov (United States)

    Luo, Yun; Wu, Jie-Ying; Lu, Min-Hua; Shi, Zhi

    2016-01-01

    TRPM7 is a potential therapeutic target for treatment of prostate cancer. In this study, we investigated the effects of nonselective TRPM7 inhibitor carvacrol on cell proliferation, migration, and invasion of prostate cancer PC-3 and DU145 cells. Our results showed that carvacrol blocked TRPM7-like currents in PC-3 and DU145 cells and reduced their proliferation, migration, and invasion. Moreover, carvacrol treatment significantly decreased MMP-2, p-Akt, and p-ERK1/2 protein expression and inhibited F-actin reorganization. Furthermore, consistently, TRPM7 knockdown reduced prostate cancer cell proliferation, migration, and invasion as well. Our study suggests that carvacrol may have therapeutic potential for the treatment of prostate cancer through its inhibition of TRPM7 channels and suppression of PI3K/Akt and MAPK signaling pathways. PMID:27803760

  2. miRNA-21 promotes proliferation and invasion of triple-negative breast cancer cells through targeting PTEN

    Science.gov (United States)

    Fang, Hong; Xie, Jiping; Zhang, Min; Zhao, Ziwei; Wan, Yi; Yao, Yongqiang

    2017-01-01

    MicroRNAs (miRNAs) are small single-stranded RNAs that bind to the 3’UTR of the mRNAs of target genes. They can target multiple genes and regulate translation or degradation of the mRNA. miRNAs target genes in a tissue-specific manner, and the role of a particular miRNA varies according to tumor origin or even subtype within the same cancer. This study evaluated the effect of miR-21 expression in triple-negative breast cancer (TNBC) tissues and MDA-MB-468, a cell line derived from TNBC tissues. miR-21 was consistently upregulated in TNBC and MDA-MB-468 cells compared to normal tissues. Inhibition of miR-21 by miR-21 antisense oligonucleotides decreased the proliferation, viability, and invasiveness of MDA-MB-468 cells and enhanced apoptosis. Furthermore, we confirmed that PTEN was downregulated by miR-21 in MDA-MB-468 cells. The results indicated that PTEN may mediate the oncogenic properties of miR-21 in TNBC. In summary, miR-21 was upregulated in TNBC tissues and cells, and promoted the proliferation and invasion of MDA-MB-468 cells, but negatively regulated the expression of PTEN protein. Inhibition of miR-21 or overexpression of PTEN protein could be promising strategies for the treatment of patients with TNBC.

  3. RNAi-mediated knockdown of FANCF suppresses cell proliferation, migration, invasion, and drug resistance potential of breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, L.; Li, N.; Yu, J.K.; Tang, H.T.; Li, Y.L.; He, M.; Yu, Z.J.; Bai, X.F. [Department of Pharmacology, School of Pharmacy, China Medical University, Heping Ward, Shenyang City, Liaoning (China); Zheng, Z.H.; Wang, E.H. [Institute of Pathology and Pathophysiology, China Medical University, Heping Ward, Shenyang City, Liaoning (China); Wei, M.J. [Department of Pharmacology, School of Pharmacy, China Medical University, Heping Ward, Shenyang City, Liaoning (China)

    2013-12-12

    Fanconi anemia complementation group F protein (FANCF) is a key factor, which maintains the function of FA/BRCA, a DNA damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. We performed a specific FANCF-shRNA knockdown of endogenous FANCF in vitro. Cell viability was measured with a CCK-8 assay. DNA damage was assessed with an alkaline comet assay. Apoptosis, cell cycle, and drug accumulation were measured by flow cytometry. The expression levels of protein were determined by Western blot using specific antibodies. Based on these results, we used cell migration and invasion assays to demonstrate a crucial role for FANCF in those processes. FANCF shRNA effectively inhibited expression of FANCF. We found that proliferation of FANCF knockdown breast cancer cells (MCF-7 and MDA-MB-435S) was significantly inhibited, with cell cycle arrest in the S phase, induction of apoptosis, and DNA fragmentation. Inhibition of FANCF also resulted in decreased cell migration and invasion. In addition, FANCF knockdown enhanced sensitivity to doxorubicin in breast cancer cells. These results suggest that FANCF may be a potential target for molecular, therapeutic intervention in breast cancer.

  4. RNAi-mediated knockdown of FANCF suppresses cell proliferation, migration, invasion, and drug resistance potential of breast cancer cells

    Directory of Open Access Journals (Sweden)

    L. Zhao

    2014-01-01

    Full Text Available Fanconi anemia complementation group F protein (FANCF is a key factor, which maintains the function of FA/BRCA, a DNA damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. We performed a specific FANCF-shRNA knockdown of endogenous FANCF in vitro. Cell viability was measured with a CCK-8 assay. DNA damage was assessed with an alkaline comet assay. Apoptosis, cell cycle, and drug accumulation were measured by flow cytometry. The expression levels of protein were determined by Western blot using specific antibodies. Based on these results, we used cell migration and invasion assays to demonstrate a crucial role for FANCF in those processes. FANCF shRNA effectively inhibited expression of FANCF. We found that proliferation of FANCF knockdown breast cancer cells (MCF-7 and MDA-MB-435S was significantly inhibited, with cell cycle arrest in the S phase, induction of apoptosis, and DNA fragmentation. Inhibition of FANCF also resulted in decreased cell migration and invasion. In addition, FANCF knockdown enhanced sensitivity to doxorubicin in breast cancer cells. These results suggest that FANCF may be a potential target for molecular, therapeutic intervention in breast cancer.

  5. Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    Xiaonan Qiu

    2017-03-01

    Full Text Available Elongation factor, RNA polymerase II, 2 (ELL2 is expressed and regulated by androgens in the prostate. ELL2 and ELL-associated factor 2 (EAF2 form a stable complex, and their orthologs in Caenorhabditis elegans appear to be functionally similar. In C. elegans, the EAF2 ortholog eaf-1 was reported to interact with the retinoblastoma (RB pathway to control development and fertility in worms. Because RB loss is frequent in prostate cancer, ELL2 interaction with RB might be important for prostate homeostasis. The present study explored physical and functional interaction of ELL2 with RB in prostate cancer. ELL2 expression in human prostate cancer specimens was detected using quantitative polymerase chain reaction coupled with laser capture microdissection. Co-immunoprecipitation coupled with deletion mutagenesis was used to determine ELL2 association with RB. Functional interaction between ELL2 and RB was tested using siRNA knockdown, BrdU incorporation, Transwell, and/or invasion assays in LNCaP, C4-2, and 22Rv1 prostate cancer cells. ELL2 expression was downregulated in high–Gleason score prostate cancer specimens. ELL2 could be bound and stabilized by RB, and this interaction was mediated through the N-terminus of ELL2 and the C-terminus of RB. Concurrent siRNA knockdown of ELL2 and RB enhanced cell proliferation, migration, and invasion as compared to knockdown of ELL2 or RB alone in prostate cancer cells. ELL2 and RB can interact physically and functionally to suppress prostate cancer progression.

  6. Correlation between Gli2, FAK expression in colonic adenocarcinoma tissue with different clinical pathological characteristics and cancer cell proliferation, invasion

    Institute of Scientific and Technical Information of China (English)

    Zhe Su

    2017-01-01

    Objective:To study the correlation between glioma-associated oncogene homologue 2 (Gli2), focal adhesion kinase (FAK) expression in colonic adenocarcinoma tissue with different clinical pathological characteristics and cancer cell proliferation, invasion.Methods: 56 patients with colonic adenocarcinoma who received surgical resection in our hospital between May 2012 and December 2015 were selected, cancer tissue and para-carcinoma tissue were collected respectively, immunohistochemical staining was used to detect the Gli2 and FAK protein-positive rate, and fluorescence quantitative PCR was used to determine the mRNA expression of Gli2 and FAK as well as the proliferation and invasionn genes.Results:Gli2 and FAK mRNA expression and protein-positive rate in colonic adenocarcinoma tissues were significantly higher than those in para-carcinoma tissues (P<0.05); Gli2 and FAK mRNA expression and protein-positive rate in colonic adenocarcinoma tissues with low differentiation, no differentiation, extraserosal infiltration and Dukes stage D were significantly higher than those in colonic adenocarcinoma tissues with high differentiation, medium differentiation, intraserosal infiltration, Dukes stage B-C (P<0.05); CyclinD1, CDK4, c-myc, N-cadherin and vimentin mRNA expression in Gli2- and FAK-positive colonic adenocarcinoma tissues were significantly higher than those in Gli2- and FAK-negative colonic adenocarcinoma tissues (P<0.05).Conclusions:Gli2 and FAK expression are high in colonic adenocarcinoma tissues and associated with the clinical pathological staging of tumor, and highly expressed Gli2 and FAK can promote cell proliferation and invasion.

  7. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer

    Science.gov (United States)

    Lan, Xiaoliang; Lu, Guifeng; Lin, Yuan; Yang, Shaoshan; Zeng, Zhicheng; Liao, Wenting; Ding, Yan-Qing; Liang, Li

    2016-01-01

    Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC. PMID:27058418

  8. Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

    Directory of Open Access Journals (Sweden)

    Brent W. Ferguson

    2011-01-01

    Full Text Available Heparan-sulfate proteoglycans (HSPGs are required for maximal growth factor signaling in prostate cancer progression. The degree of sulfate modification on the covalently attached heparan sulfate (HS chains is one of the determining factors of growth factor-HSPG interactions. Sulfate groups are transferred to HS chains via a series of O-sulfotransferases. In the present study, we demonstrate that Heparan sulfate 2-O-sulfotransferase (2OST is essential for maximal proliferation and invasion of prostate cancer cells in the LNCaP-C4-2B model. We also show that a decrease in invasion due to 2OST siRNA is associated with an increase in actin and E-cadherin accumulation at the cell surface. 2OST expression correlates with increasing metastatic potential in this model. We demonstrate that 2OST expression is upregulated by the stress-inducible transcription factors HIF1α, ATF2, and NFκB. Chromatin immunoprecipitation analysis suggests that HIF1α and ATF2 act directly on the 2OST promoter, while NFκB acts indirectly.

  9. Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.

    Directory of Open Access Journals (Sweden)

    Michelle K Y Siu

    Full Text Available Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα in carcinomas. The role of another folate transporter, reduced folate carrier (RFC, is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic and RFC (putative tumor suppressive in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.

  10. Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.

    Science.gov (United States)

    Siu, Michelle K Y; Kong, Daniel S H; Chan, Hoi Yan; Wong, Esther S Y; Ip, Philip P C; Jiang, LiLi; Ngan, Hextan Y S; Le, Xiao-Feng; Cheung, Annie N Y

    2012-01-01

    Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.

  11. miR-22 suppresses the proliferation and invasion of gastric cancer cells by inhibiting CD151

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xun [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yu, Honggang, E-mail: honggang_yuwh@163.com [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Lu, Xinyao; Zhang, Peng; Wang, Minglin [Department of Gastroenterology, Wuchang Hospital of Wuhan City, Wuhan 430063 (China); Hu, Yikui [Department of Neurology, Pu Ai Hospital of Wuhan City, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430034 (China)

    2014-02-28

    Highlights: • miR-22 was decreased in GC tissue samples and cell lines. • miR-22 suppressed GC cell growth and motility in vitro. • CD151 was a direct target of miR-22. • miR-22 suppressed GC cell growth and motility by inhibiting CD151. - Abstract: Gastric cancer (GC) is the second common cause of cancer-related death worldwide. microRNAs (miRNAs) play important roles in the carcinogenesis of GC. Here, we found that miR-22 was significantly decreased in GC tissue samples and cell lines. Ectopic overexpression of miR-22 remarkably suppressed cell proliferation and colony formation of GC cells. Moreover, overexpression of miR-22 significantly suppressed migration and invasion of GC cells. CD151 was found to be a target of miR-22. Furthermore, overexpression of CD151 significantly attenuated the tumor suppressive effect of miR-22. Taken together, miR-22 might suppress GC cells growth and motility partially by inhibiting CD151.

  12. CK2 abrogates the inhibitory effects of PRH/HHEX on prostate cancer cell migration and invasion and acts through PRH to control cell proliferation

    Science.gov (United States)

    Siddiqui, Y H; Kershaw, R M; Humphreys, E H; Assis Junior, E M; Chaudhri, S; Jayaraman, P-S; Gaston, K

    2017-01-01

    PRH/HHEX (proline-rich homeodomain protein/haematopoietically expressed homeobox protein) is a transcription factor that controls cell proliferation, cell differentiation and cell migration. Our previous work has shown that in haematopoietic cells, Protein Kinase CK2-dependent phosphorylation of PRH results in the inhibition of PRH DNA-binding activity, increased cleavage of PRH by the proteasome and the misregulation of PRH target genes. Here we show that PRH and hyper-phosphorylated PRH are present in normal prostate epithelial cells, and that hyper-phosphorylated PRH levels are elevated in benign prostatic hyperplasia, prostatic adenocarcinoma, and prostate cancer cell lines. A reduction in PRH protein levels increases the motility of normal prostate epithelial cells and conversely, PRH over-expression inhibits prostate cancer cell migration and blocks the ability of these cells to invade an extracellular matrix. We show that CK2 over-expression blocks the repression of prostate cancer cell migration and invasion by PRH. In addition, we show that PRH knockdown in normal immortalised prostate cells results in an increase in the population of cells capable of colony formation in Matrigel, as well as increased cell invasion and decreased E-cadherin expression. Inhibition of CK2 reduces PRH phosphorylation and reduces prostate cell proliferation but the effects of CK2 inhibition on cell proliferation are abrogated in PRH knockdown cells. These data suggest that the increased phosphorylation of PRH in prostate cancer cells increases both cell proliferation and tumour cell migration/invasion. PMID:28134934

  13. NDRG1 expression is related to the progression and prognosis of gastric cancer patients through modulating proliferation, invasion and cell cycle of gastric cancer cells.

    Science.gov (United States)

    Chang, Xiaojing; Xu, Xiaoyang; Ma, Jinguo; Xue, Xiaoying; Li, Zhenhua; Deng, Peng; Zhang, Shuanglong; Zhi, Yu; Chen, Jing; Dai, Dongqiu

    2014-09-01

    N-myc downstream-regulated gene 1 (NDRG1) has been proposed as a tumor suppressor gene in many different types of tumors, but its potential function and corresponding mechanism are not yet fully elucidated. This study aims to detect the possible function of NDRG1 in gastric cancer progression. In this study, 112 paired gastric cancer tissues and corresponding nonmalignant gastric tissues were utilized to identify the differential protein expression of NDRG1 by immunohistochemistry and its clinical significance was analyzed. Furthermore, 49 of 112 paired gastric specimens were used to detect the differential mRNA expression by real-time PCR. The over expression of NDRG1 in human gastric cancer cell line AGS by PcDNA3.1-NDRG1 transfection was utilized to detect the role of NDRG1 in regulating the biological behavior of gastric cancer. NDRG1 expression was significantly decreased in primary gastric cancer tissues, compared with its corresponding nonmalignant gastric tissues (p < 0.05), and its decreased expression was significantly associated with lymph node metastasis (p < 0.01), invasion depth (p < 0.01) and differentiation (p < 0.05). Additionally, the overall survival rate of gastric cancer patients with high expression of NDRG1 was higher than those with low expression during the follow-up period. NDRG1 overexpression suppressed cells proliferation, invasion and induced a G1 cell cycle arrest in gastric cancer. Furthermore, the down-regulation of NDRG1 in gastric cancer metastatic progression was correlated to E-cadherin and MMP-9. Our results verify that NDRG1 acts as a tumor suppressor gene and may play an important role in the metastasis progression and prognosis of gastric cancer.

  14. Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer.

    Science.gov (United States)

    Ramachandran, Lalitha; Manu, Kanjoormana Aryan; Shanmugam, Muthu K; Li, Feng; Siveen, Kodappully Sivaraman; Vali, Shireen; Kapoor, Shweta; Abbasi, Taher; Surana, Rohit; Smoot, Duane T; Ashktorab, Hassan; Tan, Patrick; Ahn, Kwang Seok; Yap, Chun Wei; Kumar, Alan Prem; Sethi, Gautam

    2012-11-02

    Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.

  15. MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression.

    Science.gov (United States)

    Shin, Seung-Shick; Park, Sung-Soo; Hwang, Byungdoo; Kim, Won Tae; Choi, Yung Hyun; Kim, Wun-Jae; Moon, Sung-Kwon

    2016-10-01

    Despite the clinical significance of tumorigenesis, little is known about the cellular signaling networks of microRNAs (miRs). Here we report a new finding that mir‑106a regulates the proliferation, migration, and invasion of bladder cancer cells. Basal expression levels of mir‑106a were significantly lower in bladder cancer cells than in normal urothelial cells. Overexpression of mir‑106a suppressed the proliferation of bladder cancer cell line EJ. Transient transfection of mir‑106a into EJ cells led to downregulation of ERK phosphorylation and upregulation of p38 and JNK phosphorylation over their levels in the control. Flow cytometry analysis revealed that mir‑106a-transfected cells accumulated in the G1-phase of the cell cycle, and cyclin D1 and CDK6 were significantly downregulated. This G1-phase cell cycle arrest was due in part to the upregulation of p21CIP1/WAF1. In addition, mir‑106a overexpression blocked the wound-healing migration and invasion of EJ cells. Furthermore, mir‑106a transfection resulted in decreased expression of MMP-2 and diminished binding activity of transcription factor Ets-1 in EJ cells. Collectively, we report the novel mir‑106a-mediated molecular signaling networks that regulate the proliferation, migration, and invasion of bladder cancer cells, suggesting that mir‑106a may be a therapeutic target for treating advanced bladder tumors.

  16. Long non-coding RNA BACE1-AS is a novel target for anisomycin-mediated suppression of ovarian cancer stem cell proliferation and invasion.

    Science.gov (United States)

    Chen, Qing; Liu, Xinghui; Xu, Limin; Wang, Ying; Wang, Suwei; Li, Qiong; Huang, Yongyi; Liu, Te

    2016-04-01

    Human ovarian cancer stem cells (OCSCs) are one of the main factors affecting ovarian cancer cell metastasis, recurrence, prognosis and tolerance to chemotherapy drugs. However, the mechanisms of OCSC proliferation and invasion are not clear. Recent studies suggest that anisomycin can inhibit the proliferative and invasive ability of various tumor cells by increasing the production of the toxic amyloid β (Aβ1-42) peptides from the amyloid precursor protein (APP). We explored whether anisomycin could also suppress human OCSC proliferation and invasion. The CD44+/CD117+ OCSCs were enriched from human clinical ovarian tumor tissues. OCSCs treated with anisomycin showed reduced proliferation compared to controls. Moreover, anisomycin significantly suppressed the invasive capacity of OCSCs in vitro, as indicated by cell migration assays. The mRNA expression levels of long non-coding RNA (lncRNA) β-site APP cleaving enzyme 1 antisense strand (BACE1-AS) were significantly increased in anisomycin-treated OCSCs compared to controls. In addition, mRNA and protein levels of BACE1 and Aβ1-42 were increased in anisomycin-treated OCSCs compared to controls. We confirmed that anisomycin suppressed the growth of xenograft tumors formed by OCSCs in vivo. Finally, when expression of lncRNA BACE1-AS was silenced using siRNA, BACE1 expression was downregulated and the antiproliferative and anti-invasive effects of anisomycin were reduced. Overall, we identified lncRNA BACE1-AS as a novel target for anisomycin. Elevation of lncRNA BACE1-AS expression is a potential mechanism for suppressing human OCSC proliferation and invasion.

  17. TM4SF1 Promotes Proliferation, Invasion, and Metastasis in Human Liver Cancer Cells

    Science.gov (United States)

    Huang, Yu-Kun; Fan, Xue-Gong; Qiu, Fu

    2016-01-01

    Transmembrane 4 superfamily member 1 (TM4SF1) is a member of tetraspanin family, which mediates signal transduction events regulating cell development, activation, growth and motility. Our previous studies showed that TM4SF1 is highly expressed in liver cancer. HepG2 cells were transfected with TM4SFl siRNA and TM4SF1-expressing plasmids and their biological functions were analyzed in vitro and in vivo. HepG2 cells overexpressing TM4SF1 showed reduced apoptosis and increased cell migration in vitro and enhanced tumor growth and metastasis in vivo, whereas siRNA-mediated silencing of TM4SF1 had the opposite effect. TM4SF1 exerts its effect by regulating a few apoptosis- and migration-related genes including caspase-3, caspase-9, MMP-2, MMP-9 and VEGF. These results indicate that TM4SF1 is associated with liver tumor growth and progression, suggesting that TM4SF1 may be a potential target for treatment of liver cancer in future. PMID:27153056

  18. Effect of MicroRNA-335 on the Metastasis, Invasion and Proliferation of Cells in Patients with Non-small Cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Wang He; Liu Zhili; Wang Zhaoxia

    2013-01-01

    Objective: To investigate the effect of microRNA-335 on the metastasis, invasion and proliferation of cells in patients with non-small-cell lung cancer (NSCLC). Methods:Real-time PCR was performed to detect the expression differences of microRNA-335 between 12 pairs of NSCLC and normal cancerous peripheral tissues, and between SPCA-1 cells of NSCLC and 16HBE of normal pulmonary epithelial cells, while miR-335 expression in SPCA-1 cells were down-regulated and proved by Lipofectamine 2000 transient transfection and real-time PCR, respectively. Scratch test, Transwell invasion assay as well as MTT and clone formation assays were applied to respectively determine the effect of miR-335 on the metastasis, invasion and proliferation of SPCA-1 cells. Results:Compared with para-carcinoma tissues and 16HBE cells, miR-335 expression was evidently higher in NSCLC and SPCA-1 cells. However, it decreased remarkably after transient transfection of anti-miR-335 by SPCA-1 cells with Lipofectamine 2000 for 24 h. Metastasis and invasion of SPCA-1 cells could be inhibited by suppressing miR-335 expression with suppression rates being (42.8±2.7)%and (73.25±4.4)%, respectively. However, the inhibition of miR-335 expression had no effect on the proliferation of SPCA-1 cells. Conclusion:miR-335 expresses highly in NSCLC and its low expression can obviously inhibit the metastasis and invasion of SPCA-1 cells, but has no effect on the proliferation.

  19. New alternatively spliced variant of prostate-specific membrane antigen PSM-E suppresses the proliferation, migration and invasiveness of prostate cancer cells.

    Science.gov (United States)

    Cao, Kai-Yuan; Xu, Lin; Zhang, Ding-Mei; Zhang, Xiao-Ming; Zhang, Tian; He, Xia; Wang, Zhu; Feng, Fa-Shen; Qiu, Shao-Peng; Shen, Guan-Xin

    2012-06-01

    PSM-E is a newly discovered alternatively spliced variant of prostate-specific membrane antigen (PSMA). In the current study, its role on the proliferation, invasiveness and migration in prostate cancer cell lines was analyzed. PSM-E and PSMA (as a comparison) eukaryotic expression vectors pcDNA3.0/PSM-E and pcDNA3.0/PSMA were constructed, validated by RT-PCR and Western blotting, and PSMA/PSM-E overexpression PC-3 cell models were built. Gene interference was used to block PSMA and the expression of its splice variants in LNCap cells. Three shRNA fragments were synthesized against PSMA, cloned into the vector pSilencer 2.1-U6-neo, their interference effect was evaluated by RT-PCR and Western blotting, and pSilencer 2.1-U6-neo‑shRNA3 (named p‑shRNA3) was chosen in further analyses. Growth curves were drawn to observe the proliferation change, which showed that PSM-E had the potential to suppress proliferation (PPSM-E interfering LNCap cells (P>0.05). Cross-river test showed that the migration speeds of PSM-E/PC-3 and PSMA/PC-3 were both significantly slower than the vector negative control, and faster in p-shRNA3 interfering LNCap cells compared with its vector negative control (PPSM-E/PC-3 and PSMA/PC-3 (P>0.05). Transwell assay showed that the invasive cells of both PSMA/PC-3 and PSM-E/PC-3 were fewer compared to the vector negative control (PPSM-E was weaker than PSMA (PPSM-E could suppress proliferation, migration and invasiveness of prostate cancer cells. Its suppression effect on cell proliferation is stronger compared to PSMA and the suppression effect on invasiveness is weaker than that of PSMA.

  20. ERK1/2 signalling pathway is involved in CD147-mediated gastric cancer cell line SGC7901 proliferation and invasion.

    Science.gov (United States)

    Chen, Liping; Pan, Yuqin; Gu, Ling; Nie, Zhenlin; He, Bangshun; Song, Guoqi; Li, Rui; Xu, Yeqiong; Gao, Tianyi; Wang, Shukui

    2013-08-01

    This study aimed to investigate the role of CD147 in the progression of gastric cancer and the signalling pathway involved in CD147-mediated gastric cancer cell line SGC7901 proliferation and invasion. Short hairpin RNA (shRNA) expression vectors targeting CD147 were constructed to silence CD147, and the expression of CD147 was monitored by quantitative realtime reverse transcriptase polymerase chain reaction and Western blot and further confirmed by immunohistochemistry in vivo. Cell proliferation was determined by Cell Counting Kit-8 assay, the activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by gelatin zymography, and the invasion of SGC7901 was determined by invasion assay. The phosphorylation and non-phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase1/2 (ERK1/2), P38 and c-Jun NH2-terminal kinase were examined by Western blot. Additionally, the ERK1/2 inhibitor U0126 were used to confirm the signalling pathway involved in CD147-mediated SGC7901 progression. The BALB/c nude mice were used to study tumour progression in vivo. The results revealed that CD147 silencing inhibited the proliferation and invasion of SGC7901 cells, and down-regulated the activities of MMP-2 and MMP-9 and the phosphorylation of the ERK1/2 in SGC7901 cells. ERK1/2 inhibitor U0126 decreased the proliferation, and invasion of SGC7901 cells, and down-regulated the MMP-2 and MMP-9 activities. In a nude mouse model of subcutaneous xenografts, the tumour volume was significantly smaller in the SGC7901/shRNA group compared to the SGC7901 and SGC7901/snc-RNA group. Immunohistochemistry analysis showed that CD147 and p-ERK1/2 protein expressions were down-regulated in the SGC7901/shRNA2 group compared to the SGC7901 and SGC7901/snc-RNA group. These results suggest that ERK1/2 pathway involves in CD147-mediated gastric cancer growth and invasion. These findings further highlight the importance of CD147 in cancer progression

  1. Long interspersed nucleotide acid element-1 ORF-1 protein promotes proliferation and invasion of human colorectal cancer LoVo cells through enhancing ETS-1 activity.

    Science.gov (United States)

    Li, M Y; Zhu, M; Feng, F; Cai, F Y; Fan, K C; Jiang, H; Wang, Z Q; Linghu, E Q

    2014-04-14

    The human proto-oncogene long interspersed nucleotide acid element-1 (LINE-1) open reading frame-1 protein (ORF-1p) is involved in the progress of several cancers. The transcription factor ETS-1 can mediate the transcription of some downstream genes that play specific roles in the regulation of cancerous cell invasion and metastasis. In this study, the effects of LINE-1 ORF-1p on ETS-1 activity and on the proliferation and invasion of human colorectal cancer LoVo cells were investigated. Results showed that the overexpression of LINE-1 ORF-1p enhanced the transcription of ETS-1 downstream genes and increased their protein levels, and downregulation of the LINE-1 ORF-1p level by small interfering RNA (siRNA) reduced the transcriptional activation of ETS-1. In addition, overexpression of LINE-1 ORF-1p promoted LoVo cell proliferation and anchor-independent growth, and a knockdown of the LINE-1 protein level by siRNA reduced the proliferation and anchor-independent growth ability of LoVo cells. In vivo data revealed that LINE-1 ORF-1p overexpression increased LoVo tumor growth in nude mice, whereas the siRNA knockdown of endogenous LINE-1 ORF-1p expression decreased LoVo cell growth in nude mice. Therefore, LINE- 1 ORF-1p could promote LoVo cell proliferation and invasion both in vitro and in vivo, indicating that it might be a useful molecular target for the treatment of human colorectal cancer.

  2. The effect of antisense inhibitor of miRNA 106b∼25 on the proliferation, invasion, migration, and apoptosis of gastric cancer cell.

    Science.gov (United States)

    Zhang, Rupeng; Li, Fangxuan; Wang, Weijia; Wang, Xuejun; Li, Shixia; Liu, Juntian

    2016-08-01

    Accumulating data has demonstrated that miRNA 106b∼25, which are composed of the highly conserved miRNA 106b, miRNA 93, and miRNA 25, play carcinogenic roles in cancers. We investigated the expression of miRNA 106b∼25 in gastric cancer cells (SGC 7901, MGC 803, BGC 823) and normal gastric epithelial cell then inhibited miRNA 106b∼25 expression via transiently transfecting their antisense inhibitor. After miRNA 106b∼25 cluster was inhibited, MTT, Scratch test, Transwell invasion test, and flow cytometry were applied to investigate the proliferation, invasion, migration, cell cycle, and apoptosis of gastric cancer cell. The expression of miRNA 106b, miRNA 93, and miRNA 25 in gastric cancer cells SGC 7901, MGC 803, and BGC 823 was significantly higher than in gastric epithelial cell GES-1. The most significant suppression of miRNA 106b∼25 expressions can be detected in MGC 803 cell after transiently transfecting their antisense inhibitors. So, MGC 803 cell was selected as our research object. After inhibiting miRNA 106b and miRNA 93 respectively and combined, the proliferation, migration, and invasion of gastric cancer cell MGC 803 were significantly suppressed. The most significant suppression was observed in combined inhibiting group. After miRNA 106b∼25 cluster was inhibited respectively or combined, more gastric cancer cells were arrested in the G0G1 phase. However, there was no statistical difference in comparing with control groups. While the percentages of apoptotic cells increased after miRNA 106b∼25 cluster was inhibited, the statistical difference was detected only in combined inhibiting group. Inhibiting miRNA 106b∼25 cluster via transfecting antisense inhibitor can influence biological behavior of gastric cancer cell.

  3. Long non-coding RNA lnc-MX1-1 is associated with poor clinical features and promotes cellular proliferation and invasiveness in prostate cancer.

    Science.gov (United States)

    Jiang, Chen-Yi; Gao, Yuan; Wang, Xing-Jie; Ruan, Yuan; Bei, Xiao-Yu; Wang, Xiao-Hai; Jing, Yi-Feng; Zhao, Wei; Jiang, Qi; Li, Jia; Han, Bang-Min; Xia, Shu-Jie; Zhao, Fu-Jun

    2016-02-12

    Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined by real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer.

  4. Glut1 promotes cell proliferation, migration and invasion by regulating epidermal growth factor receptor and integrin signaling in triple-negative breast cancer cells.

    Science.gov (United States)

    Oh, Sunhwa; Kim, Hyungjoo; Nam, KeeSoo; Shin, Incheol

    2017-03-01

    Elevated glucose levels in cancer cells can be attributed to increased levels of glucose transporter (GLUT) proteins. Glut1 expression is increased in human malignant cells. To investigate alternative roles of Glut1 in breast cancer, we silenced Glut1 in triple-negative breast-cancer cell lines using a short hairpin RNA (shRNA) system. Glut1 silencing was verified by Western blotting and qRT-PCR. Knockdown of Glut1 resulted in decreased cell proliferation, glucose uptake, migration, and invasion through modulation of the EGFR/ MAPK signaling pathway and integrin β1/Src/FAK signaling pathways. These results suggest that Glut1 not only plays a role as a glucose transporter, but also acts as a regulator of signaling cascades in the tumorigenesis of breast cancer. [BMB Reports 2017; 50(3): 132-137].

  5. microRNA-183 plays as oncogenes by increasing cell proliferation, migration and invasion via targeting protein phosphatase 2A in renal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Mingning, E-mail: lcuzfy@163.com; Liu, Lei, E-mail: leiliulab@163.com; Chen, Lieqian, E-mail: lieqianchen@163.com; Tan, Guobin, E-mail: guobintan@163.com; Liang, Ziji, E-mail: zijilianglab@163.com; Wang, Kangning, E-mail: kangningwanglab@163.com; Liu, Jianjun, E-mail: jianjunliulab@163.com; Chen, Hege, E-mail: hegechen@163.com

    2014-09-12

    Highlights: • miR-183 was up-regulated in renal cancer tissues. • Inhibition of endogenous miR-183 suppressed renal cancer cell growth and metastasis. • miR-183 increased cell growth and metastasis. • miR-183 regulated renal cancer cell growth and metastasis via directly targeting tumor suppressor protein phosphatase 2A. - Abstract: The aim of this study was to investigate the function of miR-183 in renal cancer cells and the mechanisms miR-183 regulates this process. In this study, level of miR-183 in clinical renal cancer specimens was detected by quantitative real-time PCR. miR-183 was up- and down-regulated in two renal cancer cell lines ACHN and A498, respectively, and cell proliferation, Caspase 3/7 activity, colony formation, in vitro migration and invasion were measured; and then the mechanisms of miR-183 regulating was analyzed. We found that miR-183 was up-regulated in renal cancer tissues; inhibition of endogenous miR-183 suppressed in vitro cell proliferation, colony formation, migration, and invasion and stimulated Caspase 3/7 activity; up-regulated miR-183 increased cell growth and metastasis and suppressed Caspase 3/7 activity. We also found that miR-183 directly targeted tumor suppressor, specifically the 3′UTR of three subunits of protein phosphatase 2A (PP2A-Cα, PP2A-Cβ, and PP2A-B56-γ) transcripts, inhibiting their expression and regulated the downstream regulators p21, p27, MMP2/3/7 and TIMP1/2/3/4. These results revealed the oncogenes role of miR-183 in renal cancer cells via direct targeting protein phosphatase 2A.

  6. Lactate dehydrogenase downregulation mediates the inhibitory effect of diallyl trisulfide on proliferation, metastasis, and invasion in triple-negative breast cancer.

    Science.gov (United States)

    Cheng, Shi-Yann; Yang, Yao-Chih; Ting, Kuan-Lun; Wen, Su-Ying; Viswanadha, Vijaya Padma; Huang, Chih-Yang; Kuo, Wei-Wen

    2017-04-01

    The Warburg effect plays a critical role in tumorigenesis, suggesting that specific agents targeting Warburg effect key proteins may be a promising strategy for cancer therapy. Previous studies have shown that diallyl trisulfide (DATS) inhibits proliferation of breast cancer cells by inducing apoptosis in vitro and in vivo. However, whether the Warburg effect is involved with the apoptosis-promoting action of DATS is unclear. Here, we show that the action of DATS is associated with downregulation of lactate dehydrogenase A (LDHA), an essential protein of the Warburg effect whose upregulation is closely related to tumorigenesis. Interestingly, inhibition of the Warburg effect by DATS in breast cancer cells did not greatly affect normal cells. Furthermore, DATS inhibited growth of breast cancer cells, particularly in MDA-MB-231, a triple-negative breast cancer (TNBC) cell, and reduced proliferation and migration; invasion was reversed by over-expression of LDHA. These data suggest that DATS inhibits breast cancer growth and aggressiveness through a novel pathway targeting the key enzyme of the Warburg effect. Our study shows that LDHA downregulation is involved in the apoptotic effect of DATS on TNBC. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1390-1398, 2017.

  7. miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G.

    Science.gov (United States)

    Sun, Huaibin; Tian, Jun; Xian, Wanhua; Xie, Tingting; Yang, Xiangdong

    2015-01-01

    miR-34a is a member of the miR-34 family and acts as a tumor suppressor in bladder cancer. This study explored the regulative role of miR-34a on an orphan nuclear receptor HNF4G, which has a well-confirmed role in bladder tumor growth and invasion. qRT-PCR analysis was applied to measure miR-34a expression in two tumorigenic bladder cancer cell lines 5637 and T24 and one normal human urothelial cell line SV-HUC-1. Luciferase assay was performed to verify the putative binding between miR-34a and HNF4G. The influence of miR-34a-HNF4G axis on cell viability, colony formation, and invasion was assessed with loss- and gain-of-function analysis. This study observed that the miR-34a expressions in 5637 and T24 cells were significantly lower than in SV-HUC-1, while the muscle invasive cell sublines 5637-M and T24-M had even lower miR-34a expression than in the nonmuscle invasive sublines. HNF4G has a 3'-UTR binding site with miR-34a and is a direct downstream target of miR-34a. miR-34a can directly downregulate the expression of HNF4G and thus inhibit tumor cell viability, colony formation, and invasion. Therefore, miR-34a-HNF4G axis is an important pathway modulating cell viability, proliferation, and invasion of bladder cancer cells.

  8. Leukocyte-associated immunoglobulin-like receptor-1 expressed in epithelial ovarian cancer cells and involved in cell proliferation and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Qizhi [Department of Immunology, Binzhou Medical University, Yantai (China); Fu, Aili [Department of Immunology, Binzhou Medical University, Yantai (China); The People' s Liberation Army 107 Hospital, Affiliated Hospital of Bin Zhou Medical University, Yantai (China); Yang, Shude [Institute of Fungi Science and Technology, Ludong University, Yantai (China); He, Xiaoli; Wang, Yue; Zhang, Xiaoshu; Zhou, Jiadi; Luan, Xiying [Department of Immunology, Binzhou Medical University, Yantai (China); Yu, Wenzheng, E-mail: bzywz2009@163.com [Department of Hemotology, The Hospital Affiliated Binzhou Medical University, Binzhou (China); Xue, Jiangnan, E-mail: xuejinagnan@263.net [Department of Immunology, Binzhou Medical University, Yantai (China)

    2015-03-06

    Previous studies have shown that leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on most types of hamatopoietic cells and negatively regulate immune response, but the roles of LAIR-1 in tumor of the non-hematopoietic lineage have not been determined. Despite advances in therapy of epithelial ovarian cancer (EOC), many questions relating to EOC pathogenesis remain unanswered. The aim of this study was to investigate the clinical significance of LAIR-1 expression in EOC and explore the possible association between LAIR-1 and cancer. In this study, a tissue microarray containing 78 ovarian cancer cases was stained following a standard immunohistochemical protocol for LAIR-1 and the correlation of LAIR-1 expression with clinicopathologic features was assessed. LAIR-1 was detected to express in tumor cells of ovarian cancer tissues (73.1%) and EOC cell lines COC1 and HO8910, not in normal ovarian tissues. In addition, LAIR-1 expression correlates significantly with tumor grade (p = 0.004). Furthermore, down-regulation of LAIR-1 in HO8910 cells increased cell proliferation, colony formation and cell invasion. These data suggest that LAIR-1 has a relevant impact on EOC progression and may be helpful for a better understanding of molecular pathogenesis of cancer. - Highlights: • LAIR-1 is expressed in epithelial ovarian cancer cells. • LAIR-1 expression correlates significantly with tumor grade. • Down-regulation of LAIR-1 expression increased cell proliferation and invasion. • LAIR-1 may be a novel candidate for cancer diagnosis and therapy.

  9. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Huang, S.Q. [Department of Urology and Center of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing (China); Institute of Urology, Peking University and Department of Urology, First Hospital, Peking University, Beijing (China); Liao, Q.J.; Wang, X.W. [Department of Urology and Center of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing (China); Xin, D.Q. [Institute of Urology, Peking University and Department of Urology, First Hospital, Peking University, Beijing (China); Chen, S.X.; Wu, Q.J.; Ye, G. [Department of Urology and Center of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing (China)

    2012-08-10

    Pituitary tumor-transforming gene-1 (PTTG1) is a proto-oncogene that promotes tumorigenesis and metastasis in numerous cell types and is overexpressed in a variety of human tumors. We have demonstrated that PTTG1 expression was up-regulated in both human prostate cancer specimens and prostate cancer cell lines. For a more direct assessment of the function of PTTG1 in prostate tumorigenesis, RNAi-mediated knockdown was used to selectively decrease PTTG1 expression in PC3 human prostate tumor cells. After three weeks of selection, colonies stably transfected with PTTG1-targeted RNAi (the knockdown PC3 cell line) or empty vector (the control PC3 cell line) were selected and expanded to investigate the role of PTTG1 expression in PC3 cell growth and invasion. Cell proliferation rate was significantly slower (28%) in the PTTG1 knockdown line after 6 days of growth as indicated by an MTT cell viability assay (P < 0.05). Similarly, a soft agar colony formation assay revealed significantly fewer (66.7%) PTTG1 knockdown PC3 cell colonies than control colonies after three weeks of growth. In addition, PTTG1 knockdown resulted in cell cycle arrest at G1 as indicated by fluorescence-activated cell sorting. The PTTG1 knockdown PC3 cell line also exhibited significantly reduced migration through Matrigel in a transwell assay of invasive potential, and down-regulation of PTTG1 could lead to increased sensitivity of these prostate cancer cells to a commonly used anticancer drug, taxol. Thus, PTTG1 expression is crucial for PC3 cell proliferation and invasion, and could be a promising new target for prostate cancer therapy.

  10. Sesamin inhibits lipopolysaccharide-induced proliferation and invasion through the p38-MAPK and NF-κB signaling pathways in prostate cancer cells.

    Science.gov (United States)

    Xu, Peiyuan; Cai, Fei; Liu, Xiaofei; Guo, Lele

    2015-06-01

    Sesamin, a lipid-soluble lignan, is one of the major constituents of sesame. Previous studies have reported that sesamin induces growth inhibition in human cancer cells, particularly prostate cancer cells. In the present study, we mainly explored the mechanism underlying the protective effect of sesamin on prostate cancer cell proliferation and invasion induced by lipopolysaccharide (LPS). We found that the proliferation of PC3 cells, as determined using the MTT assay, and the expression of cyclin D1, COX-2, Bcl-2 and survivin proteins elevated by LPS were distinctly inhibited by sesamin in a dose-dependent manner. Meanwhile, the ability of PC3 cell invasion, as determined using the Transwell assay and the expression of matrix metalloproteinase 9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) proteins increased by LPS were obviously reduced by sesamin in a dose-dependent manner. In addition, the accumulation of TGF-α and interleukin-6 (IL-6) production induced by LPS in the culture supernatant was found to be decreased dose-dependently with sesamin pretreatment in PC3 cells using the enzyme-linked immunosorbent assay (ELISA) kit. Furthermore, phosphorylation of the p38 protein and nuclear factor (NF)-κB activity in the PC3 cells were enhanced by LPS and further inhibited with sesamin, SB203580 pretreatment or p38-siRNA transfection, respectively. Sesamin or SB203580 pretreatment obviously inhibited PC3 cells-derived tumor growth induced by LPS in vivo. Taken together, these results suggest that the potential ability of sesamin to downregulate the secretion of cytokines and the expression of cell proliferative- and invasive-related gene products induced by LPS was shown to be via the p38 mitogen-activated protein kinase (p38-MAPK) and NF-κB signaling pathways, which may be one of the mechanisms of the anticancer activity of this sesamin agent in prostate cancer cells.

  11. A combination of desmopressin and docetaxel inhibit cell proliferation and invasion mediated by urokinase-type plasminogen activator (uPA) in human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Hiroshi; Klotz, Laurence H. [Division of Urology, Sunnybrook Health Sciences Center, Toronto, ON (Canada); Sugar, Linda M. [Department of Pathology, Sunnybrook Health Sciences Center, Toronto, ON (Canada); Kiss, Alexander [Department of Research Design and Biostatistics, Institute for Clinical Evaluative Sciences, Sunnybrook Health Sciences Center, Toronto, ON (Canada); Venkateswaran, Vasundara, E-mail: vasundara.venkateswaran@sunnybrook.ca [Division of Urology, Sunnybrook Health Sciences Center, Toronto, ON (Canada)

    2015-08-28

    Background: This study was designed to assess the effectiveness of a combination treatment using both desmopressin and docetaxel in prostate cancer treatment. Desmopressin is a well-known synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in in vivo models. Docetaxel is widely used for the treatment of castration resistant prostate cancer (CRPC) patients. However, durable responses have been uncommon to date. In this study, we investigated the anti-tumor effect of desmopressin in combination with docetaxel in vitro and in vivo. Methods: Two prostate cancer cells (PC3, LNCaP) were treated with different concentrations of desmopressin alone, docetaxel alone, and a combination of desmopressin and docetaxel. Cell proliferation was determined by MTS assay. The anti-invasive and anti-migration potential of desmopressin and in combination with docetaxel were examined by wound healing assay, migration chamber assay, and matrigel invasion assay. Results: The combination of desmopressin and docetaxel resulted in a significant inhibition of PC3 and LNCaP cell proliferation (p < 0.01). Additionally, cell migration and invasion were also inhibited by the combination when compared to that of either treatment alone in PC3 cells (p < 0.01). The anti-tumor effect of this combination treatment was associated with down-regulation of both urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-2 and MMP-9) in PC3 cells. Conclusions: We are the first to elucidate the anti-tumor and anti-metastatic potential of desmopressin in combination with docetaxel in a prostate cancer model via the uPA-MMP pathway. Our finding could potentially contribute to the therapeutic profile of desmopressin and enhance the efficacy of docetaxel based treatment for CRPC. - Highlights: • Desmopressin inhibits cell proliferation in prostate cancer cells. • The expression of cyclin A and CDK2

  12. HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway

    Directory of Open Access Journals (Sweden)

    Chi F

    2016-05-01

    Full Text Available Feng Chi, Rong Wu, Xueying Jin, Min Jiang, Xike Zhu Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: HER2 positivity has been well studied in various cancers, but its importance in non-small-cell lung cancer (NSCLC is still being explored. In this study, quantitative reverse transcription polymerase chain reaction (qRT-PCR was performed to detect HER2 and COX-2 expression in NSCLC tissues. Then, pcDNA3.1-HER2 was used to overexpress HER2, while HER2 siRNA and COX-2 siRNA were used to silence HER2 and COX-2 expression. MTT assay and invasion assay were used to detect the effects of HER2 on cell proliferation and invasion. Our study revealed that HER2 and COX-2 expression were upregulated in NSCLC tissues and HER2 exhibited a significant positive correlation with the levels of COX-2 expression. Overexpression of HER2 evidently elevated COX-2 expression, while silencing of HER2 evidently decreased COX-2 expression. Furthermore, overexpressed HER2 induced the ERK phosphorylation, and this was abolished by the treatment with U0126, a pharmacological inhibitor of MEK, an upstream kinase of ERK. HER2-induced expression and promoter activity of COX-2 were also suppressed by U0126, suggesting that the MEK/ERK signaling pathway regulates COX-2 expression. In addition, HER2 induced activation of AKT signaling pathway, which was reversed by pretreatment with U0126 and COX-2 siRNA. MTT and invasion assays revealed that HER2 induced cell proliferation and invasion that were reversed by pretreatment with U0126 and COX-2 siRNA. In this study, our results demonstrated for the first time that HER2 elevated COX-2 expression through the activation of MEK/ERK pathway, which subsequently induced cell proliferation and invasion via AKT pathway in NSCLC tissues. Keywords: HER2, MEK/ERK, COX-2, AKT signaling pathway, non-small-cell lung cancer

  13. Effects of adenoviral-mediated gene transduction of NK4 on proliferation, movement, and invasion of human colonic LS174T cancer cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Jian-Zheng Jie; Jian-Wei Wang; Jian-Guo Qu; Wei Wang; Tao Hung

    2006-01-01

    AIM: To investigate the inhibitory effects of a recombinant adenovirus vector that expresses NK4,a truncated form of human hepatocyte growth factor (HGF), on human colonic adenocarcinoma cells in vitro to establish a basis for future NK4 gene cancer therapy.METHODS: Cells from the LS174T human colonic adenocarcinoma cell line were infected with recombinant adenovirus rvAdCMV/NK4 and the effects of the manipulation on tumor cell proliferation, scatter,migration, and basement membrane invasion were assessed. Cells infected with a recombinant adenovirus vector (Ad-LacZ) expressing β-galactosidase served as the controls.RESULTS: We found that rvAdCMV/NK4 expression attenuated HGF-induced tumor cell scatter, migration,and basement membrane invasion (P < 0.05), but did not inhibit tumor cell proliferation.CONCLUSION: HGF-induced LS174T tumor cell scatter,migration, and invasion can be antagonized by the recombinant NK4-expressing adenovirus.

  14. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    Directory of Open Access Journals (Sweden)

    Nilgun Gurbuz

    Full Text Available Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA, induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT, concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification

  15. miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer

    Science.gov (United States)

    Mutlu, Merve; Saatci, Özge; Ansari, Suhail A.; Yurdusev, Emre; Shehwana, Huma; Konu, Özlen; Raza, Umar; Şahin, Özgür

    2016-09-01

    Dysregulation of PI3K and MAPK pathways promotes uncontrolled cell proliferation, apoptotic inhibition and metastasis. Individual targeting of these pathways using kinase inhibitors has largely been insufficient due to the existence of cross-talks between these parallel cascades. MicroRNAs are small non-coding RNAs targeting several genes simultaneously and controlling cancer-related processes. To identify miRNAs repressing both PI3K and MAPK pathways in breast cancer, we re-analyzed our previous miRNA mimic screen data with reverse phase protein array (RPPA) output, and identified miR-564 inhibiting both PI3K and MAPK pathways causing markedly decreased cell proliferation through G1 arrest. Moreover, ectopic expression of miR-564 blocks epithelial-mesenchymal transition (EMT) and reduces migration and invasion of aggressive breast cancer cells. Mechanistically, miR-564 directly targets a network of genes comprising AKT2, GNA12, GYS1 and SRF, thereby facilitating simultaneous repression of PI3K and MAPK pathways. Notably, combinatorial knockdown of these target genes using a cocktail of siRNAs mimics the phenotypes exerted upon miR-564 expression. Importantly, high miR-564 expression or low expression of target genes in combination is significantly correlated with better distant relapse-free survival of patients. Overall, miR-564 is a potential dual inhibitor of PI3K and MAPK pathways, and may be an attractive target and prognostic marker for breast cancer.

  16. Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway.

    Science.gov (United States)

    Li, Qi; Lai, Yiming; Wang, Chengbin; Xu, Guibin; He, Zheng; Shang, Xiaohong; Sun, Yi; Zhang, Fan; Liu, Leyuan; Huang, Hai

    2016-01-01

    Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC-3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKα/β, p-IKKα/β, IKBα and p-IKBα as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-κB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer.

  17. Inhibition of CD147 expression by RNA interference reduces proliferation, invasion and increases chemosensitivity in cancer stem cell-like HT-29 cells.

    Science.gov (United States)

    Chen, Jie; Pan, Yuqin; He, Bangshun; Ying, Houqun; Wang, Feng; Sun, Huiling; Deng, Qiwen; Liu, Xian; Lin, Kang; Peng, Hongxin; Cho, William C; Wang, Shukui

    2015-10-01

    The association between CD147 and cancer stem cells (CSCs) provides a new angle for cancer treatments. The aim of this study was to investigate the biological roles of CD147 in colorectal CSCs. The Oct4-green fluorescent protein (GFP) vector was used to isolate CSCs and pYr-mir30-shRNA was used to generate short hairpin RNA (shRNA) specifically for CD147. After RNA interference (RNAi), CD147 was evaluated by reverse transcription‑quantitative PCR and western blot analysis, and its biological functions were assessed by MTT and invasion assays. The results showed that the differentiation of isolated CSC-like HT-29 cells was blocked and these cells were highly positive for CD44 and CD147. RNAi-mediated CD147 silencing reduced the expression of CD147 at both mRNA and protein levels. Moreover, the activities of proliferation and invasion were decreased obviously in CSCs. Knockdown of CD147 increased the chemosensitivity of CSC-like cells to gemcitabine, cisplatin, docetaxel at 0.1, 1 and 10 µM respectively, however, there was no significant difference among the three groups to paclitaxel at 10 µM. In conclusion, these results suggest that CD147 plays an important role in colorectal CSCs and might be regarded as a novel CSC-specific targeted strategy against colorectal cancer.

  18. Human papillomavirus 16/18 E5 promotes cervical cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo.

    Science.gov (United States)

    Liao, Shujie; Deng, Dongrui; Zhang, Weina; Hu, Xiaoji; Wang, Wei; Wang, Hui; Lu, Yunping; Wang, Shixuan; Meng, Li; Ma, Ding

    2013-01-01

    High-risk human papillomaviruses (HR-HPVs) are consistently associated with human cervical cancer Additionally, the early oncoproteins of HPVs E5, E6 and E7 are known to contribute to tumor progression. The role of E5 is still nebulous. In this study, we aimed to explore the mechanism of E5 action during the human cervical carcinogenesis process. We created four cell models overexpressing HPV16 or HPV18 E5 (HPV16/18 E5) and investigated their ability to proliferate, along with their metastatic characteristics such as migration and invasion. The expression of HPV16/18 E5 protein in various cell lines was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, we compared the levels of phosphorylated paxillin as well as E-cadherin in cell models and controls by western blot analysis. Finally, we assessed the tumor growth rate of human cervical cancer cells overexpressing HPV16/18 E5 in vivo. We discovered that the expression of HPV16/18 E5 consistently increased the malignant potential of various human cervical cancer cells compared with the primary counterparts. We demonstrated the involvement of HPV16/18 E5 in proliferation, migration, invasion and regulation of the actin cytoskeleton in human cervical cancer cells. In particular we discovered that HPV16/18 E5 overexpression in human cervical cancer cells correlated with higher levels of paxillin proteins phosphorylated on tyrosine residues and with the downregulation of E-cadherin. Importantly, injection of HPV16/18 E5-overexpressing human cervical cancer cells into mice increased both HPV-and non-HPV-derived tumor growth. Collectively, our data indicate that HPV16/18 E5 influences progression of the human cervical cancer malignant phenotype. This study provides new insights into HPV16/18 E5 as a possible agent that may have an impact on the therapeutic strategies targeting human cervical cancer.

  19. Influences of the interferon induced transmembrane protein I on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines

    Institute of Scientific and Technical Information of China (English)

    HE Jing-dong; LUO Hong-lei; LI Jin; FENG Wan-ting; CHEN Long-bang

    2012-01-01

    Background Interferon-induced transmembrane protein 1 (IFITM1) has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells are currently unknown.We aimed to study the influences of IFITM1 on the proliferation,invasion,and metastasis of the colorectal cancer SW480 cell lines.Methods We constructed IFITM1/pEGFP-C3 recombinant plasmids and transfected them into the colorectal cancer SW480 cell lines.IFITM1/pEGFP-C3 recombinant plasmids were identified by means of immunofluorescence,laser confocal scanning microscopy,and reverse transcription polymerase chain reaction.IFITM1/SW480 cells with stable over-expression of IFITM1 were confirmed by G418 screening.The influences of IFITM1 on the proliferation of the SW480 cell lines were investigated by MTT assay and tumor transplantation experiments in nude mice.Cell invasion experiments were performed to determine the invasion capacity of the IFITM1/SW480 cells.Matrix metalloproteinase 2 (MMP-2) and MMP-9 activities were detected by the gelatin zymographic analysis,and MMP-9 expression by the Western blotting analysis.Results IFITM1/pEGFP-C3 recombinant plasmids were successfully constructed in this study,and the IFITM1/SW480 cells with stable IFITM1 gene over-expression were confirmed by G418 screening.MTT results showed that the proliferation of the IFITM1/SW480 cells was significantly enhanced (P <0.01).Tumors were harvested from four weeks old mice.Tumor volumes were (1347.00±60.94) mm3,(1032.40±111.38) mm3 and (1018.78±28.83) mm3; and tumor weights were (1522.34±62.76) mg,(1137.78±97.22) mg and (1155.76±133.31) mg for mice inoculated with the IFITM1/SW480 cells,pEGFP-C3/SW480 cells and SW480 cells,respectively.Tumor volumes and weights from mice inoculated with the IFITM1/SW480 cells were significantly increased (P <0.01).In addition,the numbers of the SW480 cells and IFITM1/SW480 cells that migrated through Matrigel were

  20. MicroRNA-124 (MiR-124 Inhibits Cell Proliferation, Metastasis and Invasion in Colorectal Cancer by Downregulating Rho-Associated Protein Kinase 1(ROCK1

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    Liqing Zhou

    2016-05-01

    Full Text Available Background/Aims: MiR-124 inhibits neoplastic transformation, cell proliferation, and metastasis and downregulates Rho-associated protein kinase (ROCK1 in Colorectal Cancer (CRC. The aim of this study was to further investigate the roles and interactions of ROCK1 and miR-124 and the effects of knockdown of ROCK1and MiR-124 in human Colorectal Cancer (CRC. Methods: Three Colorectal cancer cell lines (HCT116, HT29 and SW620 and one Human Colonic Mucosa Epithelial cell line (NCM460 were studied. The protein expression of ROCK1 was examined by Western-blot and qRT-PCR were performed to examine the expression levels of ROCK1 mRNA and miR-124. Furthermore, We performed transfection of cancer cell line (SW620 with pre-miR-124(mimics, anti-miR-124(inhibitor, ROCK1 siRNA and the control, then observed the affects of ROCK1 protein expression by westen-blot, cell proliferation by EDU (5-ethynyl-2'deoxyuridine assay and expression levels of ROCK1mRNA by qRT-PCR . A soft agar formation assay, Migration and invasion assays were used to determine the effect of regulation of miR-124 and ROCK1, and survivin on the transformation and invasion capability of colorectal cancer cell. Results: MiR-124 expression was significantly downregulated in CRC cell lines compare to normal (P 0.05. ROCK1 mRNA was unaltered in cells transfected with miR-124 mimic and miR-124 inhibitor, compared to normal controls. There was a significant reduction in ROCK1 protein in cells transfected with miR-124 mimic and a significant increase in cells transfected with miR-124 inhibitor (P Conclusions: In conclusion, our results demonstrated that miR-124 not only promoted cancer cell hyperplasia and significantly associated with CRC metastasis and progression, but also downregulated ROCK1 protein expression. More importantly, increased ROCK1 expression or inhibited miR-124 expression may constitute effective new therapeutic strategies for the treatment of renal cancer in the future.

  1. Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors

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    Sallam, Asmaa A.; Houssen, Wael E.; Gissendanner, Chris R.; Orabi, Khaled Y.; Foudah, Ahmed I.; El Sayed, Khalid A.

    2013-01-01

    Marine-derived fungi have proven to be important sources of bioactive natural organohalides. The genus Penicillium is recognized as a rich source of chemically diverse bioactive secondary metabolites. This study reports the fermentation, isolation and identification of a marine-derived Penicillium species. Bioassay-guided fractionation afforded the indole diterpene alkaloids penitrems A, B, D, E and F as well as paspaline and emnidole SB (1–7). Supplementing the fermentation broth of the growing fungus with KBr afforded the new 6-bromopenitrem B (8) and the known 6-bromopenitrem E (9). These compounds showed good antiproliferative, antimigratory and anti-invasive properties against human breast cancer cells. Penitrem B also showed a good activity profile in the NCI-60 DTP human tumor cell line screen. The nematode Caenorhabditis elegans was used to assess the BK channel inhibitory activity and toxicity of select compounds. A pharmacophore model was generated to explain the structural relationships of 1–9 with respect to their antiproliferative activity against the breast cancer MCF-7 cells. The structurally less complex biosynthetic precursors, paspaline (6) and emindole SB (7), were identified as potential hits suitable for future studies. PMID:24273638

  2. The putative tumor suppressor microRNA-497 modulates gastric cancer cell proliferation and invasion by repressing eIF4E

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    Li, Weidong; Jin, Xuejun; Deng, Xubin [Department of Medical Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Cancer Center of Guangzhou Medical University (CCGMU), Guangzhou (China); Zhang, Gong [Department of Radiotherapy, People’s Hospital of Shanxi Province, Taiyuan (China); Zhang, Bingqian [Cancer Research Institution, Southern Medical University, Guangzhou (China); Ma, Lei, E-mail: malei01@yeah.net [Department of Medical Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Cancer Center of Guangzhou Medical University (CCGMU), Guangzhou (China)

    2014-06-27

    Highlights: • MiR-497 expression was down-regulated in GC patients and GC cell lines. • MiR-497 inhibited cell proliferation and invasion of GC cells in vitro. • MiR-497 modulated eIF4E expression in GC cells. • Restoration of miR-497 decreased tumor growth and metastasis in vivo. - Abstract: Accumulating evidence has shown that microRNAs are involved in multiple processes in gastric cancer (GC) development and progression. Aberrant expression of miR-497 has been frequently reported in cancer studies; however, the role and mechanism of its function in GC remains unknown. Here, we reported that miR-497 was frequently downregulated in GC tissues and associated with aggressive clinicopathological features of GC patients. Further in vitro observations showed that the enforced expression of miR-497 inhibited cell proliferation by blocking the G1/S transition and decreased the invasion of GC cells, implying that miR-497 functions as a tumor suppressor in the progression of GC. In vivo study indicated that restoration of miR-497 inhibited tumor growth and metastasis. Luciferase assays revealed that miR-497 inhibited eIF4E expression by targeting the binding sites in the 3′-untranslated region of eIF4E mRNA. qRT-PCR and Western blot assays verified that miR-497 reduced eIF4E expression at both the mRNA and protein levels. A reverse correlation between miR-497 and eIF4E expression was noted in GC tissues. Taken together, our results identify a crucial tumor suppressive role of miR-497 in the progression of GC and suggest that miR-497 might be an anticancer therapeutic target for GC patients.

  3. Overexpression of the long non-coding RNA, linc-UBC1, is associated with poor prognosis and facilitates cell proliferation, migration, and invasion in colorectal cancer

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    Gao X

    2017-02-01

    Full Text Available Xunfeng Gao, Jianfan Wen, Peng Gao, Guowei Zhang, Gangqing Zhang Department of General Surgery, The Second People’s Hospital of Guangdong Province, The Third Clinical Medical College of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China Abstract: Long non-coding RNAs (lncRNAs serve comprehensive roles in various diseases, including cancer. lncRNA upregulated in bladder cancer 1 (linc-UBC1 is a notable biomarker of prognosis in certain cancer types; however, its involvement in the progression of colorectal cancer (CRC remains unknown. The present study aimed to investigate the expression of linc-UBC1 in patients with CRC and to investigate its effect on CRC cells. The expression levels of linc-UBC1 were estimated by reverse transcription-quantitative polymerase chain reaction in clinical CRC specimens and matched adjacent non-tumor mucosa from 96 cases of CRC, as well as in a number of CRC cell lines. In addition, the biological roles of linc-UBC1 were examined using a cell counting kit-8 assay, flow cytometry, and migration and invasion assays following the downregulation of linc-UBC1 by small interfering RNA. The results revealed that linc-UBC1 was significantly overexpressed in CRC tissues and the majority of CRC cell lines compared with the matched non-tumor mucosa and normal intestinal epithelial cells. Furthermore, high expression levels of linc-UBC1 were significantly associated with large tumor size, greater tumor depth, lymph node metastasis, and advanced tumor-node-metastasis stages. Patients with abnormal expression of linc-UBC1 had poorer overall survival times according to Kaplan–Meier analyses. Furthermore, multivariate Cox regression analysis indicated that linc-UBC1 was a significant independent prognostic factor. The results also revealed that reducing the expression of linc-UBC1 led to the inhibition of migration, invasion, and proliferation of CRC cells in vitro. Taken together, the results of

  4. MicroRNA-125a reduces proliferation and invasion of oral squamous cell carcinoma cells by targeting estrogen-related receptor α: implications for cancer therapeutics.

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    Tiwari, Ankana; Shivananda, Swamy; Gopinath, Kodaganur S; Kumar, Arun

    2014-11-14

    Estrogen-related receptor α (ESRRA) functions as a transcription factor and regulates the expression of several genes, such as WNT11 and OPN. Up-regulation of ESRRA has been reported in several cancers. However, the mechanism underlying its up-regulation is unclear. Furthermore, the reports regarding the role and regulation of ESRRA in oral squamous cell carcinoma (OSCC) are completely lacking. Here, we show that tumor suppressor miR-125a directly binds to the 3'UTR of ESRRA and represses its expression. Overexpression of miR-125a in OSCC cells drastically reduced the level of ESRRA, decreased cell proliferation, and increased apoptosis. Conversely, the delivery of an miR-125a inhibitor to these cells drastically increased the level of ESRRA, increased cell proliferation, and decreased apoptosis. miR-125a-mediated down-regulation of ESRRA impaired anchorage-independent colony formation and invasion of OSCC cells. Reduced cell proliferation and increased apoptosis of OSCC cells were dependent on the presence of the 3'UTR in ESRRA. The delivery of an miR-125a mimic to OSCC cells resulted in marked regression of xenografts in nude mice, whereas the delivery of an miR-125a inhibitor to OSCC cells resulted in a significant increase of xenografts and abrogated the tumor suppressor function of miR-125a. We observed an inverse correlation between the expression levels of miR-125a and ESRRA in OSCC samples. In summary, up-regulation of ESRRA due to down-regulation of miR-125a is not only a novel mechanism for its up-regulation in OSCC, but decreasing the level of ESRRA by using a synthetic miR-125a mimic may have an important role in therapeutic intervention of OSCC and other cancers.

  5. Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity.

    Science.gov (United States)

    Hsu, F-F; Yeh, C-T; Sun, Y-J; Chiang, M-T; Lan, W-M; Li, F-A; Lee, W-H; Chau, L-Y

    2015-04-30

    Heme oxygenase-1 (HO-1) is a heme-degrading enzyme anchored in the endoplasmic reticulum by a carboxyl-terminal transmembrane segment (TMS). HO-1 is highly expressed in various cancers and its nuclear localization is associated with the progression of some cancers. Nevertheless, the mechanism underlying HO-1 nuclear translocation and its pathological significance remain elusive. Here we show that the signal peptide peptidase (SPP) catalyzes the intramembrane cleavage of HO-1. Coexpression of HO-1 with wild-type SPP, but not a dominant-negative SPP, promoted the nuclear localization of HO-1 in cells. Mass spectrometry analysis of cytosolic HO-1 isolated from HeLa cells overexpressing HO-1 and SPP revealed two adjacent intramembrane cleavage sites located after S275 and F276 within the TMS. Mutations of S275F276 to A275L276 significantly hindered SPP-mediated HO-1 cleavage and nuclear localization. Nuclear HO-1 was detected in A549 and DU145 cancer cell lines expressing high levels of endogenous HO-1 and SPP. SPP knockdown or inhibition significantly reduced nuclear HO-1 localization in A549 and DU145 cells. The positive nuclear HO-1 stain was also evident in lung cancer tissues expressing high levels of HO-1 and SPP. Overexpression of a truncated HO-1 (t-HO-1) lacking the TMS in HeLa and H1299 cells promoted cell proliferation and migration/invasion. The effect of t-HO-1 was not affected by a mutation in the catalytic site. However, blockade of t-HO-1 nuclear localization abolished t-HO-1-mediated effect. The tumorigenic effect of t-HO-1 was also demonstrated in the mouse model. These findings disclose that SPP-mediated intramembrane cleavage of HO-1 promotes HO-1 nuclear localization and cancer progression independent of HO-1 enzymatic activity.

  6. MicroRNA-17-5p promotes gastric cancer proliferation, migration and invasion by directly targeting early growth response 2

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    Chen, Peng; Zhao, Huasi; Huang, Jingjing; Yan, Xizhong; Zhang, Yunfei; Gao, Yongshun

    2016-01-01

    MicroRNA-17-5p (miR-17-5p) has previously been reported to play an important role in tumor development and progression. However, it functions differently regarding different kinds of malignant tumor, and its role and mechanism in gastric cancer (GC) still lacks investigation. In this study, we detected the relationship between miR-17-5p and the development of GC by qRT-PCR, and it turned out that the level of miR-17-5p was significantly higher in GC patients than that in normal controls, and the aberrant expression of miR-17-5p was correlated with lymph node metastasis. After that, we examined the effect of miR-17-5p taking on the proliferation, apoptosis, migration and invasion of GC cells and the underlying mechanism. Experiments indicated that knockdown of miR-17-5p inhibited the proliferation, invasion and migration, while promoting apoptosis of SGC7901 cells. Early Growth Response 2 (EGR2) protein or mRNA levels were downregulated or upregulated after overexpression or knockdown of miR-17-5p, respectively. By using dual luciferase assay and Western blot, we identified EGR2 as a functional target of miR-17-5p. As far as we know, this could be the first study to demonstrate that miR-17-5p is associated with tumor stage of GC and that it could possibly become a new therapeutic method for the treatment of GC.

  7. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer.

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    Kowshik, J; Baba, Abdul Basit; Giri, Hemant; Deepak Reddy, G; Dixit, Madhulika; Nagini, Siddavaram

    2014-01-01

    Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.

  8. Preclinical evaluation of destruxin B as a novel Wnt signaling target suppressing proliferation and metastasis of colorectal cancer using non-invasive bioluminescence imaging

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    Yeh, Chi-Tai [Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan (China); Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Rao, Yerra Koteswara [Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan (China); Ye, Min [Department of Natural Medicine, School of Pharmaceutical Sciences, Peking University, Beijing (China); Wu, Wen-Shi [Department of Horticulture and Biotechnology, Chinese Culture University, Taipei, Taiwan (China); Chang, Tung-Chen [Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Wang, Liang-Shun [Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan (China); Wu, Chih-Hsiung [Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan (China); Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Wu, Alexander T.H., E-mail: chaw1211@tmu.edu.tw [Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan (China); Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); Tzeng, Yew-Min, E-mail: ymtzeng@cyut.edu.tw [Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan (China)

    2012-05-15

    In continuation to our studies toward the identification of direct anti-cancer targets, here we showed that destruxin B (DB) from Metarhizium anisopliae suppressed the proliferation and induced cell cycle arrest in human colorectal cancer (CRC) HT29, SW480 and HCT116 cells. Additionally, DB induced apoptosis in HT29 cells by decreased expression level of anti-apoptotic proteins Bcl-2 and Bcl-xL while increased pro-apoptotic Bax. On the other hand, DB attenuated Wnt-signaling by downregulation of β-catenin, Tcf4 and β-catenin/Tcf4 transcriptional activity, concomitantly with decreased expression of β-catenin target genes cyclin D1, c-myc and survivin. Furthermore, DB affected the migratory and invasive ability of HT29 cells through suppressed MMPs-2 and -9 enzymatic activities. We also found that DB targeted the MAPK and/or PI3K/Akt pathway by reduced expression of Akt, IKK-α, JNK, NF-κB, c-Jun and c-Fos while increased that of IκBα. Finally, we demonstrated that DB inhibited tumorigenesis in HT29 xenograft mice using non-invasive bioluminescence technique. Consistently, tumor samples from DB-treated mice demonstrated suppressed expression of β-catenin, cyclin D1, survivin, and endothelial marker CD31 while increased caspase-3 expression. Collectively, our data supports DB as an inhibitor of Wnt/β-catenin/Tcf signaling pathway that may be beneficial in the CRC management. Highlights: ► Destruxin B (DB) inhibited colorectal cancer cells growth and induced apoptosis. ► MAPK and/or PI3K/Akt cascade cooperates in DB induced apoptosis. ► DB affected the migratory and invasive ability of HT29 cells through MMP-9. ► DB attenuated Wnt-signaling components β-catenin, Tcf4. ► DB attenuated cyclin D1, c-myc, survivin and tumorigenesis in HT29 xenograft mice.

  9. The expression of Cullin1 is increased in renal cell carcinoma and promotes cancer cell proliferation, migration, and invasion.

    Science.gov (United States)

    Ping, Ji-Gen; Wang, Fei; Pu, Jin-Xian; Hou, Ping-Fu; Chen, Yan-Su; Bai, Jin; Zheng, Jun-Nian

    2016-09-01

    Cullin1 (Cul1) is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex, which ubiquitinates a broad range of proteins involved in cell-cycle progression, signal transduction, and transcription. To investigate the role of Cul1 in the development of renal cell carcinoma (RCC), we evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) containing 307 cases of RCC tissues and 34 normal renal tissues. The Cul1 expression was increased significantly in RCC and was correlated with renal carcinoma histology grade (P = 0.007), tumor size (P = 0.013), and pT status (P = 0.023). Also, we found that silencing of Cul1 leads to increased expression of p21 and p27 that could inhibit the cyclin D1 and cyclin E2 expressions and arrest cell cycle at the G1 phase. Furthermore, knockdown of Cul1 inhibits RCC cell migration and invasion abilities by up-regulating the expression of TIMP-1 which could inhibit the expression of MMP-9. Finally, using bioluminescence imaging, we found that Cul1 knockdown significantly reduced the tumor growth in vivo. Cul1 may constitute a potential therapeutic target in RCC.

  10. Down-regulation of c9orf86 in human breast cancer cells inhibits cell proliferation, invasion and tumor growth and correlates with survival of breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Yang-Yang Li

    Full Text Available C9orf86 which is a novel subfamily within the Ras superfamily of GTPases, is overexpressed in the majority of primary breast tumors. Few functional studies have focused on the C9orf86 protein; therefore, in this study, we explored the role of C9orf86 in breast carcinogenesis. In our study, we found that silencing of C9orf86 by siRNA in MCF-7 and SK-BR-3 cells resulted in suppressed cell proliferation as well as in vitro cell invasion capabilities. Moreover, knockdown of C9orf86 inhibited tumor growth in nude mice. Cell cycle and apoptotic assays showed that the anti-proliferative effect of C9orf86-siRNA was mediated by arresting cells in the G1 phase and promoting apoptosis. In addition, we found that patients with high levels of C9orf86 expression showed a significant trend towards worse survival compared to patients with low C9orf86 expression (P = 0.002. These results provide evidence that C9orf86 represents a novel and clinically useful biomarker for BC patients and plays an important role during the progression of BC.

  11. Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells

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    Tiang, Jacky M. [School of Biomedical Sciences, University of Queensland, St. Lucia, Qld 4072 (Australia); Butcher, Neville J., E-mail: n.butcher@uq.edu.au [School of Biomedical Sciences, University of Queensland, St. Lucia, Qld 4072 (Australia); Minchin, Rodney F. [School of Biomedical Sciences, University of Queensland, St. Lucia, Qld 4072 (Australia)

    2010-02-26

    Arylamine N-acetyltransferase 1 is a phase II metabolizing enzyme that has been associated with certain breast cancer subtypes. While it has been linked to breast cancer risk because of its role in the metabolic activation and detoxification of carcinogens, recent studies have suggested it may be important in cell growth and survival. To address the possible importance of NAT1 in breast cancer, we have used a novel small molecule inhibitor (Rhod-o-hp) of the enzyme to examine growth and invasion of the breast adenocarcinoma line MDA-MB-231. The inhibitor significantly reduced cell growth by increasing the percent of cells in G2/M phase of the cell cycle. Rhod-o-hp also reduced the ability of the MDA-MB-231 cells to grow in soft agar. Using an in vitro invasion assay, the inhibitor significantly reduced the invasiveness of the cells. To test whether this effect was due to inhibition of NAT1, the enzyme was knocked down using a lentivirus-based shRNA approach and invasion potential was significantly reduced. Taken together, the results of this study demonstrate that NAT1 activity may be important in breast cancer growth and metastasis. The study suggests that NAT1 is a novel target for breast cancer treatment.

  12. ZHX1 Promotes the Proliferation, Migration and Invasion of Cholangiocarcinoma Cells

    Science.gov (United States)

    Kim, Ji-young; Liu, Liangwen; Kim, Yun-Hak; Jung, Jin-Sup; Oh, Sae-Ock

    2016-01-01

    Zinc-fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been associated with the progressions of hepatocellular carcinoma, gastric cancer, and breast cancer. However, the functional roles of ZHX1 in cholangiocarcinoma (CCA) have not been determined. We investigated the expression and roles of ZHX1 during the proliferation, migration, and invasion of CCA cells. In silico analysis and immunohistochemical studies showed amplification and overexpression of ZHX1 in CCA tissues. Furthermore, ZHX1 knockdown using specific siRNAs decreased CCA cell proliferation, migration, and invasion, whereas ZHX1 overexpression promoted all three characteristics. In addition, results suggested EGR1 might partially mediate the effect of ZHX1 on the proliferation of CCA cells. Taken together, these results show ZHX1 promotes CCA cell proliferation, migration, and invasion, and present ZHX1 as a potential target for the treatment of CCA. PMID:27835650

  13. MicroRNA‑21 expression is associated with the clinical features of patients with gastric carcinoma and affects the proliferation, invasion and migration of gastric cancer cells by regulating Noxa.

    Science.gov (United States)

    Sun, Haibin; Wang, Panzhi; Zhang, Qiangnu; He, Xiaoyan; Zai, Guozhen; Wang, Xudong; Ma, Mei; Sun, Xiaoli

    2016-03-01

    The expression levels of microRNA‑21 (miR‑21) are increased in a number of types of solid tumors. However, the association between miR‑21 expression and clinical features of patients with gastric carcinoma, and gastric cancer proliferation, invasion and migration remains to be elucidated. The present study investigated the effect of miR‑21 on the clinical features, proliferation, invasion and migration of gastric cancer and the underlying mechanisms associated with Noxa. Reverse transcription quantitative polymerase chain reaction (RT‑qPCR) was performed to detect the expression levels of miR‑21 and Noxa in samples of gastric cancer tissue and matched, adjacent, non‑tumor tissue. The association between miR‑21 expression and the clinical features of patients with gastric carcinoma, as well as the correlation between the mRNA and protein expression levels of miR‑21 and Noxa were analyzed. SGC‑7901 gastric cancer cells were cultured in vitro and transfected with an miR‑21 mimic. The effect of miR‑21 upregulation on proliferation and the cell cycle was determined using the MTT assay and flow cytometry. In addition, migration and invasion of SGC‑7901 cells were observed using the Transwell assay. The target gene of miR‑21 was identified using bioinformatics software and a dual luciferase reporting system. The effect of miR‑21 upregulation on Noxa expression levels in SGC‑7901 cells was also analyzed by RT‑qPCR and western blotting. Increased levels of miR‑21 expression and decreased levels of Noxa expression were observed in gastric cancer tissue samples when compared with the adjacent non‑tumor tissue samples. An increased miR‑21 expression level was identified as a risk factor for advanced stage gastric cancer, lymph node metastasis and larger primary tumors. Furthermore, the overexpression of miR‑21 inhibited Noxa expression levels in SGC‑7901 cells. Therefore, high levels of miR‑21 expression may induce gastric cancer

  14. Anti-Proliferation and Anti-Invasion Effects of Diosgenin on Gastric Cancer BGC-823 Cells with HIF-1α shRNAs

    Directory of Open Access Journals (Sweden)

    Yuan-Neng Chou

    2012-05-01

    Full Text Available Drug resistance is a major factor for the limited efficacy of chemotherapy in gastric cancer treatment. Hypoxia-inducible factor-1α (HIF-1α, a central transcriptional factor in hypoxia, is suggested to participate in the resistance. Here, we identified a hypoxia-mimic (cobalt chloride sensitive gastric cell line BGC-823 to explore whether diosgenin, an aglycone of steroidal saponins, can inhibit cancer cell invasion and survival of solid tumor in a hypoxic mimic microenvironment. We have shown that diosgenin is a potent candidate for decreasing the ability of invasion and survival in cobalt chloride treated BGC-823 cells. In addition, when combined with HIF-1α specific short hairpin RNA (shRNA, diosgenin can inhibit BGC-823 cells more effectively. The anti-invasion role of diosgenin may be related to E-cadherin, integrinα5 and integrinβ6. These results suggest that diosgenin may be a useful compound in controlling gastric cancer cells in hypoxia condition, especially when combined with down-regulated HIF-1α.

  15. EPO gene expression induces the proliferation, migration and invasion of bladder cancer cells through the p21WAF1‑mediated ERK1/2/NF-κB/MMP-9 pathway.

    Science.gov (United States)

    Park, Sung Lyea; Won, Se Yeon; Song, Jun-Hui; Kim, Wun-Jae; Moon, Sung-Kwon

    2014-11-01

    Erythropoietin (EPO) is a cytokine that modulates the production of red blood cells. Previous studies have contradicted the assumed role of EPO in tumor cell proliferation. In the present study, we investigated the effect of EPO in the proliferation, migration and invasion that is involved in the signaling pathways and cell-cycle regulation of bladder cancer 5637 cells. The results showed that an overexpression of the EPO gene has a potent stimulatory effect on DNA synthesis, migration and invasion. EPO gene expression increased the expression of matrix metalloproteinase (MMP)-9 via the binding activity of NF-κB, AP-1 and Sp-1 in 5637 cells. The transfection of 5637 cells with the EPO gene induced the phosphorylation of ERK1/2. Treatment with ERK1/2 inhibitor U0126 significantly inhibited the increased proliferation, migration and invasion of EPO gene-transfected cells. U0126 treatment suppressed the induction of MMP-9 expression through NF-κB binding activity in EPO gene transfectants. In addition, EPO gene expression was correlated with the upregulation of cyclins/CDKs and the upregulation of the CDK inhibitor p21WAF1 expression. Finally, the inhibition of p21WAF1 function by siRNA blocked the proliferation, migration, invasion and phosphorylation of ERK1/2 signaling, as well as MMP-9 expression and activation of NF-κB in EPO gene-transfected cells. These novel findings suggest that the molecular mechanisms of EPO contribute to the progression and development of bladder tumors.

  16. Whole Genome Sequencing of Newly Established Pancreatic Cancer Lines Identifies Novel Somatic Mutation (c.2587G>A in Axon Guidance Receptor Plexin A1 as Enhancer of Proliferation and Invasion.

    Directory of Open Access Journals (Sweden)

    Rebecca Sorber

    Full Text Available The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor's natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression.

  17. Noscapine targets EGFRp-Tyr1068 to suppress the proliferation and invasion of MG63 cells

    Science.gov (United States)

    He, Ming; Jiang, Linlin; Ren, Zhaozhou; Wang, Guangbin; Wang, Jiashi

    2016-01-01

    Osteosarcoma, the most common primary malignant bone tumor, usually arises in the metaphysis of long bones. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities encountered in osteosarcoma. Noscapine is a benzylisoquinoline alkaloid derived from the opium poppy Papaver somniferum. Recently several studies have suggested its anti-cancer effect in melanoma, ovarian cancer, gliomas, breast cancer, lung cancer, and colon cancer. However, the underlying molecular mechanism for its anti-cancer effect still remains unclear. In this paper, we found the mechanism of noscapine effectively suppressed proliferation and invasion of MG63 cell line by inhibiting the phosphorylation of EGFR and its downstream pathway. PMID:27830833

  18. Interstitial guidance of cancer invasion.

    NARCIS (Netherlands)

    Gritsenko, P.G.; Ilina, O.; Friedl, P.H.

    2012-01-01

    Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In

  19. HSPA6 augments garlic extract-induced inhibition of proliferation, migration, and invasion of bladder cancer EJ cells; Implication for cell cycle dysregulation, signaling pathway alteration, and transcription factor-associated MMP-9 regulation

    Science.gov (United States)

    Hwang, Byungdoo; Noh, Dae-Hwa; Park, Sung Lyea; Kim, Won Tae; Park, Sung-Soo; Kim, Wun-Jae; Moon, Sung-Kwon

    2017-01-01

    Although recent studies have demonstrated the anti-tumor effects of garlic extract (GE), the exact molecular mechanism is still unclear. In this study, we investigated the molecular mechanism associated with the inhibitory action of GE against bladder cancer EJ cell responses. Treatment with GE significantly inhibited proliferation of EJ cells dose-dependently through G2/M-phase cell cycle arrest. This G2/M-phase cell cycle arrest by GE was due to the activation of ATM and CHK2, which appears to inhibit phosphorylation of Cdc25C (Ser216) and Cdc2 (Thr14/Tyr15), this in turn was accompanied by down-regulation of cyclin B1 and up-regulation of p21WAF1. Furthermore, GE treatment was also found to induce phosphorylation of MAPK (ERK1/2, p38MAPK, and JNK) and AKT. In addition, GE impeded the migration and invasion of EJ cells via inhibition of MMP-9 expression followed by decreased binding activities of AP-1, Sp-1, and NF-κB motifs. Based on microarray datasets, we selected Heat shock protein A6 (HSPA6) as the most up-regulated gene responsible for the inhibitory effects of GE. Interestingly, overexpression of HSPA6 gene resulted in an augmentation effect with GE inhibiting proliferation, migration, and invasion of EJ cells. The augmentation effect of HSPA6 was verified by enhancing the induction of G2/M-phase-mediated ATM-CHK2-Cdc25C-p21WAF1-Cdc2 cascade, phosphorylation of MAPK and AKT signaling, and suppression of transcription factor-associated MMP-9 regulation in response to GE in EJ cells. Overall, our novel results indicate that HSPA6 reinforces the GE-mediated inhibitory effects of proliferation, migration, and invasion of EJ cells and may provide a new approach for therapeutic treatment of malignancies. PMID:28187175

  20. Effect of Leptin on Cytotrophoblast Proliferation and Invasion

    Institute of Scientific and Technical Information of China (English)

    Haiyi LIU; Yuanyuan WU; Fuyuan QIAO; Xun GONG

    2009-01-01

    The effects of leptin on cytotrophoblast proliferation and invasion activity were investigated.Immunohistochemistry was used to determine the placental expression of leptin in first-trimester preg-nancy. By using RT-PCR and quantitative real-time PCR, the expression of leptin in cytotrophoblast and the effect of leptin on cytotrophoblast secretion were detected. The potential of cell proliferation, inva-siveness and migration was assessed by MTT, Transwell invasion assay and migration assay respec-tively when the cytotrophoblast was cultured with different concentrations of leptin. The results showed that: (1) Leptin was distributed diffusely around cell membrane, in cytoplasma, and on nuclear mem-brane of cytotrophoblast; (2) Leptin mRNA was expressed in cytotrophoblast. Ten ng/mL leptin could promote the secretion of cytotrophoblast significantly (P<0.01); (3) After culture with different concen-trations of leptin for 24 h or longer, the proliferation of cytotrophoblast was inhibited, while in 24 h leptin could promote cytotrophoblast invasion and migration. Leptin at a concentration of 500 ng/mL could promote cytotrophoblast invasiveness and migration significantly as compared with controls (P<0.05). It was suggested that leptin could inhibit cytotrophoblast proliferation, and promote cytotro-phoblast invasion and migration activity.

  1. Intrinsic effects of gold nanoparticles on proliferation and invasion activity in SGC-7901 cells.

    Science.gov (United States)

    Wu, Yucheng; Zhang, Qingqing; Ruan, Zhongbao; Yin, Yigang

    2016-03-01

    Although biomedical applications of functionalized nanoparticles have taken significant strides, biological characterization of unmodified nanoparticles remains unclear. In the present study, we investigated the cell viability and invasion activity of gastric cancer cells after treatment with gold nanoparticles. The growth of SGC-7901 cells was inhibited significantly after treatment with 5-nm gold nanoparticles, and the cell invasion decreased markedly. These effects were not seen by different size gold nanoparticles (10, 20 and 40 nm). The attenuated invasion activity may be associated with the decreased expression of matrix metalloproteinase 9 and intercellular adhesion molecule-1. These data indicated that the response of SGC-7901 cells to gold nanoparticles was strongly associated with their unique size-dependent physiochemical properties. Therefore, we provided new evidence for the effect of gold nanoparticles on gastric cancer cell proliferation and invasion in vitro, making a contribution to the application of gold nanoparticles to novel therapies in gastric cancer.

  2. TGF-beta and BMP in breast cancer cell invasion

    NARCIS (Netherlands)

    Naber, Hildegonda Petronella Henriëtte

    2012-01-01

    TGF-beta and BMPs are members of the TGF-beta superfamily of cytokines which play an important role in a multitude of processes. In cancer, TGF-beta is known for its dual role: in early stages it inhibits cancer cell proliferation, whereas in later stages it promotes invasion and metastasis. In this

  3. Invasion and metastasis in pancreatic cancer.

    Science.gov (United States)

    Keleg, Shereen; Büchler, Peter; Ludwig, Roman; Büchler, Markus W; Friess, Helmut

    2003-01-22

    Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate below 1%. The process of cancer initiation, progression and metastasis is still not understood well. Invasion and tumor metastasis are closely related and both occur within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate cell migration, and promote cell proliferation and tumor cell survival. During the last decade considerable progress has been made in understanding genetic alterations of genes involved in local and systemic tumor growth. The most important changes occur in genes which regulate cell cycle progression, extracellular matrix homeostasis and cell migration. Furthermore, there is growing evidence that epigenetic factors including angiogenesis and lymphangiogenesis may participate in the formation of tumor metastasis. In this review we highlight the most important genetic alterations involved in tumor invasion and metastasis and further outline the role of tumor angiogenesis and lymphangiogenesis in systemic tumor dissemination.

  4. Sulforaphane Derived from Broccoli Inhibit Proliferation and Invasion of Gastric Cancer and Pancreatic Cancer%西兰花提取物萝卜硫素抑制胃癌和胰腺癌的生长与侵袭

    Institute of Scientific and Technical Information of China (English)

    贺云冲; 贾侃; 王川; 沈雯; 洪姣; 黄春琦; 任军; 许健

    2015-01-01

    Objective:To investigate the effect of vitality, invasion, cell cycle, apoptosis, DNA fragment and relative proteins expression in gastric cancer SGC-7901 and pancreatic cancer PANC-1 cell line by sulforaphane(SFN)derived from broccoli, to provide reference for daily diet and supply experiment data for treatment gastric cancer and pancreatic cancer. Methods:Analyzed vitality and invasion of SGC-7901 and PANC-1 cells treated with sulforaphane by cell counting kit (CCK8) and transwell, then measure the half maximal (50%) inhibitory concentration (IC50) of sulforaphane for SGC-7901 and PANC-1 cells. The cells cycle, apoptosis and DNA fragment were analyzed using Flow Cytometry Analysis and agarose electrophoresis, TNF-α, TGF-β and NF-κB were analyzed by western blot and immunohistochemistry after treatment with sulforaphane. Results:Results showed that SGC-7901 and PANC-1 cells proliferate and invade were inhibited by sulforaphane with a dose-dependent manner, IC50 of sulforaphane was 4.5μg/mL(SGC-7901,24h) and 5.5μg/mL (PANC-1,24h), and the cell cycle were arrested at G0/G1 phase. 4.5μg/mL and 5.5μg/mL sulforaphane induced apoptosis, DNA fragment, decreased the expression of TNF-α, TGF-β and NF-κB in SGC-7901 and PANC-1 cells. Conclusion: Sulforaphane inhibited proliferation and invasion of gastric cancer SGC-7901 and pancreatic cancer PANC-1 cells in vitro, decreased the expression of inflammation proteins, maybe a novel chemotherapy for gastric cancer and pancreatic cancer.%目的:观察萝卜硫素对胃癌和胰腺癌细胞活力、侵袭能力、周期、凋亡、DNA片段和相关蛋白的影响,为日常饮食提供参考,为临床治疗胃癌和胰腺癌提供实验数据。方法:通过CCK-8和transwell侵袭实验分析初步判断萝卜硫素对SGC-7901胃癌细胞和PANC-1胰腺癌细胞活性和转移侵袭的影响,计算体外干预SGC-7901和PANC-1的IC50,流式细胞学分析IC50浓度萝卜硫素对细胞周期

  5. The indole alkaloid meleagrin, from the olive tree endophytic fungus Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation, migration and invasion.

    Science.gov (United States)

    Mady, Mohamed S; Mohyeldin, Mohamed M; Ebrahim, Hassan Y; Elsayed, Heba E; Houssen, Wael E; Haggag, Eman G; Soliman, Randa F; El Sayed, Khalid A

    2016-01-15

    Fungi of the genus Penicillium produce unique and chemically diverse biologically active secondary metabolites, including indole alkaloids. The role of dysregulated hepatocyte growth factor (HGF) and its receptor, c-Met, in the development and progression of breast carcinoma is documented. The goal of this work is to explore the chemistry and bioactivity of the secondary metabolites of the endophytic Penicillium chrysogenum cultured from the leaf of the olive tree Olea europea, collected in its natural habitat in Egypt. This fungal extract showed good inhibitory activities against the proliferation and migration of several human breast cancer lines. The CH2Cl2 extract of P. chrysogenum mycelia was subjected to bioguided chromatographic separation to afford three known indole alkaloids; meleagrin (1), roquefortine C (2) and DHTD (3). Meleagrin inhibited the growth of the human breast cancer cell lines MDA-MB-231, MDA-468, BT-474, SK BR-3, MCF7 and MCF7-dox, while similar treatment doses were found to have no effect on the growth and viability of the non-tumorigenic human mammary epithelial cells MCF10A. Meleagrin also showed excellent ATP competitive c-Met inhibitory activity in Z-Lyte assay, which was further confirmed via molecular docking studies and Western blot analysis. In addition, meleagrin treatment caused a dose-dependent inhibition of HGF-induced cell migration, and invasion of breast cancer cell lines. Meleagrin treatment potently suppressed the invasive triple negative breast tumor cell growth in an orthotopic athymic nude mice model, promoting this unique natural product from hit to a lead rank. The indole alkaloid meleagrin is a novel lead c-Met inhibitory entity useful for the control of c-Met-dependent metastatic and invasive breast malignancies.

  6. SRC kinase regulation in progressively invasive cancer.

    Directory of Open Access Journals (Sweden)

    Weichen Xu

    Full Text Available Metastatic progression is a multistep process that involves tumor growth and survival, motility and invasion, and subsequent proliferation in an inappropriate environment. The Src protein tyrosine kinase has been implicated in many of the biochemical pathways that drive these behaviors. Although Src itself is only rarely mutated in human tumors, its aberrant activity has been noted in various cancers and suggested to serve as a barometer of metastatic potential. With these features in mind, we examined Src kinase regulation at the structural, enzymatic, and expression levels as a function of progressively invasive prostate cancer cell lines. Surprisingly, both total Src content and kinase activity decrease with increasing cell line aggressiveness, an observation that appears to be inconsistent with the well-documented role of Src in the signaling pathways that drive growth and invasion. However, we do observe a direct correlation between Src kinase specific activity (total Src kinase activity/total Src content and metastatic aggressiveness, possibly suggesting that in highly aggressive cell lines, key signaling enzymes are globally recruited to drive the cancerous phenotype. In addition, although the expected enhanced phosphorylation of Src at Tyr-416 (activation site is present in the most aggressive prostate cancer cell lines, unexpectedly high phosphorylation levels at the Tyr-527 inhibitory site are observed as well. The latter, rather than representative of inhibited enzyme, is more indicative of primed Src responsive to local phosphorylated binding partners.

  7. Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness.

    Science.gov (United States)

    Xu, Y; Chen, Q; Li, W; Su, X; Chen, T; Liu, Y; Zhao, Y; Yu, C

    2010-06-10

    Amplified in breast cancer 1 (AIB1) is a transcriptional coactivator for nuclear receptors and other transcription factors. AIB1 has an important role in malignancy of several cancers such as breast and prostate cancers. However, its involvement in human hepatocellular carcinoma (HCC) progression remains unclear. Here, we found that AIB1 protein was overexpressed in 23 of 34 human HCC specimens (68%). Down-regulation of AIB1 reduced HCC cell proliferation, migration, invasion, colony formation ability and tumorigenic potential in nude mice. These phenotypic changes caused by AIB1 knockdown correlated with increased expression of the cell cycle inhibitor p21(Cip1/Waf1) and decreased Akt activation and the expression of proliferating cell nuclear antigen (PCNA) and matrix metallopeptidase MMP-9. In agreement with these findings, clinical AIB1-positive HCC expressed higher levels of PCNA than AIB1-negative HCC. A positive correlation was established between the levels of AIB1 protein and PCNA protein in HCC, suggesting that AIB1 may contribute to HCC cell proliferation. In addition, MMP-9 expression in AIB1-postive HCC was significantly higher than that in AIB1-negative HCC, suggesting that AIB1-postive HCC may be more invasive. Collectively, our results show that overexpression of AIB1 promotes human HCC progression by enhancing cell proliferation and invasiveness. Therefore, AIB1 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment.

  8. Interstitial guidance of cancer invasion.

    Science.gov (United States)

    Gritsenko, Pavlo G; Ilina, Olga; Friedl, Peter

    2012-01-01

    Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In the brain, the guidance is provided by myelinated axons, astrocyte processes, and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen-rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if not all, tissues include (i) guidance by integrins towards fibrillar interstitial collagen and/or laminins and type IV collagen in basement membranes decorating vessels and adipocytes, and, likely, CD44 engaging with hyaluronan; (ii) haptotactic guidance by chemokines and growth factors; and likely (iii) physical pushing mechanisms. Tissue-specific, resticted guidance cues include ECM proteins with restricted expression (tenascins, lecticans), cell-cell interfaces, and newly secreted matrix molecules decorating ECM fibres (laminin-332, thrombospondin-1, osteopontin, periostin). We here review physical and molecular guidance mechanisms in interstitial tissue and brain parenchyma and explore shared principles and organ-specific differences, and their implications for experimental model design and therapeutic targeting of tumour cell invasion.

  9. SOST Inhibits Prostate Cancer Invasion.

    Directory of Open Access Journals (Sweden)

    Bryan D Hudson

    Full Text Available Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC metastasis; however the role of Sclerostin (Sost has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.

  10. Effects of Ginkgo biloba exocarp polysaccharides on proliferation and invasion of cervix cancer cells line siha%银杏外种皮多糖对人宫颈癌细胞系Siha增殖及侵袭的影响

    Institute of Scientific and Technical Information of China (English)

    杨滨; 娄晓明; 吴春丽; 李婉萍

    2011-01-01

    Objective To investigate the effect of proliferation and invasion on Siha with Ginkgo biloba exocarp polysaccharides.Methods The proliferation and invasion of Ginkgo biloba exocarp polysaccharides on Siha were reduced by MTT and Transwell.The expression of MMP-2 was examined by real time PCR and ELISA.Results For Siha cell with the increasing of Ginkgo biloba exocarp polysaccharides concentrations, the inhibitory rate increased.Moreover, Ginkgo biloba exocarp polysaccharides notably decreased the secretion of MMP-2.Conclusion The results indicated that Ginkgo biloba exocarp polysaccharides might be valuable in cervix cancer.%目的 研究银杏外种皮多糖(Ginkgo biloba exocarp polysaccharides,GBEP)对宫颈癌细胞生长及增殖的影响.方法 通过经典方法提取银杏外种皮多糖,通过MTT方法检测GBEP对处理宫颈癌细胞增殖的影响:Transwell检测GBFP对宫颈癌细胞迁移的作用;通过Real time PCR和ELISA检测细胞迁移相关蛋白MMP-2的表达.结果 银杏外种皮多糖处理后的宫颈癌细胞增殖抑制率上升,与对照组比较,差异有统计学意义.银杏外种皮多糖用药后,迁移能力降低,MMP-2基因表达下降.结论 银杏外种皮多糖对宫颈癌细胞的增殖和迁移可能会起到抑制作用.

  11. Research on the effects of piperine on proliferation and invasion of human bladder cancer T24 ;Cells%胡椒碱对人膀胱癌 T24细胞增殖及侵袭作用的研究

    Institute of Scientific and Technical Information of China (English)

    周俊杰

    2015-01-01

    目的:探讨不同浓度胡椒碱对膀胱癌 T24细胞增殖和侵袭作用的影响。方法用不同浓度的胡椒碱(5、10、20、40、80、160μmol/L)处理体外培养的膀胱癌 T24细胞,然后通过 MTT实验、Transwell 实验、Western blot 等方法检测 bax 和 bcl-2的表达以及 T24细胞的增殖和凋亡情况。结果胡椒碱作用于 T24细胞24 h 后,IC50值为38.73μmol/L,并且呈剂量依赖性。随着胡椒碱浓度的增加,T24细胞活性被抑制作用明显增加,且抑凋亡蛋白 bcl-2的表达量减少,促凋亡蛋白 bax 的表达量增加。结论胡椒碱对膀胱癌 T24细胞具有抑制增殖及促进其凋亡的作用。%Objective To investigate the effects of differentpiperine concentrationson the prolif-eration and invasion of bladder cancer T24 cells.Methods Bladder cancer T24 cells were treated with different concentrations of piperine(5,1 0,20,40,80,and 1 60μmol/L).Then MTT assay,Transwell exper-iments,and western blot were used to detect the expression of bax and bcl-2,and the proliferation and ap-optosis of T24 cells.Results After a 24-hour treatment of piperine,IC50 value was 38.73μmol/L.With the increaseof piperine concentrations,the activity of T24 cell was significantly inhibited in a dose-depend-ent manner.Westernblot showed that the expression of anti-apoptotic protein bcl-2 reduced,and the pro-apoptotic protein bax increased.Conclusion Piperine could inhibit the proliferation of bladder cancer T24 cells and promote the apoptosis of T24 cells.

  12. Comment on "Effect of transferred NK4 gene on proliferation,migration, invasion, and apoptosis of human prostate cancer DU145 cells" by Dan Yue et al. in Asian Journal of Andrology

    Institute of Scientific and Technical Information of China (English)

    Shahriar Koochekpour

    2010-01-01

    @@ Hepatocyte growth factor/scatter factor (HGF/SF) interacting with its cell surface receptor tyrosine kinase (RTK) c-met proto-oncogene drives downstream signaling pathways which lead to cell proliferation, migration,invasion, apoptotic cell-death protection, angiogenesis during embryogenesis, repair and regeneration, and neoplastic growth and metastatic progression [1-6].

  13. MLK3 Signaling in Cancer Invasion

    Science.gov (United States)

    Rattanasinchai, Chotirat; Gallo, Kathleen A.

    2016-01-01

    Mixed-lineage kinase 3 (MLK3) was first cloned in 1994; however, only in the past decade has MLK3 become recognized as a player in oncogenic signaling. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates signals from several cell surface receptors including receptor tyrosine kinases (RTKs), chemokine receptors, and cytokine receptors. Once activated, MLK3 transduces signals to multiple downstream pathways, primarily to c-Jun terminal kinase (JNK) MAPK, as well as to extracellular-signal-regulated kinase (ERK) MAPK, P38 MAPK, and NF-κB, resulting in both transcriptional and post-translational regulation of multiple effector proteins. In several types of cancer, MLK3 signaling is implicated in promoting cell proliferation, as well as driving cell migration, invasion and metastasis. PMID:27213454

  14. Sulforaphane derived from broccoli inhibit proliferation and invasion of lung cancer A549 cells in vitro%西兰花提取物萝卜硫素抑制肺癌细胞的生长和侵袭

    Institute of Scientific and Technical Information of China (English)

    贾侃; 贺云冲; 洪姣; 黄春琦; 任军; 许健

    2014-01-01

    Sulforaphane was a multifunction compound derived from brassicaceous vegetable such as broccoli, reports showed that Sulforaphane provided with effection of antitumor and antioxidant. Lung cancer is an aggressive malignancy with a tendency of early distant metastases, the antitumor function of sulforaphane was corroborated by numerous lines of evidence, but the anticancer mechanism of this compound has not been wel obsvered. In this work, we analyzed vitality and invasion of A549 cels treated with sulforaphane by cellcounting kit (CCK8) and transwel, then measure the half maximal (50%) inhibitory concentration (IC50) of sulforaphane for A549 cels. The cels cycle, apoptosis and DNA fragment were analyzed using Flow Cytometry Analysis and agarose electrophoresis, TGF-βand NF-κB were analyzed by western blot after treatment with 3μg/mL sulforaphane. Results showed that A549 cels proliferate and invade were inhibited by sulforaphane with a dose-dependent manner, IC50 of sulforaphane was 3μg/mL, and the cellcycle were arrested at G2/M phase. 3μg/mL sulforaphane induced apoptosis , DNA fragment, decreased the expression of TGF-βand NF-κB in A549 cels. Our results pointed out that sulforaphane inhibited proliferation and invasion of lung cancer A549 cels in vitro, decreased the expression of inflammation proteins, maybe a novel chemotherapy for lung cancer.%萝卜硫素是从十字花科蔬菜中提取的多功能物质,研究已证实其具有抗癌、抗氧化等功效。肺癌是恶性程度高、具有转移倾向的恶性肿瘤,萝卜硫素抗肺癌的机制尚不是十分清楚。本研究通过CCK-8和transwel侵袭实验分析初步判断萝卜硫素对A549肺癌细胞活性和转移侵袭的影响,计算体外干预A549的IC50,流式细胞学分析IC50浓度萝卜硫素对细胞周期和凋亡的影响,电泳分析DNA片段化改变。结果显示A549细胞活性对萝卜硫素剂量依赖性下降,萝卜硫素作用于A549细胞的IC50为3μg

  15. Invasive cancer cells and metastasis

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  16. Biology of cancer invasion and metastasis.

    Science.gov (United States)

    Mareel, M M; Crombez, R

    1992-01-01

    Current concepts of invasion eventually leading to metastasis are discussed and exemplified by cancers of the head and neck mucosa. Invasion occurs at a number of steps, each step making an ecosystem comprising not only the neoplastic cells but also their normal counterparts, a variety of host cells and the extracellular matrix. The ecosystem concept may explain aspects of metastasis such as site-dependence and organ-specificity of cancer metastasis as well as invasiveness of normal leucocytes. Genes implicated in invasion and metastasis are actively searched for. Recently, the epithelial cell-cell adhesion molecule E-cadherin has been identified as an i- (invasion suppressor) gene product, i.e. a molecule the expression of which counterbalances i+ (invasion promotor) gene activity. Downregulation of E-cadherin in human head and neck cancers may account for their invasive and metastatic behaviour.

  17. Study on Invasion of Artesunate on Inhibiting Human Colon Cancer Cell SW620

    Directory of Open Access Journals (Sweden)

    Yu Fan

    2013-09-01

    Full Text Available Objective: To observe the invasive effect of Chinese extraction artesunate on human colon cancer cell SW620 and explore its possible mechanisms. Methods: Colon cancer cell SW620 was managed by different concentrations of artesunate, and soft agar colony-cultivating trial was applied to detect anchorage independent proliferation of cancer cells, Boyden chamber model method to detect the invasive capability of cancer cells and Western blot method to detect the change of intercellular adhesion molecule-1 (ICAM-1 proteins. Results: Artesunate can effectively inhibit malignant proliferation and invasive capability of colon cancer cell SW620, and was dose-dependent (P < 0.01. Artesunate can effectively inhibit the expression of cancer cell ICAM-1 gene proteins, and was time- and concentration-dependant (P <0.01. Conclusion: Artesunate can significantly inhibit the invasion of colon cancer cell SW620, which can be related to down-regulation of ICAM-1 protein level.

  18. Doxycycline Induces Apoptosis and Inhibits Proliferation and Invasion of Human Cervical Carcinoma Stem Cells.

    Directory of Open Access Journals (Sweden)

    Binlie Yang

    Full Text Available Cancer stem cells (CSCs are proposed to be responsible for high recurrence rate in cervical carcinoma. Reagents that can suppress the proliferation and differentiation of CSCs would provide new opportunities to fight against tumor recurrence. Doxycycline has been reported as a potential anti-cancer compound. However, few studies investigated its inhibitory effect against cervical cancer stem cells.HeLa cells were cultured in cancer stem cell conditional media in a poly-hema-treated dish. In this non-adhesive culture system, HeLa cells were treated with cisplatin until some cells survived and formed spheroids, which were then collected and injected into the immunodeficient mice. Cisplatin was administered every three days for five times. The tumor xenografts with CSC enrichment were cultured in cancer stem cell specific medium again to form tumorsphere, which we called HeLa-CSCs. Expression of cancer stem cell markers in HeLa-CSCs was measured by flow cytometry and qPCR. HeLa-CSCs were then treated with doxycycline. Proliferation and differentiation rates were determined by the size of spheres formed in vitro and tumor formed in vivo.We developed a new strategy to selectively enrich CSCs from human cervical carcinoma cell line HeLa, and these HeLa-CSCs are CD133+/CD49f+ cell populations with significantly enhanced expression of stem cell markers. When these HeLa-CSCs were treated with doxycycline, the colony formation, proliferation, migration and invasion, and differentiation were all suppressed. Meanwhile, stem cell markers SOX-2, OCT-4, NANOG, NOTCH and BMI-1 decreased in doxycycline treated cells, so as the surface markers CD133 and CD49f. Furthermore, proliferation markers Ki67 and PCNA were also decreased by doxycycline treatment in the in vivo xenograft mouse model.Cancer stem cells are enriched from sphere-forming and chemoresistant HeLa-derived tumor xenografts in immunodeficient mice. Doxycycline inhibits proliferation, invasion, and

  19. Extracellular Molecules Involved in Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Stivarou, Theodora; Patsavoudi, Evangelia, E-mail: epatsavoudi@pasteur.gr [Department of Biochemistry, Hellenic Pasteur Institute, Athens 11521 (Greece); Technological Educational Institute of Athens, Egaleo, Athens 12210 (Greece)

    2015-01-26

    Nowadays it is perfectly clear that understanding and eradicating cancer cell invasion and metastasis represent the crucial, definitive points in cancer therapeutics. During the last two decades there has been a great interest in the understanding of the extracellular molecular mechanisms involved in cancer cell invasion. In this review, we highlight the findings concerning these processes, focusing in particular on extracellular molecules, including extracellular matrix proteins and their receptors, growth factors and their receptors, matrix metalloproteinases and extracellular chaperones. We report the molecular mechanisms underlying the important contribution of this pool of molecules to the complex, multi-step phenomenon of cancer cell invasion.

  20. Extracellular Molecules Involved in Cancer Cell Invasion

    Directory of Open Access Journals (Sweden)

    Theodora Stivarou

    2015-01-01

    Full Text Available Nowadays it is perfectly clear that understanding and eradicating cancer cell invasion and metastasis represent the crucial, definitive points in cancer therapeutics. During the last two decades there has been a great interest in the understanding of the extracellular molecular mechanisms involved in cancer cell invasion. In this review, we highlight the findings concerning these processes, focusing in particular on extracellular molecules, including extracellular matrix proteins and their receptors, growth factors and their receptors, matrix metalloproteinases and extracellular chaperones. We report the molecular mechanisms underlying the important contribution of this pool of molecules to the complex, multi-step phenomenon of cancer cell invasion.

  1. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells

    OpenAIRE

    Lu, Yong; Jiang, Feng; JIANG, Hao; Wu, Kalina; Zheng, Xuguang; Cai, Yizhong; Katakowski, Mark; Chopp, Michael; To, Shing-Shun Tony

    2010-01-01

    Gallic acid, an organic acid, also known as 3,4,5-trihydroxybenzoic acid, is cytotoxic against certain cancer cells, without harming normal cells. The objective of this study is to evaluate whether gallic acid can inhibit glioma cell viability, proliferation, invasion and reduce glioma cell mediated angiogenesis. Treatment of U87 and U251n glioma cells with gallic acid inhibited cell viability in a dose- and time-dependent manner. BrdU and tube formation assays indicated that gallic acid sign...

  2. Study on Invasion of Artesunate on Inhibiting Human Colon Cancer Cell SW620

    Institute of Scientific and Technical Information of China (English)

    Fan Yu; Zhang Youli; Yao Guangtao; Li Yikui

    2013-01-01

    Objective:To observe the invasive effect of Chinese extraction artesunate on human colon cancer cell SW620 and explore its possible mechanisms. Methods:Colon cancer cell SW620 was managed by different concentrations of artesunate, and soft agar colony-cultivating trial was applied to detect anchorage independent proliferation of cancer cells, Boyden chamber model method to detect the invasive capability of cancer cells and Western blot method to detect the change of intercellular adhesion molecule-1 (ICAM-1) proteins. Results:Artesunate can effectively inhibit malignant proliferation and invasive capability of colon cancer cell SW620, and was dose-dependent (P Conclusion:Artesunate can signiifcantly inhibit the invasion of colon cancer cell SW620, which can be related to down-regulation of ICAM-1 protein level.

  3. Fascin promotes the motility and invasiveness of pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Yan-Feng Xu; Shuang-Ni Yu; Zhao-Hui Lu; Jian-Ping Liu; Jie Chen

    2011-01-01

    AIM: To explore the role of actin-bundling protein, fascin during the progression of pancreatic cancer. METHODS: The plasmid expressing human fascin-1 was stably transfected into the pancreatic cancer cell line MIA PaCa-2. The proliferation, cell cycle, motility, scattering, invasiveness and organization of the actin filament system in fascin-transfected MIA PaCa-2 cells and control non-transfected cells were determined. RESULTS: Heterogeneous overexpression of fascin markedly enhanced the motility, scattering, and invasiveness of MIA PaCa-2 cells. However, overexpression of fascin had minimal effect on MIA PaCa-2 cell proliferation and cell cycle. In addition, cell morphology and organization of the actin filament system were distinctly altered in fascin overexpressed cells. When transplanted into BALB/c-nu mice, fascin-transfected pancreatic cancer cells developed solid tumors at a slightly slower rate, but these tumors displayed more aggressive behavior in comparison with control tumors. CONCLUSION: Fascin promotes pancreatic cancer cell migration, invasion and scattering, thus contributes to the aggressive behavior of pancreatic cancer cells.

  4. 小RNA干扰STAT3基因表达对胃癌细胞增殖和侵袭的影响%Effect of RNA interference targeting STAT3 on the proliferation and invasion of gastric cancer cell

    Institute of Scientific and Technical Information of China (English)

    龚福生; 郑秋红; 汪相如; 许扬梅

    2011-01-01

    OBJECTIVE, To construct a expression vector of short hairpin RNA targeting STAT3 gene and observe its effects on cell growth and invasion ability of human gastric cancer cell line BGC-823 in vitro. METHODS: The recombinant plasmid pSilencer-STAT3 was constructed by combination of double-strand DNA containing STAT3 with vector pSilencer that underwent restriction digest. Then these recombinant plasmids were transfected by tipo-some into BGC-823 cells. The expression of STAT3 mRNA and protein were detected by RT-PCR and Western-blot, MTT assay was applied to assess cell proliferation. The invasion ability of BGC-823 cells was determined by transwells assay. RESULTS: Restriction enzyme digesting assay and DNA sequencing analysis was confirmed successful construction of recombinant plasmid pSilencer-STAT3. Compared with the non-transfected group and pSilencer-neospecial group, pSilencer-STAT3 inhibited the expression of STAT3 mRNA in BGC-823 cells (F=39, 424,P = 0. 000). The expression of STAT3 protein was also knocked down by pSilencer-STAT3 siRNA (F=31. 911, P = 0. 001). The proliferation of the BGC-823 cells was suppressed significantly (47. 3%) after transfec-tion of pSilencer-STAT3 recombinant plasmid, which was markedly higher than that of the pSilencer-neospecial vector control group (8. 1% , F=40. 835,P = 0. 000). The migration of the recombinant plasmid-transfected cells was significantly suppressed compared with that of cells transfected with pSilencer-neospecial vector or non-transfected (75± 10,111 + 10,104±9,F=ll. 311 ,P = 0. 009). CONCLUSION:Recombinant plasmid pSilencer-STAT3 can significantly reduce STAT3 gene expression in human gastric cancer cell BGC-823 and inhibit the proliferation and invasion ability.%目的:构建针对STAT3基因的短发夹状小干扰RNA重组质粒,探讨应用RNAi技术沉默STAT3基因对胃癌细胞BGC-823增殖和侵袭的影响.方法:应用DNA重组技术,构建针对STAT3基因的干扰RNA重组质粒(pSilencerSTAT3

  5. Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuanyuan; Jia, Qingzhu [Biomedical Analysis Center, Third Military Medical University, Chongqing (China); Chongqing Key Laboratory of Cytomics, Chongqing (China); Zhang, Qian [Department of Urology, Xinqiao Hospital, Third Military Medical University, Chongqing (China); Wan, Ying, E-mail: wanying_cn@163.com [Biomedical Analysis Center, Third Military Medical University, Chongqing (China); Chongqing Key Laboratory of Cytomics, Chongqing (China)

    2015-03-20

    Renal cell carcinoma (RCC) is a common urological cancer with a poor prognosis. A recent cohort study revealed that the median survival of RCC patients was only 1.5 years and that <10% of the patients in the study survived up to 5 years. In tumor development, Rab GTPase are known to play potential roles such as regulation of cell proliferation, migration, invasion, communication, and drug resistance in multiple tumors. However, the correlation between Rabs expression and the occurrence, development, and metastasis of RCC remains unclear. In this study, we analyzed the transcriptional levels of 52 Rab GTPases in RCC patients. Our results showed that high levels of Rab25 expression were significantly correlated with RCC invasion classification (P < 0.01), lymph-node metastasis (P < 0.001), and pathological stage (P < 0.01). Conversely, in 786-O and A-498 cells, knocking down Rab25 protein expression inhibited cell proliferation, migration, and invasion. Our results also demonstrated that Rab25 is a target gene of let-7d, and further suggested that Rab25 upregulation in RCC is due to diminished expression of let-7d. These findings indicate that Rab25 might be a novel candidate molecule involved in RCC development, thus identifying a potential biological therapeutic target for RCC. - Highlights: • The transcriptional levels of 52 Rab GTPases were analyzed in renal cell carcinoma (RCC). • High levels of Rab25 expression were significantly correlated with clinicopathological factors of RCC. • Knockdown of Rab25 protein expression reduced RCC cells proliferation, migration, and invasion. • Rab25 is a target gene of let-7d in RCC.

  6. High interstitial fluid pressure promotes tumor cell proliferation and invasion in oral squamous cell carcinoma.

    Science.gov (United States)

    Yu, Tao; Liu, Kun; Wu, Yingying; Fan, Jinchuan; Chen, Jianchao; Li, Chao; Zhu, Guiquan; Wang, Zhaohui; Li, Longjiang

    2013-11-01

    It has been shown that interstitial fluid pressure (IFP) is elevated in many solid tumors. The elevated IFP in tumors is responsible, at least in part, for the poor blood supply, inadequate delivery of therapeutic agents to solid tumors and poor treatment response in patients. The present study was carried out to examine alterations in malignant phenotypes in oral squamous cell carcinoma cells subjected to conditions mimicking IFP and to identify the relevant molecular mechanisms. We investigated tumor cell proliferation and invasion using SCC-4 and SCC-9 cells subjected to an increased extracellular pressure of 0, 15 and 30 mmHg in vitro. The results revealed that the increased IFP resulted in a marked increase in cancer cell proliferation, survival and invasion in vitro and altered the expression of >1,800 genes involved in invasion and metastasis, the heat shock pathway, the p38 and JNK signaling pathway, apoptosis and the cell growth and differentiation signaling pathway. These results suggest the important potential clinical application of measuring IFP, which can be used as a generic marker of prognosis and response to therapy.

  7. NSAIDs and Cell Proliferation in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Raj Ettarh

    2010-06-01

    Full Text Available Colon cancer is common worldwide and accounts for significant morbidity and mortality in patients. Fortunately, epidemiological studies have demonstrated that continuous therapy with NSAIDs offers real promise of chemoprevention and adjunct therapy for colon cancer patients. Tumour growth is the result of complex regulation that determines the balance between cell proliferation and cell death. How NSAIDs affect this balance is important for understanding and improving treatment strategies and drug effectiveness. NSAIDs inhibit proliferation and impair the growth of colon cancer cell lines when tested in culture in vitro and many NSAIDs also prevent tumorigenesis and reduce tumour growth in animal models and in patients, but the relationship to inhibition of tumour cell proliferation is less convincing, principally due to gaps in the available data. High concentrations of NSAIDs are required in vitro to achieve cancer cell inhibition and growth retardation at varying time-points following treatment. However, the results from studies with colon cancer cell xenografts are promising and, together with better comparative data on anti-proliferative NSAID concentrations and doses (for in vitro and in vivo administration, could provide more information to improve our understanding of the relationships between these agents, dose and dosing regimen, and cellular environment.

  8. MiR-126 regulates proliferation and invasion in the bladder cancer BLS cell line by targeting the PIK3R2-mediated PI3K/Akt signaling pathway

    Directory of Open Access Journals (Sweden)

    Xiao J

    2016-08-01

    Full Text Available Jun Xiao,1 Huan-Yi Lin,2 Yuan-Yuan Zhu,3 Yu-Ping Zhu,1 Ling-Wu Chen2 1Department of Urology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 2Department of Urology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 3Clinical Laboratory, Anhui Provincial Hospital, Anhui Medical University, Hefei, People’s Republic of China Objective: To assess whether microRNA-126 (miR-126 targets phosphatidylinositol 3-kinase regulatory subunit beta (PIK3R2 and to determine the potential roles of miR-126 in regulating proliferation and invasion via the PIK3R2-mediated phosphatidylinositol 3 kinase (PI3K-protein kinase B (Akt signaling pathway in the human bladder BLS cell line. Materials and methods: A recombinant lentivirus (Lv vector expressing miR-216 (Lv-miR-126 was successfully constructed, and Lv-miR-126 and Lv vector were transfected into the BLS cell line. A direct regulatory relationship between miR-126 and the PIK3R2 gene was demonstrated by luciferase reporter assays. To determine whether PIK3R2 directly participates in the miR-126-induced effects in BLS cells, anti-miR-126 and a PIK3R2 small interfering RNA (siRNA were transfected into the BLS cells. Quantitative real-time polymerase chain reaction was used to measure miR-126 and PIK3R2 expressions. 5-Ethynyl-2'-deoxyuridine and colony formation assays to assess cell proliferation, flow cytometry for cell apoptosis and cell cycle analysis, Transwell assays for cell migration and invasion, and Western blots for PIK3R2, PI3K, phosphorylated PI3K (p-PI3K, Akt, and phosphorylated Akt (p-Akt protein expressions were performed. Results: Lv-miR-126 significantly enhanced the relative expression of miR-126 in the BLS cells after infection (P<0.0001. MiR-126 overexpression inhibited the proliferation, cloning, migration, and invasion of BLS cells, promoted cell apoptosis, and induced S phase arrest (all P<0.05. PIK3R2, p-PI3K, and p-Akt protein expressions were significantly

  9. Regulation of cancer cell migration and invasion by sphingosine-1-phosphate

    Institute of Scientific and Technical Information of China (English)

    James; R; Van; Brocklyn

    2010-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingo-lipid that has been implicated in regulation of a number of cancer cell malignant behaviors, including cell proliferation, survival, chemotherapeutic resistance and angiogenesis. However, the effects of S1P on cancer cell migration, invasion and metastasis, are perhaps its most complex, due to the fact that, depending upon the S1P receptors that mediate its responses and the crosstalk with other signaling pathways, S1P can either positively or negatively regulate invasion. This review summarizes the effects of S1P on cancer cell invasion and the mechanisms by which it affects this important aspect of cancer cell behavior.

  10. miR-4295 promotes cell proliferation and invasion in anaplastic thyroid carcinoma via CDKN1A

    Energy Technology Data Exchange (ETDEWEB)

    Shao, Mingchen; Geng, Yiwei [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Xi, Ying [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Wei, Sidong [Liver Transplantation Hepatobiliary Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Wang, Liuxing; Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Ma, Wang, E-mail: doctormawang@126.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China)

    2015-09-04

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in anaplastic thyroid carcinoma (ATC), has remained elusive. Here, we identified that miR-4295 promotes ATC cell proliferation by negatively regulates its target gene CDKN1A. In ATC cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-4295, while miR-4295 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-4295 mimics significantly promoted the migration and invasion of ATC cells, whereas miR-4295 inhibitors significantly reduced cell migration and invasion. luciferase assays confirmed that miR-4295 directly bound to the 3'untranslated region of CDKN1A, and western blotting showed that miR-4295 suppressed the expression of CDKN1A at the protein levels. This study indicated that miR-4295 negatively regulates CDKN1A and promotes proliferation and invasion of ATC cell lines. Thus, miR-4295 may represent a potential therapeutic target for ATC intervention. - Highlights: • miR-4295 mimics promote the proliferation and invasion of ATC cells. • miR-4295 inhibitors inhibit the proliferation and invasion of ATC cells. • miR-4295 targets 3′UTR of CDKN1A in ATC cells. • miR-4295 negatively regulates CDKN1A in ATC cells.

  11. Dynamics of cancerous tissue correlates with invasiveness

    Science.gov (United States)

    West, Ann-Katrine Vransø; Wullkopf, Lena; Christensen, Amalie; Leijnse, Natascha; Tarp, Jens Magelund; Mathiesen, Joachim; Erler, Janine Terra; Oddershede, Lene Broeng

    2017-01-01

    Two of the classical hallmarks of cancer are uncontrolled cell division and tissue invasion, which turn the disease into a systemic, life-threatening condition. Although both processes are studied, a clear correlation between cell division and motility of cancer cells has not been described previously. Here, we experimentally characterize the dynamics of invasive and non-invasive breast cancer tissues using human and murine model systems. The intrinsic tissue velocities, as well as the divergence and vorticity around a dividing cell correlate strongly with the invasive potential of the tissue, thus showing a distinct correlation between tissue dynamics and aggressiveness. We formulate a model which treats the tissue as a visco-elastic continuum. This model provides a valid reproduction of the cancerous tissue dynamics, thus, biological signaling is not needed to explain the observed tissue dynamics. The model returns the characteristic force exerted by an invading cell and reveals a strong correlation between force and invasiveness of breast cancer cells, thus pinpointing the importance of mechanics for cancer invasion. PMID:28262796

  12. Dynamics of cancerous tissue correlates with invasiveness

    Science.gov (United States)

    West, Ann-Katrine Vransø; Wullkopf, Lena; Christensen, Amalie; Leijnse, Natascha; Tarp, Jens Magelund; Mathiesen, Joachim; Erler, Janine Terra; Oddershede, Lene Broeng

    2017-03-01

    Two of the classical hallmarks of cancer are uncontrolled cell division and tissue invasion, which turn the disease into a systemic, life-threatening condition. Although both processes are studied, a clear correlation between cell division and motility of cancer cells has not been described previously. Here, we experimentally characterize the dynamics of invasive and non-invasive breast cancer tissues using human and murine model systems. The intrinsic tissue velocities, as well as the divergence and vorticity around a dividing cell correlate strongly with the invasive potential of the tissue, thus showing a distinct correlation between tissue dynamics and aggressiveness. We formulate a model which treats the tissue as a visco-elastic continuum. This model provides a valid reproduction of the cancerous tissue dynamics, thus, biological signaling is not needed to explain the observed tissue dynamics. The model returns the characteristic force exerted by an invading cell and reveals a strong correlation between force and invasiveness of breast cancer cells, thus pinpointing the importance of mechanics for cancer invasion.

  13. Role of B7-H4 siRNA in Proliferation, Migration, and Invasion of LOVO Colorectal Carcinoma Cell Line

    Directory of Open Access Journals (Sweden)

    Hai-xia Peng

    2015-01-01

    Full Text Available Objectives. Colorectal cancer is one of the most common malignancies. Recent studies investigated that B7-H4 is highly expressed in various cancers. We aimed at exploring the effect of B7-H4 siRNA on proliferation, invasion, and migration of LOVO cells which expressed B7-H4 notably. Design and Methods. Colon adenocarcinoma dataset was downloaded from The Cancer Genome Atlas. 35 colorectal cancer patients admitted to Shanghai Tongren Hospital were enrolled in this study. Cell proliferation and cell cycle distribution were identified by CCK8 and flow cytometry, respectively. Transwell assay was performed to detect the invasion and migration of LOVO cells. CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were determined by real-time PCR and western blot. Results. B7-H4 expressed is elevated in colorectal cancer tissues than in the adjacent normal tissues. B7-H4 siRNA effectively inhibited the proliferation at 24 h and 48 h, arrested cell cycle at G0/G1, and suppressed cell invasion and migration. Gene set enrichment analysis showed that CXCL12/CXCR4 and JAK/STAT were correlative with the B7-H4 expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced. Conclusions. B7-H4 siRNA can effectively inhibit proliferation, invasion, and migration of LOVO cells by targeting CXCL12/CXCR4 and JAK2/STAT3 signaling, which can serve as a new target for colorectal carcinoma treatment.

  14. Host epithelial geometry regulates breast cancer cell invasiveness

    Science.gov (United States)

    Boghaert, Eline; Gleghorn, Jason P.; Lee, KangAe; Gjorevski, Nikolce; Radisky, Derek C.; Nelson, Celeste M.

    2012-01-01

    Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells. Here we explored how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development, by using a 3D microfabrication-based approach to engineer ducts composed of normal mammary epithelial cells that contained a single tumor cell. We found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining microcomputed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. This work suggests that the mechanical tone of nontumorigenic host epithelium directs the phenotype of tumor cells and provides additional insight into the instructive role of the mechanical tumor microenvironment. PMID:23150585

  15. TRPM7 is required for ovarian cancer cell growth, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing; Liao, Qian-jin [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Yi [Department of Obstetrics and Gynaecology, Xiangya Hospital, Central South University, Changsha 410078 (China); Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Qiong-yu [Department of Basic Medical Science, Yongzhou Vocational Technical College, Yong Zhou 425100 (China); Xiao, Ling, E-mail: lingxiaocsu@126.com [Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013 (China); Institute of Clinical Pharmacology, Central South University, Changsha 410018 (China)

    2014-11-28

    Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

  16. Quercetin-induced downregulation of phospholipase D1 inhibits proliferation and invasion in U87 glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Mi Hee [Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735 (Korea, Republic of); Min, Do Sik, E-mail: minds@pusan.ac.kr [Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735 (Korea, Republic of)

    2011-09-09

    Highlights: {yields} Quercetin, a bioactive flavonoid, suppresses expression and enzymatic activity of phospholipase D1. {yields} Quercetin abolishes NFkB-induced phospholipase D1 expression via inhibition of NFkB transactivation. {yields} Quercetin-induced suppression of phospholipase D1 inhibits invasion and proliferation of human glioma cells. -- Abstract: Phospholipase D (PLD) has been recognized as a regulator of cell proliferation and tumorigenesis, but little is known about the molecules regulating PLD expression. Thus, the identification of small molecules inhibiting PLD expression would be an important advance in PLD-mediated physiology. Quercetin, a ubiquitous bioactive flavonoid, is known to inhibit proliferation and induce apoptosis in a variety of cancer cells. In the present study, we examined the effect of quercetin on the expression of PLD in U87 glioma cells. Quercetin significantly suppressed the expression of PLD1 at the transcriptional level. Moreover, quercetin abolished the protein expression of PLD1 in a time and dose-dependent manner, as well as inhibited PLD activity. Quercetin suppressed NF{kappa}B-induced PLD1 expression via inhibition of NFkB transactivation. Furthermore, quercetin inhibited activation and invasion of metalloproteinase-2 (MMP-2), a key modulator of glioma cell invasion, induced by phosphatidic acid (PA), a product of PLD activity. Taken together these data demonstrate that quercetin abolishes PLD1 expression and subsequently inhibits invasion and proliferation of glioma cells.

  17. Involvement of calreticulin in cell proliferation, invasion and differentiation in diallyl disulfide-treated HL-60 cells.

    Science.gov (United States)

    Yi, Lan; Shan, Jian; Chen, Xin; Li, Guoqing; Li, Linwei; Tan, Hui; Su, Qi

    2016-09-01

    Diallyl disulfide (DADS) has shown potential as a therapeutic agent in various cancers. Previously, calreticulin (CRT) was found to be downregulated in differentiated HL-60 cells treated with DADS. The present study investigated the role of CRT proteins in DADS-induced proliferation, invasion and differentiation in HL-60 cells. The present study demonstrated that DADS treatment significantly changed the morphology of HL-60 cells and caused the significant time-dependent downregulation of CRT. Small interfering RNA (siRNA)-mediated knockdown of CRT expression significantly inhibited proliferation, decreased invasion ability, increased the expression of cluster of differentiation (CD)11b and reduced the expression of CD33 in DADS-treated HL-60 cells. DADS also significantly affected cell proliferation, invasion and differentiation in CRT-overexpressed HL-60 cells. Nitroblue tetrazolium (NBT) reduction assays showed decreased NBT reduction activity in the CRT overexpression group and increased NBT reduction in the CRT siRNA group. Following treatment with DADS, the NBT reduction abilities in all groups were increased. In conclusion, the present study clearly demonstrates the downregulation of CRT during DADS-induced differentiation in HL-60 cells and indicates that CRT is involved in cell proliferation, invasion and differentiation in DADS-treated HL-60 cells.

  18. GLUL Promotes Cell Proliferation in Breast Cancer.

    Science.gov (United States)

    Wang, Yanyan; Fan, Shaohua; Lu, Jun; Zhang, Zifeng; Wu, Dongmei; Wu, Zhiyong; Zheng, Yuanlin

    2016-10-28

    Glutamate-ammonia ligase (GLUL) belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. Here, we found higher expression of GLUL in the breast cancer patients was associated with larger tumor size and higher level of HER2 expression. In addition, GLUL was heterogeneously expressed in various breast cancer cells. The mRNA and protein expression levels of GLUL in SK-BR-3 cells were obviously higher than that in the other types of breast cancer cells. Results showed GLUL knockdown in SK-BR-3 cells could significantly decrease the proliferation ability. Furthermore, GLUL knockdown markedly inhibited the p38 MAPK and ERK1/ERK2 signaling pathways in SK-BR-3 cells. Thus, GLUL may represent a novel target for selectively inhibiting p38 MAPK and ERK1/ERK2 signaling pathways and the proliferation potential of breast cancer cells. This article is protected by copyright. All rights reserved.

  19. EZH2 depletion blocks the proliferation of colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Bettina Fussbroich

    Full Text Available The Enhancer of Zeste 2 (EZH2 protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer.

  20. Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro

    Institute of Scientific and Technical Information of China (English)

    Dong Xia; Lu-Nan Yan; Jian-Guo Xie; Yu Tong; Mao-Lin Yan; Xin-Ping Wang; Ming-Man Zhang; Lan-Ying Zhao

    2006-01-01

    BACKGROUND: Matrix metalloproteinases (MMPs) and its natural tissue inhibitors of metalloproteinases (TIMPs) are involved in cancer progression. This study was undertaken to determine the effects of overexpression of TIMP-1 on human hepatocellular carcinoma (HCC) cell growth, proliferation, and invasion. METHODS: Employing the efifcient AdEasyTM system, recombinant adenovirus AdTIMP-1 containing full-length cDNA of TIMP-1 was generated by homologous recombination and ampliifed in 293 cells. Then, human HCC cell line (HepG2) underwent gene transfection to overexpress TIMP-1 (so-called HepG-T cells). The mRNA and protein expressions of TIMP-1 were detected with RT-PCR and Western blotting, respectively. The ultrastructure was observed with a transmission electron microscope and the proliferation of HepG-T cells was determined by MTT assay and growth curve. The potential of in vitro invasion was measured with Millicell Chamber. RESULTS:The resulting AdTIMP-1 and HepG-T cells were generated and the expression of TIMP-1 was detected in vitro. The cell proliferation curves and MTT assay showed HepG-T cells' growth, and proliferation were obviously inhibited. The invasion across Matrigel-coated iflters was signiifcantly decreased compared with controls. The suppression rate of HepG-2 cells with AdhTIMP-1 transfection was 50%, and AdhTIMP-1 transfection inhibited by more than 91.6% of the invasion into the Matrigel-coated iflter (P CONCLUSIONS: TIMP-1 overexpression results in the suppression of proliferative and invasive potential of HepG2 cells in vitro. This study demonstrates the potential role of TIMP-1 as a target for liver cancer gene therapy and has laid a foundation for further study on its anticancer function.

  1. [Lobular neoplasms and invasive lobular breast cancer].

    Science.gov (United States)

    Sinn, H-P; Helmchen, B; Heil, J; Aulmann, S

    2014-02-01

    The term lobular neoplasia (LN) comprises both atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS) and thus a spectrum of morphologically heterogeneous but clinically and biologically related lesions. LN is regarded as a nonobligatory precursor lesion of invasive breast cancer and at the same time as an indicator lesion for ipsilateral and contralateral breast cancer risk of the patient. Rare pleomorphic or florid variants of LCIS must be differentiated from classical LCIS. The classical type of invasive lobular carcinoma (ILC) can be distinguished from the non-special type of invasive breast cancer (NST) by E-cadherin inactivation, loss of E-cadherin related cell adhesion and the subsequent discohesive growth pattern. Variant forms of ILC may show different molecular features, and solid and pleomorphic differentiation patterns in cases of high grade variants. Important parameters for the prognostic assessment of ILC are tumor grading and the recognition of morphological variants.

  2. The Transcriptional Repressor ZNF503/Zeppo2 Promotes Mammary Epithelial Cell Proliferation and Enhances Cell Invasion*

    Science.gov (United States)

    Shahi, Payam; Slorach, Euan M.; Wang, Chih-Yang; Chou, Jonathan; Lu, Angela; Ruderisch, Aline; Werb, Zena

    2015-01-01

    The NET (nocA, Nlz, elB, TLP-1) subfamily of zinc finger proteins is an important mediator during developmental processes. The evolutionary conserved zinc finger protein ZNF503/Zeppo2 (zinc finger elbow-related proline domain protein 2, Zpo2) plays critical roles during embryogenesis. We found that Zpo2 is expressed in adult tissue and examined its function. We found that ZPO2 is a nuclearly targeted transcriptional repressor that is expressed in mammary epithelial cells. Elevated Zpo2 levels increase mammary epithelial cell proliferation. Zpo2 promotes cellular invasion through down-regulation of E-cadherin and regulates the invasive phenotype in a RAC1-dependent manner. We detect elevated Zpo2 expression during breast cancer progression in a MMTV-PyMT transgenic mouse model. Tumor transplant experiments indicated that overexpression of Zpo2 in MMTV-PyMT mammary tumor cell lines enhances lung metastasis. Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development. PMID:25538248

  3. Aquatic invasive species: Lessons from cancer research

    Science.gov (United States)

    Sepulveda, Adam; Ray, Andrew; Al-Chokhachy, Robert K.; Muhlfeld, Clint C.; Gresswell, Robert E.; Gross, Jackson A.; Kershner, Jeffrey L.

    2014-01-01

    Aquatic invasive species are disrupting ecosystems with increasing frequency. Successful control of these invasions has been rare: Biologists and managers have few tools for fighting aquatic invaders. In contrast, the medical community has long worked to develop tools for preventing and fighting cancer. Its successes are marked by a coordinated research approach with multiple steps: prevention, early detection, diagnosis, treatment options and rehabilitation. The authors discuss how these steps can be applied to aquatic invasive species, such as the American bullfrog (Lithobates catesbeianus), in the Northern Rocky Mountain region of the United States, to expedite tool development and implementation along with achievement of biodiversity conservation goals.

  4. Endostatin induces proliferation of oral carcinoma cells but its effect on invasion is modified by the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Alahuhta, Ilkka [Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland); Aikio, Mari [Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu (Finland); Oulu Center for Cell-Matrix Research, University of Oulu (Finland); Väyrynen, Otto; Nurmenniemi, Sini [Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland); Suojanen, Juho [Department of Oral and Maxillo-facial Diseases, University of Helsinki, Helsinki University Central Hospital (Finland); Teppo, Susanna [Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland); Pihlajaniemi, Taina; Heljasvaara, Ritva [Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu (Finland); Oulu Center for Cell-Matrix Research, University of Oulu (Finland); Salo, Tuula [Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland); Department of Oral and Maxillo-facial Diseases, University of Helsinki, Helsinki University Central Hospital (Finland); Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, Sao Paolo (Brazil); Nyberg, Pia, E-mail: pia.nyberg@oulu.fi [Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland)

    2015-08-01

    The turnover of extracellular matrix liberates various cryptic molecules with novel biological activities. Endostatin is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of collagen XVIII. Although there are a large number of studies on its anti-tumor effects, the molecular mechanisms are not yet completely understood, and the reasons why endostatin has not been successful in clinical trials are unclear. Research has mostly focused on its anti-angiogenic effect in tumors. Here, we aimed to elucidate how endostatin affects the behavior of aggressive tongue HSC-3 carcinoma cells that were transfected to overproduce endostatin. Endostatin inhibited the invasion of HSC-3 cells in a 3D collagen–fibroblast model. However, it had no effect on invasion in a human myoma organotypic model, which lacks vital fibroblasts. Recombinant endostatin was able to reduce the Transwell migration of normal fibroblasts, but had no effect on carcinoma associated fibroblasts. Surprisingly, endostatin increased the proliferation and decreased the apoptosis of cancer cells in organotypic models. Also subcutaneous tumors overproducing endostatin grew bigger, but showed less local invasion in nude mice xenografts. We conclude that endostatin affects directly to HSC-3 cells increasing their proliferation, but its net effect on cancer invasion seem to depend on the cellular composition and interactions of tumor microenvironment. - Highlights: • Endostatin affects not only angiogenesis, but also carcinoma cells and fibroblasts. • Endostatin increased carcinoma cell proliferation, but decreased 3D invasion. • The invasion inhibitory effect was sensitive to the microenvironment composition. • Fibroblasts may be a factor regulating the fluctuating roles of endostatin.

  5. MicroRNA-133a Inhibits Osteosarcoma Cells Proliferation and Invasion via Targeting IGF-1R

    Directory of Open Access Journals (Sweden)

    Guangnan Chen

    2016-02-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a class of small noncoding RNAs that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Downregulated microRNAs and their roles in cancer development have attracted much attention. A growing body of evidence showed that microRNA-133a (miR-133a has inhibitory effects on cell proliferation, migration, invasion, and metastasis of osteosarcoma. Methods: MiR-133a expression in human osteosarcoma cell lines and human normal osteoblastic cell line hFOB was investigated by real-time PCR (RT-PCR. The role of miR-133a in human osteosarcoma growth and invasion was assessed in cell lines in vitro and in vivo. Then, luciferase reporter assay validated IGF-1R as a downstream and functional target of miR-133a, and functional studies revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of IGF-1R expression. Results: MiR-133a was lower expressed in human osteosarcoma cell lines than human normal osteoblastic cell line hFOB and its effect on inhibiting proliferation, invasion and metastasis is mediated by its direct interaction with the IGF-1R. Furthermore, the tumour-suppressive function of miR-133a probably contributed to inhibiting the activation AKT and ERK signaling pathway. Conclusion: MiR-133a suppresses osteosarcoma progression and metastasis by targeting IGF-1R in human osteosarcoma cells, providing a novel candidate prognostic factor and a potential anti-metastasis therapeutic target in osteosarcoma.

  6. Long noncoding RNA SPRY4-IT1 promotes esophageal squamous cell carcinoma cell proliferation, invasion, and epithelial-mesenchymal transition.

    Science.gov (United States)

    Cui, Fei; Wu, Duoguang; He, Xiaotian; Wang, Wenjian; Xi, Jingle; Wang, Minghui

    2016-08-01

    The biology of esophageal squamous cell carcinoma (ESCC) remains poorly understood. Long noncoding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including ESCC. SPRY4-IT1 has been recently revealed as oncogenic regulator or tumor suppressors in different cancers; however, whether SPRY4-IT1 is involved in ESCC remains poorly understood. To investigate the role of SPRY4-IT1 in ESCC, we evaluated the SPRY4-IT1 expression levels in a series of ESCC patients and a panel of ESCC cell line using qRT-PCR. CCK8 and colony formation assay were performed to assess the effect of SPRY4-IT1siRNA on cell proliferation, migration, and invasion of ESCC cell lines. SPRY4-IT1 expression was upregulated in ESCC tissues and the higher expression of SPRY4-IT1 was significantly correlated with tumor grade, depth of invasion, and lymph node metastasis. Moreover, silencing of SPRY4-IT1 expression inhibited ESCC cell proliferation, colony formation, migration, and invasion. Therefore, our study indicates that SPRY4-IT1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.

  7. HPV genotypes in invasive cervical cancer in Danish women

    DEFF Research Database (Denmark)

    Kirschner, Benny; Junge, Jette; Holl, Katsiaryna;

    2013-01-01

    Human papillomavirus (HPV) genotype distribution in invasive cervical cancers may differ by geographic region. The primary objective of this study was to estimate HPV-genotype distribution in Danish women with a diagnosis of invasive cervical cancer.......Human papillomavirus (HPV) genotype distribution in invasive cervical cancers may differ by geographic region. The primary objective of this study was to estimate HPV-genotype distribution in Danish women with a diagnosis of invasive cervical cancer....

  8. Inhibition of chemokine (C-C motif receptor 7 sialylation suppresses CCL19-stimulated proliferation, invasion and anti-anoikis.

    Directory of Open Access Journals (Sweden)

    Mei-Lin Su

    Full Text Available Chemokine (C-C motif receptor 7 (CCR7 is involved in lymph-node homing of naive and regulatory T cells and lymphatic metastasis of cancer cells. Sialic acids comprise a group of monosaccharide units that are added to the terminal position of the oligosaccharide chain of glycoproteins by sialyation. Recent studies suggest that aberrant sialylation of receptor proteins contributes to proliferation, motility, and drug resistance of cancer cells. In this study, we addressed whether CCR7 is a sialylated receptor protein and tried to elucidate the effect of sialylation in the regulation of signal transduction and biological function of CCR7. Our results demonstrated that α-2, 3-sialyltransferase which catalyze sialylation reaction in vivo was overexpressed in breast tumor tissues and cell lines. Lectin blot analysis clearly demonstrated that CCR7 receptor was sialyated in breast cancer cells. Chemokine (C-C motif ligand 19 (CCL19, the cognate ligand for CCR7, induced the activation of extracellular signal-regulated kinase (ERK and AKT signaling and increased the expression of cell cycle regulatory proteins and proliferation of breast cancer cells. When cells were pre-treated with a sialyltransferase inhibitor AL10 or sialidase, CCL19-induced cell growth was significantly suppressed. CCL19 also increased invasion and prevented anoikis by up-regulating pro-survival proteins Bcl-2 and Bcl-xL. Inhibition of sialylation by AL10 totally abolished these effects. Finally, we showed that AL10 inhibited tumorigenicity of breast cancer in experimental animals. Taken together, we demonstrate for the first time that CCR7 receptor is a sialylated protein and sialylation is important for the paracrine stimulation by its endogenous ligand CCL19. In addition, inhibition of aberrant sialylation of CCR7 suppresses proliferation and invasion and triggers anoikis in breast cancer cells. Targeting of sialylation enzymes may be a novel strategy for breast cancer treatment.

  9. MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Ying; Gao, Yan, E-mail: gaoyanhdhos@126.com

    2014-05-09

    Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.

  10. Mini-invasive surgery for colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Wei-Gen Zeng; Zhi-Xiang Zhou

    2014-01-01

    Laparoscopic techniques have been extensively used for the surgical management of colorectal cancer during the last two decades. Accumulating data have demonstrated that laparoscopic colectomy is associated with better short-term outcomes and equivalent oncologic outcomes when compared with open surgery. However, some controversies regarding the oncologic quality of mini-invasive surgery for rectal cancer exist. Meanwhile, some progresses in colorectal surgery, such as robotic technology, single-incision laparoscopic surgery, natural orifice specimen extraction, and natural orifice transluminal endoscopic surgery, have been made in recent years. In this article, we review the published data and mainly focus on the current status and latest advances of mini-invasive surgery for colorectal cancer.

  11. Upregulation of metastasis-associated gene 2 promotes cell proliferation and invasion in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Wu MH

    2016-03-01

    Full Text Available Minhua Wu,1,2,* Xiaoxia Ye,2,* Xubin Deng,3,* Yanxia Wu,4 Xiaofang Li,4 Lin Zhang11Department of Histology and Embryology, Southern Medical University, Guangzhou, 2Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, 3Affiliated Cancer Hospital of Guangzhou Medical University, Cancer Center of Guangzhou Medical University, Guangzhou, 4Pathological Diagnosis and Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China*These authors contributed equally to this workAims: Metastasis-associated gene 2 (MTA2 is reported to play an important role in tumor progression, but little is known about the role of MTA2 in nasopharyngeal carcinoma (NPC. The aim of the study was to explore the expression and function of MTA2 in NPC.Methods: Expression of MTA2 in NPC tissues and cell lines was detected by immunohistochemistry and Western blotting. Relationship between MTA2 expression and clinicopathological features was analyzed. Stable MTA2-overexpressing and MTA2-siliencing NPC cells were established by transfection with plasmids encoding MTA2 cDNA and lentivirus-mediated short hairpin RNA, respectively. Cell viability was determined by Cell Counting Kit-8 and colony formation assay. Cell migration ability was evaluated by wound healing and transwell invasion assay. The impact of MTA2 knockdown on growth and metastasis of CNE2 cells in vivo was determined by nude mouse xenograft models. Expression of several Akt pathway proteins was detected by Western blotting.Results: MTA2 was upregulated in NPC tissues and three NPC cell lines detected (CNE1, CNE2, and HNE1. MTA2 expression was related to clinical stage and lymph node metastasis of patients with NPC. MTA2 upregulation promoted proliferation and invasion of CNE1 cells, while MTA2 depletion had opposite effects on CNE2 cells. Moreover, MTA2 depletion suppressed growth and metastasis of CNE2 cells in vivo. MTA2 overexpression

  12. Epigenetic suppression of neprilysin regulates breast cancer invasion

    Science.gov (United States)

    Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

    2016-01-01

    In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT–PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

  13. CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells.

    Science.gov (United States)

    Gao, Darrin; Rahbar, Ramtin; Fish, Eleanor N

    2016-06-01

    In earlier studies, we showed that CCL5 enhances proliferation and survival of MCF-7 breast cancer cells in an mTOR-dependent manner and we provided evidence that, for T cells, CCL5 activation of CCR5 results in increased glycolysis and enhanced ATP production. Increases in metabolic activity of cancer cells, specifically increased glycolytic activity and increased expression of glucose transporters, are associated with tumour progression. In this report, we provide evidence that CCL5 enhances the proliferation of human breast cancer cell lines (MDA-MB-231, MCF-7) and mouse mammary tumour cells (MMTV-PyMT), mediated by CCR5 activation. Concomitant with enhanced proliferation we show that CCL5 increases cell surface expression of the glucose transporter GLUT1, and increases glucose uptake and ATP production by these cells. Blocking CCL5-inducible glucose uptake abrogates the enhanced proliferation induced by CCL5. We provide evidence that increased glucose uptake is associated with enhanced glycolysis, as measured by extracellular acidification. Moreover, CCL5 enhances the invasive capacity of these breast cancer cells. Using metabolomics, we demonstrate that the metabolic signature of CCL5-treated primary mouse mammary tumour cells reflects increased anabolic metabolism. The implications are that CCL5-CCR5 interactions in the tumour microenvironment regulate metabolic events, specifically glycolysis, to promote tumour proliferation and invasion.

  14. RNAi-mediated silencing of CD147 inhibits tumor cell proliferation, invasion and increases chemosensitivity to cisplatin in SGC7901 cells in vitro

    Directory of Open Access Journals (Sweden)

    Zhu Chan

    2010-06-01

    Full Text Available Abstract Background CD147 is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily. CD147 has been implicated in numerous physiological and pathological activities. Enriched on the surface of many tumor cells, CD147 promotes tumor growth, invasion, metastasis and angiogenesis and confers resistance to some chemotherapeutic drugs. In this study, we investigated the possible role of CD147 in the progression of gastric cancer. Methods Short hairpin RNA (shRNA expressing vectors targeting CD147 were constructed and transfected into human gastric cancer cells SGC7901 and CD147 expression was monitored by quantitative realtime RT-PCR and Western blot. Cell proliferation, the activities of MMP-2 and MMP-9, the invasive potential and chemosensitivity to cisplatin of SGC7901 cells were determined by MTT, gelatin zymography, Transwell invasion assay and MTT, respectively. Results Down-regulation of CD147 by RNAi approach led to decreased cell proliferation, MMP-2 and MMP-9 activities and invasive potential of SGC7901 cells as well as increased chemosensitivity to cisplatin. Conclusion CD147 involves in proliferation, invasion and chemosensitivity of human gastric cancer cell line SGC7901, indicating that CD147 may be a promising therapeutic target for gastric cancer.

  15. CRISPR-Cas9 Mediated NOX4 Knockout Inhibits Cell Proliferation and Invasion in HeLa Cells

    Science.gov (United States)

    Park, Rackhyun; Li, Liqing; Jang, Minsu; Morris, Andrew J.; Huang, Cai

    2017-01-01

    Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M population. Moreover, NOX4 deficiency resulted in a dramatic decrease in invadopodium formation and the invasive activity. In addition, NOX4 deficiency also caused a decrease in focal adhesions and cell migration in HeLa cells. These results suggest that NOX4 is required for both efficient proliferation and invasion of HeLa cells. PMID:28099519

  16. CRISPR-Cas9 Mediated NOX4 Knockout Inhibits Cell Proliferation and Invasion in HeLa Cells.

    Science.gov (United States)

    Jafari, Naser; Kim, Hyunju; Park, Rackhyun; Li, Liqing; Jang, Minsu; Morris, Andrew J; Park, Junsoo; Huang, Cai

    2017-01-01

    Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M population. Moreover, NOX4 deficiency resulted in a dramatic decrease in invadopodium formation and the invasive activity. In addition, NOX4 deficiency also caused a decrease in focal adhesions and cell migration in HeLa cells. These results suggest that NOX4 is required for both efficient proliferation and invasion of HeLa cells.

  17. Pathologic findings in nonpalpable invasive breast cancer.

    Science.gov (United States)

    McKinney, C D; Frierson, H F; Fechner, R E; Wilhelm, M C; Edge, S B

    1992-01-01

    Previous studies have shown that patients with nonpalpable invasive breast cancer have a favorable prognosis. These studies, however, have not analyzed pathologic features of mammographically detected tumors according to tumor size. We describe the histopathologic features of 77 nonpalpable invasive breast cancers, comparing neoplasms less than or equal to 1 cm with larger clinically occult tumors. Forty-seven lesions (61%) were less than or equal to 1 cm (group A) and 30 (39%) were greater than 1 cm (group B). In group A, there were 30 infiltrating ductal carcinomas (IDC); seven infiltrating lobular carcinomas (ILC); and two cases each of mixed ILC and IDC, mixed tubular carcinoma and ILC, and infiltrating cribriform carcinoma. There was one case each of mucinous carcinoma, apocrine carcinoma, tubular carcinoma, and mixed mucinous and IDC. In group B, there were 23 (77%) IDC, five (17%) ILC, and two mixed IDC and ILC. Tumors in group B were more frequently grade 3 (22% versus 7%), but this was not statistically significant (p = 0.21). There were no important differences in the frequency, subtypes and location of carcinoma in situ, or other histopathologic parameters evaluated in the biopsy specimens. Mastectomy specimens with axillary lymph node dissections were available for review in 64 cases (83%). Group B patients had a higher rate of residual invasive carcinoma (31% versus 13%) and lymph node metastases (31% versus 16%), but these differences were not statistically significant. Residual carcinoma in situ was more frequent in group B (54%) compared with group A (26%) (p = .036). Of seven group B cases with negative biopsy margins, residual invasive carcinoma was present in five (71%). We conclude that small nonpalpable invasive breast cancers differ from larger nonpalpable tumors primarily in size. The finding of negative biopsy margins should not be construed as conclusive evidence for the absence of residual infiltrating disease.

  18. Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles

    Directory of Open Access Journals (Sweden)

    Chen Kun-Wan

    2011-10-01

    Full Text Available Abstract Background The invasion of a new species into an established ecosystem can be directly compared to the steps involved in cancer metastasis. Cancer must grow in a primary site, extravasate and survive in the circulation to then intravasate into target organ (invasive species survival in transport. Cancer cells often lay dormant at their metastatic site for a long period of time (lag period for invasive species before proliferating (invasive spread. Proliferation in the new site has an impact on the target organ microenvironment (ecological impact and eventually the human host (biosphere impact. Results Tilman has described mathematical equations for the competition between invasive species in a structured habitat. These equations were adapted to study the invasion of cancer cells into the bone marrow microenvironment as a structured habitat. A large proportion of solid tumor metastases are bone metastases, known to usurp hematopoietic stem cells (HSC homing pathways to establish footholds in the bone marrow. This required accounting for the fact that this is the natural home of hematopoietic stem cells and that they already occupy this structured space. The adapted Tilman model of invasion dynamics is especially valuable for modeling the lag period or dormancy of cancer cells. Conclusions The Tilman equations for modeling the invasion of two species into a defined space have been modified to study the invasion of cancer cells into the bone marrow microenvironment. These modified equations allow a more flexible way to model the space competition between the two cell species. The ability to model initial density, metastatic seeding into the bone marrow and growth once the cells are present, and movement of cells out of the bone marrow niche and apoptosis of cells are all aspects of the adapted equations. These equations are currently being applied to clinical data sets for verification and further refinement of the models.

  19. CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling.

    Science.gov (United States)

    Fritz, Rafael D; Radziwill, Gerald

    2010-03-01

    Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-kappaB-dependent manner. Moreover, CNK1 cooperates with the NF-kappaB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-kappaB pathway because knockdown of CNK1 interferes with processing of NF-kappaB2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1-depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy.

  20. Minimally invasive surgery for esophageal cancer.

    Science.gov (United States)

    Santillan, Alfredo A; Farma, Jeffrey M; Meredith, Kenneth L; Shah, Nilay R; Kelley, Scott T

    2008-10-01

    Esophageal cancer represents a major public health problem worldwide. Several minimally invasive esophagectomy (MIE) techniques have been described and represent a safe alternative for the surgical management of esophageal cancer in selected centers with high volume and expertise in them. This article reviews the most recent and largest series evaluating MIE techniques. Recent larger series have shown MIE to be equivalent in postoperative morbidity and mortality rates to conventional surgery. MIE has been associated with less blood loss, less postoperative pain, and decreased intensive care unit and hospital length of stay compared with conventional surgery. Despite limited data, conventional surgery and MIE have shown no significant difference in survival, stage for stage. The myriad of MIE techniques complicates the debate of defining the optimal surgical approach for treating esophageal cancer. Randomized controlled trials comparing MIE with conventional open esophagectomy are needed to clarify the ideal procedure with the lowest postoperative morbidity, best quality of life after surgery, and long-term survival.

  1. Primary cilia are lost in preinvasive and invasive prostate cancer.

    Directory of Open Access Journals (Sweden)

    Nadia B Hassounah

    Full Text Available Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN, and invasive prostate cancer (including perineural invasion were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human

  2. Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yeying Fang

    2014-01-01

    Full Text Available Background. Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. Methods. Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. Results. We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. Conclusions. Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

  3. MicroRNA-663 inhibits the proliferation, migration and invasion of glioblastoma cells via targeting TGF-β1.

    Science.gov (United States)

    Li, Qizhuang; Cheng, Quan; Chen, Zigui; Peng, Renjun; Chen, Rui; Ma, Zhiming; Wan, Xin; Liu, Jincan; Meng, Ming; Peng, Zhigang; Jiang, Bing

    2016-02-01

    Cell migration and invasion are key processes involved during tumor metastasis. Recently, microRNAs (miRs) have been demonstrated to play important roles in the regulation of cancer metastasis. However, the underlying mechanisms remain unknown. Here, we aimed to investigate the exact role of miR-663 in the metastasis of glioblastoma as well as the underlying mechanisms. By performing quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, we demonstrated that miR-663 was significantly downregulated in glioblastoma tissues (n=25), when compared to that in normal brain tissues (n=15). In addition, its expression levels were also reduced in human glioblastoma cell lines, A172 and U87. Furthermore, restoration of miR-663 expression led to a significant decrease in the cell proliferation, migration and invasion of human glioblastoma A172 and U87 cells. We further identified TGF-β1 as a direct target of miR-663, and found that the expression of TGF-β1 was negatively mediated by miR-663 at the post-transcriptional level in glioblastoma cells. Moreover, overexpression of TGF-β1 significantly reversed the inhibitory effects of miR-663 upregulation on the proliferation, migration and invasion in A172 and U87 cells. In addition, our data suggest that MMP2 and E-cadherin, a key factor in epithelial-mesenchymal transition (EMT), are involved in the miR-633/TGF-β1-mediated metastasis of glioblastoma. In summary, miR-663 plays an inhibitory role in the regulation of proliferation, migration and invasion of glioblastoma cells, partly at least, via direct mediation of TGF-β1 as well as downstream MMP2 and E-cadherin. Therefore, we suggest that miR-663 is a potential candidate for the prevention of glioblastoma metastasis.

  4. Identification of pancreatic cancer invasion-related proteins by proteomic analysis

    Directory of Open Access Journals (Sweden)

    Clynes Martin

    2009-02-01

    Full Text Available Abstract Background Markers of pancreatic cancer invasion were investigated in two clonal populations of the cell line, MiaPaCa-2, Clone #3 (high invasion and Clone #8 (low invasion using proteomic profiling of an in vitro model of pancreatic cancer. Materials and methods Using 2D-DIGE followed by MALDI-TOF MS, two clonal sub-populations of the pancreatic cancer cell line, MiaPaCa-2 with high and low invasive capacities were incubated on matrigel 24 hours prior to analysis to stimulate cell-ECM contact and mimic in vivo interaction with the basement membrane. Results Sixty proteins were identified as being differentially expressed (> 1.2 fold change and p ≤ 0.05 between Clone #3 and Clone #8. Proteins found to have higher abundance levels in the highly invasive Clone #3 compared to the low invasive Clone #8 include members of the chaperone activity proteins and cytoskeleton constituents whereas metabolism-associated and catalytic proteins had lower abundance levels. Differential protein expression levels of ALDH1A1, VIM, STIP1 and KRT18 and GAPDH were confirmed by immunoblot. Using RNAi technology, STIP1 knockdown significantly reduced invasion and proliferation of the highly invasive Clone #3. Knockdown of another target, VIM by siRNA in Clone #3 cells also resulted in decreased invasion abilities of Clone #3. Elevated expression of STIP1 was observed in pancreatic tumour tissue compared to normal pancreas, whereas ALDH1A1 stained at lower levels in pancreatic tumours, as detected by immunohistochemistry. Conclusion Identification of targets which play a role in the highly invasive phenotype of pancreatic cancer may help to understand the biological behaviour, the rapid progression of this cancer and may be of importance in the development of new therapeutic strategies for pancreatic cancer.

  5. Fatty acid metabolites in rapidly proliferating breast cancer.

    Directory of Open Access Journals (Sweden)

    Joseph T O'Flaherty

    Full Text Available PURPOSE: Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer. EXPERIMENTAL DESIGN: We used selective ion monitoring-mass spectrometry to quantify in the cancer and normal breast tissue of 27 patients metabolites that stimulate (15-, 12-, 5-hydroxy-, and 5-oxo-eicosatetraenoate, 13-hydroxy-octadecaenoate [HODE] or inhibit (prostaglandin [PG]E2 and D2 breast cancer cell proliferation. We then related their levels to each cancer's proliferation rate as defined by its Mib1 score. RESULTS: 13-HODE was the only metabolite strongly, significantly, and positively associated with Mib1 scores. It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations. CONCLUSIONS: Our data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival.

  6. Apigenin inhibits the proliferation and invasion of osteosarcoma cells by suppressing the Wnt/β-catenin signaling pathway.

    Science.gov (United States)

    Liu, Xiaofeng; Li, Liubing; Lv, Ling; Chen, Dongmei; Shen, Liqin; Xie, Zonggang

    2015-08-01

    Osteosarcoma (OS) is the most common type of bone cancer. Even with early diagnosis and aggressive treatment, the prognosis for OS is poor. In the present study, we investigated the proliferation and invasion inhibitory effect of apigenin on human OS cells and the possible molecular mechanisms involved. The cell viability of U2OS and MG63 human OS cell lines was detected by MTT assay. Cell cycle progression and invasion were assessed by flow cytometry and the Matrigel Boyden chamber assay, respectively, and the involvement of molecular mechanisms was examined by western blot analysis. We demonstrated that apigenin inhibited proliferation and reduced invasion in human OS cells, and downregulated the expression of β-catenin in OS cells. Furthermore, the inhibitory effect of apigenin on OS cells was reversed by overexpression of β-catenin, but enhanced by knockdown of β-catenin. Collectively, our results showed that apigenin inhibits the tumor growth of OS cells by inactivating Wnt/β-catenin signaling. Therefore, apigenin is a promising chemotherapeutic agent that may be used in the treatment of human OS.

  7. c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion.

    Science.gov (United States)

    Wang, Liyang; Hou, Yixuan; Sun, Yan; Zhao, Liuyang; Tang, Xi; Hu, Ping; Yang, Jiajia; Zeng, Zongyue; Yang, Guanglun; Cui, Xiaojiang; Liu, Manran

    2013-12-01

    Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression in immortalized breast normal fibroblasts (NFs) induces conversion to breast CAFs by repressing p53 and thereby upregulating SDF-1 in NFs. SDF-1 treatment or p53 knockdown in NFs had similar effects on the activation of NFs as c-Ski overexpression. The c-Ski-activated CAFs show increased proliferation, migration, invasion and contraction compared with NFs. Furthermore, c-Ski-activated CAFs facilitated the migration and invasion of MDA-MB-231 breast cancer cells. Our data suggest that c-Ski is an important regulator in the activation of CAFs and may serve as a potential therapeutic target to block breast cancer progression.

  8. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Loomans, Holli A. [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Andl, Claudia D., E-mail: claudia.andl@vanderbilt.edu [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2014-12-30

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion.

  9. The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

    Science.gov (United States)

    Yin, Haoyuan; Shao, Ying; Chen, Xuan

    2017-01-01

    To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

  10. Role of HLA-G1 in trophoblast cell proliferation, adhesion and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Feng, E-mail: jiangfeng1161@163.com [Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi' an 710038 (China); Zhao, Hongxi [Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi' an 710038 (China); Wang, Li [Department of Gynecology and Obstetrics, The Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853 (China); Guo, Xinyu [Assisted Reproductive Center, General Hospital of Guangzhou Military Command, Guangzhou 510010 (China); Wang, Xiaohong; Yin, Guowu [Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi' an 710038 (China); Hu, Yunsheng [Department of Orthopedics, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China); Li, Yi [Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi' an 710038 (China); Yao, Yuanqing, E-mail: yuanqingyaoxa@163.com [Department of Gynecology and Obstetrics, The Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853 (China)

    2015-02-27

    Trophoblast cells are important in embryo implantation and fetomaternal tolerance. HLA-G is specifically expressed at the maternal–fetal interface and is a regulator in pregnancy. The aim of the present study was to detect the effect of HLA-G1 on trophoblast cell proliferation, adhesion, and invasion. Human trophoblast cell lines (JAR and HTR-8/SVneo cells) were infected with HLA-G1-expressing lentivirus. After infection, HLA-G1 expression of the cells was detected by western blotting. Cell proliferation was detected by the BrdU assay. The cell cycle and apoptosis of JAR and HTR-8/SVneo cells was measured by flow cytometry (FCM). The invasion of the cells under different conditions was detected by the transwell invasion chamber assay. HLA-G1 didn't show any significant influence on the proliferation, apoptosis, adhesion, and invasion of trophocytes in normal culture conditions. However, HLA-G1 inhibited JAR and HTR-8/SVneo cells invasion induced by hepatocyte growth factor (HGF) under normal oxygen conditions. In conditions of hypoxia, HLA-G1 couldn't inhibit the induction of cell invasion by HGF. HLA-G1 is not an independent factor for regulating the trophocytes. It may play an indirect role in embryo implantation and formation of the placenta. - Highlights: • HLA-G1 could not influence trophocytes under normal conditions. • HLA-G1 inhibited cell invasion induced by HGF under normal oxygen condition. • HLA-G1 could not influence cell invasion under hypoxia conditions.

  11. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

    Science.gov (United States)

    Ciriello, Giovanni; Gatza, Michael L; Beck, Andrew H; Wilkerson, Matthew D; Rhie, Suhn K; Pastore, Alessandro; Zhang, Hailei; McLellan, Michael; Yau, Christina; Kandoth, Cyriac; Bowlby, Reanne; Shen, Hui; Hayat, Sikander; Fieldhouse, Robert; Lester, Susan C; Tse, Gary M K; Factor, Rachel E; Collins, Laura C; Allison, Kimberly H; Chen, Yunn-Yi; Jensen, Kristin; Johnson, Nicole B; Oesterreich, Steffi; Mills, Gordon B; Cherniack, Andrew D; Robertson, Gordon; Benz, Christopher; Sander, Chris; Laird, Peter W; Hoadley, Katherine A; King, Tari A; Perou, Charles M

    2015-10-08

    Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

  12. Downregulation of CD147 expression by RNA interference inhibits HT29 cell proliferation, invasion and tumorigenicity in vitro and in vivo.

    Science.gov (United States)

    Li, Rui; Pan, Yuqin; He, Bangshun; Xu, Yeqiong; Gao, Tianyi; Song, Guoqi; Sun, Huiling; Deng, Qiwen; Wang, Shukui

    2013-12-01

    We investigated the effect of CD147 silencing on HT29 cell proliferation and invasion. We constructed a novel short hairpin RNA (shRNA) expression vector pYr-mir30-shRNA. The plasmid was transferred to HT29 cells. The expression of CD147, MCT1 (lactate transporters monocarboxylate transporter 1) and MCT4 (lactate transporters monocarboxylate transporter 4) were monitored by quantitative PCR and western blotting, respectively. The MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) activities were determined by gelatin zymography assay, while the intracellular lactate concentration was determined by the lactic acid assay kit. WST-8 assay was used to determine the HT29 cell proliferation and the chemosensitivity. Invasion assay was used to determine the invasion of HT29 cells. In addition, we established a colorectal cancer model, and detected CD147 expression in vivo. The results showed that the expression of CD147 and MCT1 was significantly reduced at both mRNA and protein levels, and also the activity of MMP-2 and MMP-9 was reduced. The proliferation and invasion were decreased, but chemosensitivity to cisplatin was increased. In vivo, the CD147 expression was also significantly decreased, and reduced the tumor growth after CD147 gene silencing. The results demonstrated that silencing of CD147 expression inhibited the proliferation and invasion, suggesting CD147 silencing might be an adjuvant gene therapy strategy to chemotherapy.

  13. Minimal Invasive Surgery for Esophageal Cancer

    Institute of Scientific and Technical Information of China (English)

    A.H.Hoelscher; Ch.Gutschow

    2004-01-01

    Thoracoscopic esophagectomy is only established in some centers and affords a cervical anastomosis because intrathoracic anastomosis as a routine is technically too difficult. Laparoscopic mobilisation of the stomach (gastrolysis) is an important contribution for minimal invasive surgery of esophageal cancer.This procedure reduces the stress of the two cavity operation for the patient and allows the construction of a comparable gastric conduit like by open surgery. The technique of laparoscopic gastrolysis as preparation for transthoracic en bloc esophagectomy is described in detail and preliminary results are briefly mentioned.

  14. DDRs: receptors that mediate adhesion, migration and invasion in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Emmanuel Reyes-Uribe

    2015-08-01

    Full Text Available Discoidin domain receptors (DDRs are receptor tyrosine kinases that are activated by native collagens and have an important role during cell adhesion, development, differentiation, proliferation, and migration. DDR deregulation is associated with progression of several different cancers. However, there is limited information about the role of DDRs in the progression of breast cancer. In this review we attempt to collect the most relevant information about DDR signaling and their role in various cancer-related processes such as adhesion, epithelial to mesenchymal transition, migration, invasion, and survival, with a focus on breast cancer.

  15. miR-107 and miR-25 simultaneously target LATS2 and regulate proliferation and invasion of gastric adenocarcinoma (GAC) cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Mingjun; Wang, Xiaolei [Cancer Center, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601 (China); Li, Wanhu [MRI Room of Shandong Cancer Hospital & Institute, Jinan 250117 (China); Cui, Yongchun, E-mail: yongchuncui1@126.com [Drug Clinical Trial Institution of Shandong Cancer Hospital & Institute, #440, Jiyan Road, Jinan 250117 (China)

    2015-05-08

    Although a series of oncogenes and tumor suppressors were identified in the pathological development of gastric adenocarcinoma (GAC), the underlying molecule mechanism were still not fully understood. The current study explored the expression profile of miR-107 and miR-25 in GAC patients and their downstream regulative network. qRT-PCR analysis was performed to quantify the expression of these two miRNAs in serum samples from both patients and healthy controls. Dual luciferase assay was conducted to verify their putative bindings with LATS2. MTT assay, cell cycle assay and transwell assay were performed to explore how miR-107 and miR-25 regulate proliferation and invasion of gastric cancer cells. Findings of this study demonstrated that total miR-107 or miR-25 expression might be overexpressed in gastric cancer patients and they can simultaneously and synchronically regulate LATS2 expression, thereby affecting gastric cancer cell growth and invasion. Therefore, the miR-25/miR-107-LATS2 axis might play an important role in proliferation and invasion of the gastric cancer cells. - Highlights: • Total miR-107 and miR-25 expression is significantly increased in GAC patients. • Both miR-107 and miR-25 can promote proliferation and invasion of GAC cells. • Both miR-107 and miR-25 can target LATS2 and regulate its expression. • miR-107 and miR-25 regulate proliferation and invasion of GAC cells though LATS2.

  16. 乌司他丁和泰索帝对人乳腺癌细胞MDA-MB-231增殖和侵袭的影响及其机制%Effect of Ulinastatin and Taxotere on Proliferation and Invasion of Human Breast Cancer Line MDA-MB-231 Ce1Ps and Relevant Mechanism

    Institute of Scientific and Technical Information of China (English)

    赵晓亮; 孙治君; 罗杰; 高峰

    2011-01-01

    Objective To observe the effect of ulinastatin (ULI)and taxotere (TXT) on proliferation and invasion of human breast cancer MDA-MB-231 cells as well as expressions of IL-6, IL-8 and TNF-α.Methods The estrogen receptor-negative MDAMB-231 cells cultured in vitro were randomly divided into blank control, ULI (800 U/mi), TXT (3.7 μg/ml) and ULI + TXT groups, and determined for the transcription levels of IL-6, IL-8 and TNF-α mRNAs by fluorescent quantitative RT-PCR, for proliferation ability by MTF method, and for invasion ability by Transwell chamber assay.Results Both TXT and ULI inhibited the expressions of IL-6, IL-8 and TNF-α genes as well as the proliferation and invasion of MDA-MB-231 cells, while the inhibition ability of ULI was lower than that of TXT.However, TXT combined with ULI showed the strongest inhibitory effect in all the four groups.Conclusion ULI inhibited the proliferation and invasion of human breast cancer MDA-MB-231 cells by a mechanism which might be associated with the down-regulation of expressions of IL-6, IL-8 and TNF-α genes.%目的 探讨乌司他丁(Ulinastatin,ULI)和泰索帝(Taxotere,TXT)对人乳腺癌细胞MDA-MB-231增殖、侵袭及白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)表达的影响.方法 将体外培养的人乳腺癌细胞MDA-MB-231(雌激素受体阴性)随机分为4组:对照组、ULI组(800 U/ml),TXT组(3.7 Rg/ml)和ULI+TXT组,采用荧光定量RT-PCR法检测细胞IL-6、IL-8和TNF-α基因mRNA的转录水平;MTT法检测细胞的增殖能力;TransweⅡ小室侵袭试验检测细胞的浸润能力.结果 TXT和ULI均能抑制MDA-MB-231细胞IL-6、IL-8和TNF-α基因的表达及细胞的增殖和侵袭能力,ULI的抑制作用低于TXT,但TXT与ULI联合应用,抑制作用最强.结论 ULI能抑制人乳腺癌细胞MDA-MB-231的增殖、侵袭,其作用机制可能与ULI降低IL-6、IL-8及TNF-α基因的表达有关.

  17. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun, E-mail: xuejunshao@hotmail.com

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  18. Neoadjuvant chemotherapy for invasive bladder cancer.

    Science.gov (United States)

    Sonpavde, Guru; Sternberg, Cora N

    2012-04-01

    Neoadjuvant cisplatin-based combination chemotherapy is an established standard for resectable muscle-invasive bladder cancer, a disease with a pattern of predominantly distant and early recurrences. Pathologic complete remission appears to be an intermediate surrogate for survival when employing combination chemotherapy. Moreover, baseline host and tumor tissue studies may enable the discovery of biomarkers predictive of activity. The neoadjuvant setting also provides a window of opportunity to evaluate novel biologic agents or rational combinations of biologic agents to obtain a signal of biologic activity. The residual tumor after neoadjuvant therapy may be exploited to study the mechanism of action and resistance. Cisplatin-ineligible patients warrant the evaluation of tolerable neoadjuvant regimens. Given that bladder cancer is characterized by initial localized presentation in the vast majority of cases, the paradigm of neoadjuvant therapy may expedite the development of novel systemic agents.

  19. Higher molecular weight polyethylene glycol increases cell proliferation while improving barrier function in an in vitro colon cancer model.

    Science.gov (United States)

    Bharadwaj, Shruthi; Vishnubhotla, Ramana; Shan, Sun; Chauhan, Chinmay; Cho, Michael; Glover, Sarah C

    2011-01-01

    Polyethylene glycol (PEG) has been previously shown to protect against enteric pathogens and prevent colon cancer invasion. To determine if PEG could indeed protect against previously observed pro-invasive effects of commensal E. coli and EPEC, Caco-2 cells grown in an in vitro model of colon cancer were infected with strains of human commensal E. coli or EPEC and treated with 10% PEG 3350, PEG 8000, and PEG 20,000, respectively. At 24 hours after infection, MMP-1 and MMP-13 activities, cell cluster thickness, depth of invasion, and proliferation were determined using standard molecular biology techniques and advanced imaging. We found that higher molecular weight PEG, especially PEG 8000 and 20,000, regardless of bacterial infection, increased proliferation and depth of invasion although a decrease in cellular density and MMP-1 activity was also noted. Maximum proliferation and depth of invasion of Caco-2 cells was observed in scaffolds treated with a combination of commensal E. coli strain, HS4 and PEG 8000. In conclusion, we found that PEG 8000 increased cell proliferation and led to the preservation of cell density in cells treated with commensal bacteria. This is important, because the preservation of a proliferative response in colon cancer results in a more chemo-responsive tumor.

  20. Minimally invasive local therapies for liver cancer

    Institute of Scientific and Technical Information of China (English)

    David Li; Josephine Kang; Benjamin J Golas; Vincent W Yeung; David C Madoff

    2014-01-01

    Primary and metastatic liver tumors are an increasing global health problem, with hepatocellular carcinoma (HCC) now being the third leading cause of cancer-related mortality worldwide. Systemic treatment options for HCC remain limited, with Sorafenib as the only prospectively validated agent shown to increase overall survival. Surgical resection and/or transplantation, locally ablative therapies and regional or locoregional therapies have iflled the gap in liver tumor treatments, providing improved survival outcomes for both primary and metastatic tumors. Minimally invasive local therapies have an increasing role in the treatment of both primary and metastatic liver tumors. For patients with low volume disease, these therapies have now been established into consensus practice guidelines. This review highlights technical aspects and outcomes of commonly utilized, minimally invasive local therapies including laparoscopic liver resection (LLR), radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), irreversible electroporation (IRE), and stereotactic body radiation therapy (SBRT). In addition, the role of combination treatment strategies utilizing these minimally invasive techniques is reviewed.

  1. Multiple early gastric cancer with duodenal invasion

    Directory of Open Access Journals (Sweden)

    Okino Tetsuya

    2007-10-01

    Full Text Available Abstract Background Early gastric cancers with duodenal invasion are rare, and no previous case of multiple early gastric cancer, one invading the duodenal bulb, has been reported. Case presentation A 79-year-old woman was investigated for upper abdominal discomfort. Endoscopic examination revealed an irregular nodulated lesion in the antrum area, and a reddish aggregated-type semi-circumferential nodulated lesion extending from the prepyloric area to the duodenal bulb through the normal mucosa with the antrum lesion. Biopsy revealed a tubular adenoma for the antrum lesion and a well-differentiated tubular adenocarcinoma for the prepyloric lesion. Distal gastrectomy with sufficient duodenal resection was performed. Microscopically, the antrum lesion appeared as a papillary adenocarcinoma, and the prepyloric lesion as a mainly papillary adenocarcinoma which partially invaded the submucosa without any sequential elongation for endoscopic findings. The lesion extended into the duodenal bulb, and was 12 mm in length from the oral end of Brunner's gland's area and limited within the duodenal mucosa. Conclusion Here, we present an unusual case of multiple early gastric cancer, one of which invaded the duodenum with relative wide mucosal spreading. This case illustrates that even early stage cancers located in the gastric antrum, particularly in the prepyloric area can invade the duodenum directly.

  2. miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhengyu [Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai (China); Wang, Tao, E-mail: wangtaohappy2010@sohu.com [Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai (China)

    2014-06-27

    Highlights: • miR-214 is upregulated in human OS tissues and inversely correlated with LZTS1 expression. • miR-214 directly targets LZTS1 by binding to its 3′-UTR. • miR-214 promotes OS cell proliferation, invasion and tumor growth. • Overexpression of LZTS1 reverses miR-214-induced proliferation and invasion of OS cells. - Abstract: Previous studies have shown that miR-214 functions either as an oncogene or a tumor suppressor in various human cancer types. The role of this microRNA in osteosarcoma (OS) is presently unclear. Here, we demonstrated that miR-214 is frequently upregulated in OS specimens, compared with noncancerous bone tissues. Bioinformatics analysis further revealed leucine zipper, putative tumor suppressor 1 (LZTS1) as a potential target of miR-214. Expression patterns of miR-214 were inversely correlated with those of LZTS1 mRNA and protein in OS tissues. Data from reporter assays showed that miR-214 directly binds to the 3′-untranslated region (3′-UTR) of LZTS1 mRNA and suppresses expression at both transcriptional and translational levels. In functional assays, miR-214 promoted OS cell proliferation, invasion and tumor growth in nude mice, which could be reversed by overexpression of LZTS1. Taken together, our data provide compelling evidence that miR-214 functions as an onco-miRNA in OS, and its oncogenic effects are mediated chiefly through downregulation of LZTS1.

  3. Effects of curcuma extract-elemene on proliferation, invasion and tumor-associated calcium signal transducer-2 gene expression of various cancer cells%莪术提取物榄香烯对多种癌细胞增殖、侵袭及肿瘤相关钙信号传导蛋白-2基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    祁卫东; 龚丹丹; 钟锡明; 沈荣; 张恒; 范钰

    2014-01-01

    Objective To study the effects and mechanism of curcuma extract-elemene on proliferation,invasion and tumor-associated calcium signal transducer-2 (TROP-2) gene expression of various cancer cells.Methods Human esophageal carcinoma TE-1 and Ca-ES-17 cells,laryngeal squamous cell carcinoma Hep-2 cells,lung cancer NCI-H1975 cells,colorectal cancer SW-480 cells,and prostate cancer PC-3 cells were prepared.After all group cancers were treated with different doses of elemene,and proliferation of cancer cells was studied by methyl thiazol tetrazolium (MTT) assay,and invasion ability was determined by Boyden chamber assay.TROP-2 mRNA level was detected by real-time fluorescent quantitative polymerase chain reaction (FQ-PCR).Results Elemene has an inhibitory effect on all group cancer cells in a dose-dependent manner.The MTT assay showed that the inhibition rate of proliferation was 43.919,189.036,48.690,75.538,35.145,and 31.063 mg/L in TE-1,Ca-ES-17,Hep-2,NCI-H1975,SW-480,and PC-3 cells,respectively.The Boyden chamber test showed that the inhibition rate of invasion was 25.6%,18.9%,23.8%,22.2%,26.5%,and 27.8% in TE-1,Ca-ES-17,Hep-2,NCI-H1975,SW-480,and PC-3,respectively.The FQ-PCR assay showed that the inhibition rate of TROP-2 mRNA was 35.8%,25.6%,32.5%,25.6%,29.8%,and 33.6% in TE-1,Ca-ES-17,Hep-2,NCI-H1975,SW-480,and PC-3,respectively.Conclusion Elemene could reduce cell proliferation and invasion of various cancer cells through down-regulation of TROP-2 gene.%目的 探讨莪术提取物榄香烯对多种人癌细胞增殖、侵袭的影响及其机制.方法 采用不同浓度的榄香烯处理人食管癌TE-1和Ca-ES-17细胞、喉鳞癌Hep-2细胞、肺癌NCI-H1975细胞、大肠癌SW-480细胞、前列腺癌PC-3细胞后,以噻唑蓝(MTT)方法检测癌细胞增殖,以Boyden小室方法检测癌细胞侵袭能力,以实时荧光定量聚合酶链反应(FQ-PCR)方法检测癌细胞肿瘤相关钙信号传导蛋白(TROP)-2

  4. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells

    NARCIS (Netherlands)

    Liu, Su; Uppal, Harpreet; Demaria, Marco; Desprez, Pierre-Yves; Campisi, Judith; Kapahi, Pankaj

    2015-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and preven

  5. Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Nancy L., E-mail: nlcho@partners.org [Department of Surgery, Brigham and Women' s Hospital, Boston, MA 02115 (United States); Lin, Chi-Iou [Department of Surgery, Brigham and Women' s Hospital, Boston, MA 02115 (United States); Du, Jinyan [Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02142 (United States); Whang, Edward E. [Department of Surgery, Brigham and Women' s Hospital, Boston, MA 02115 (United States); Ito, Hiromichi [Department of Surgery, Michigan State University, Lansing, MI 48912 (United States); Moore, Francis D.; Ruan, Daniel T. [Department of Surgery, Brigham and Women' s Hospital, Boston, MA 02115 (United States)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Kinome profiling is a novel technique for identifying activated kinases in human cancers. Black-Right-Pointing-Pointer Src activity is increased in invasive thyroid cancers. Black-Right-Pointing-Pointer Inhibition of Src activity decreased proliferation and invasion in vitro. Black-Right-Pointing-Pointer Further investigation of Src targeted therapies in thyroid cancer is warranted. -- Abstract: Background: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. Methods: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. Results: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p < 0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation

  6. Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells.

    Science.gov (United States)

    Qin, Yong; Xu, Sheng-Qian; Pan, De-Biao; Ye, Guan-Xiong; Wu, Cheng-Jun; Wang, Shi; Wang, Chao-Jun; Jiang, Jin-Yan; Fu, Jing

    2016-05-01

    The role and clinical implication of the WWP2 E3 ubiquitin ligase in liver cancer are poorly understood. In the current study, we investigated the expression level of WWP2 and its functions in cell adhesion, invasion, and migration in liver cancer. We used real-time PCR to detect the expression of WWP2 in liver cancer and adjacent samples from the People's Hospital of Lishui and also analyzed The Cancer Genome Atlas (TCGA) RNA-seq data by bioinformatics. Migration and invasion were detected by transwell analysis. We detected a strong WWP2 expression in tumor tissues of the People's Hospital of Lishui, and the survival rate was significantly higher in patients with lower WWP2-expressing tumors. WWP2 small hairpin RNA (shRNA) lentivirus stably infected cells (shWWP2), Huh7, showed slower growth speed compared with scramble control-infected cells in a xenograft mouse model. Knockdown of WWP2 Huh7 and BEL-7404 cells demonstrated a reduction in adhesion, invasion, and migration. Gene set enrichment analysis (GSEA) showed that WWP2 is positively correlated to cancer-related pathways including the chemokine signaling pathway. WWP2 also regulated MMP-9, caspase-9, CXCR3, and CCR5 expression in liver cancer cells. In addition, knockdown of CXCR3 and CCR5 significantly inhibited cell proliferation, adhesion, invasion, and migration in Huh7 and BEL-7404 cells. Our data suggest that targeting of WWP2 may be a therapeutic strategy for liver cancer treatment.

  7. Grhl2 reduces invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer

    Science.gov (United States)

    Xiang, J; Fu, X; Ran, W; Wang, Z

    2017-01-01

    Metastasis is one of the typical features of malignancy that significantly increases cancer-related mortality. Recent studies have shown that epithelial–mesenchymal transition (EMT) is closely related to the invasion and migration of cancer cells. Grainyhead-like 2 (Grhl2), a transcription factor, has been reported to be associated with several tumor processes including EMT. In the previous study, we have reported that Grhl2 functioned as a tumor suppressor in proliferation and apoptosis of gastric cancer. Here we aim to explore the effects of Grhl2 on invasion and migration of gastric cancer and further clarify its possible underlying mechanisms. As a result, in both SGC7901 and MKN45 cells, Grhl2 overexpression significantly inhibited the ability of invasion and migration. In addition, preliminary experiments showed that Grhl2 reduces the protein expression of matrix metalloproteinase-2, -7 and -9 (MMP-2, MMP-7 and MMP-9). Most importantly, Grhl2 antagonizes transforming growth factor-β (TGFβ)-induced EMT, and inhibition of TGFβ signaling pathways can restore Grhl2 expression. Finally, the results of subcutaneous xenograft model indicated that Grhl2 suppresses the growth of gastric cancer and reverses EMT process in vivo. Meanwhile, the metastatic tumor model further confirmed the inhibition of Grhl2 on metastasis of gastric cancer. Taken together, our findings proved that Grhl2, functioned as a tumor suppressor, reduces the invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer. PMID:28067907

  8. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis.

    Science.gov (United States)

    Dang, Qiang; Song, Wenbin; Xu, Defeng; Ma, Yanmin; Li, Feng; Zeng, Jin; Zhu, Guodong; Wang, Xinyang; Chang, Luke S; He, Dalin; Li, Lei

    2015-09-01

    The effects of the flavonoid compound, kaempferol, which is an inhibitor of cancer cell proliferation and an inducer of cell apoptosis have been shown in various cancers, including lung, pancreatic, and ovarian, but its effect has never been studied in bladder cancer. Here, we investigated the effects of kaempferol on bladder cancer using multiple in vitro cell lines and in vivo mice studies. The MTT assay results on various bladder cancer cell lines showed that kaempferol enhanced bladder cancer cell cytotoxicity. In contrast, when analyzed by the flow cytometric analysis, DNA ladder experiment, and TUNEL assay, kaempferol significantly was shown to induce apoptosis and cell cycle arrest. These in vitro results were confirmed in in vivo mice studies using subcutaneous xenografted mouse models. Consistent with the in vitro results, we found that treating mice with kaempferol significant suppression in tumor growth compared to the control group mice. Tumor tissue staining results showed decreased expressions of the growth related markers, yet increased expressions in apoptosis markers in the kaempferol treated group mice tissues compared to the control group mice. In addition, our in vitro and in vivo data showed kaempferol can also inhibit bladder cancer invasion and metastasis. Further mechanism dissection studies showed that significant down-regulation of the c-Met/p38 signaling pathway is responsible for the kaempferol mediated cell proliferation inhibition. All these findings suggest kaempferol might be an effective and novel chemotherapeutic drug to apply for the future therapeutic agent to combat bladder cancer.

  9. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yoon Pyo; Kim, Baek Gil [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Gao, Ming-Qing; Kang, Suki [Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cho, Nam Hoon, E-mail: cho1988@yuhs.ac [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  10. Complement component 1, q subcomponent binding protein is a marker for proliferation in breast cancer.

    Science.gov (United States)

    Scully, Olivia Jane; Yu, Yingnan; Salim, Agus; Thike, Aye Aye; Yip, George Wai-Cheong; Baeg, Gyeong Hun; Tan, Puay-Hoon; Matsumoto, Ken; Bay, Boon Huat

    2015-07-01

    Complement component 1, q subcomponent binding protein (C1QBP), is a multi-compartmental protein with higher mRNA expression reported in breast cancer tissues. This study evaluated the association between immunohistochemical expression of the C1QBP protein in breast cancer tissue microarrays (TMAs) and clinicopathological parameters, in particular tumor size. In addition, an in vitro study was conducted to substantiate the breast cancer TMA findings. Breast cancer TMAs were constructed from pathological specimens of patients diagnosed with invasive ductal carcinoma. C1QBP protein and proliferating cell nuclear antigen (PCNA) immunohistochemical analyses were subsequently performed in the TMAs. C1QBP immunostaining was detected in 131 out of 132 samples examined. The C1QBP protein was predominantly localized in the cytoplasm of the breast cancer cells. Univariate analysis revealed that a higher C1QBP protein expression was significantly associated with older patients (P = 0.001) and increased tumor size (P = 0.002). Multivariate analysis showed that C1QBP is an independent predictor of tumor size in progesterone-positive tumors. Furthermore, C1QBP was also significantly correlated with expression of PCNA, a known marker of proliferation. Inhibition of C1QBP expression was performed by transfecting C1QBP siRNA into T47D breast cancer cells, a progesterone receptor-positive breast cancer cell line. C1QBP gene expression was analyzed by real-time RT-PCR, and protein expression by Western blot. Cell proliferation assays were also performed by commercially available assays. Down-regulation of C1QBP expression significantly decreased cell proliferation and growth in T47D cells. Taken together, our findings suggest that the C1QBP protein could be a potential proliferative marker in breast cancer.

  11. Human bone marrow mesenchymal stem cells induce collagen production and tongue cancer invasion.

    Directory of Open Access Journals (Sweden)

    Sirpa Salo

    Full Text Available Tumor microenvironment (TME is an active player in carcinogenesis and changes in its composition modify cancer growth. Carcinoma-associated fibroblasts, bone marrow-derived multipotent mesenchymal stem cells (BMMSCs, and inflammatory cells can all affect the composition of TME leading to changes in proliferation, invasion and metastasis formation of carcinoma cells. In this study, we confirmed an interaction between BMMSCs and oral tongue squamous cell carcinoma (OTSCC cells by analyzing the invasion progression and gene expression pattern. In a 3-dimensional myoma organotypic invasion model the presence of BMMSCs inhibited the proliferation but increased the invasion of OTSCC cells. Furthermore, the signals originating from OTSCC cells up-regulated the expression of inflammatory chemokines by BMMSCs, whereas BMMSC products induced the expression of known invasion linked molecules by carcinoma cells. Particularly, after the cell-cell interactions, the chemokine CCL5 was abundantly secreted from BMMSCs and a function blocking antibody against CCL5 inhibited BMMSC enhanced cancer invasion area. However, CCL5 blocking antibody did not inhibit the depth of invasion. Additionally, after exposure to BMMSCs, the expression of type I collagen mRNA in OTSCC cells was markedly up-regulated. Interestingly, also high expression of type I collagen N-terminal propeptide (PINP in vivo correlated with the cancer-specific mortality of OTSCC patients, whereas there was no association between cancer tissue CCL5 levels and the clinical parameters. In conclusion, our results suggest that the interaction between BMMSC and carcinoma cells induce cytokine and matrix molecule expression, of which high level of type I collagen production correlates with the prognosis of OTSCC patients.

  12. The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice

    Energy Technology Data Exchange (ETDEWEB)

    Han, Miaojun [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Wang, Hailun [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Zhang, Hua-Tang [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Han, Zhaozhong, E-mail: zhaozhong.han@vanderbilt.edu [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Department of Cancer Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Vanderbilt-Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States)

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

  13. ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma.

    Directory of Open Access Journals (Sweden)

    Songtao Qi

    Full Text Available BACKGROUND: The aim of the present study was to analyze the expression of Zinc finger E-box Binding homeobox 2 (ZEB2 in glioma and to explore the molecular mechanisms of ZEB2 that regulate cell proliferation, migration, invasion, and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Expression of ZEB2 in 90 clinicopathologically characterized glioma patients was analyzed by immunohistochemistry. Furthermore, siRNA targeting ZEB2 was transfected into U251 and U87 glioma cell lines in vitro and proliferation, migration, invasion, and apoptosis were examined separately by MTT assay, Transwell chamber assay, flow cytometry, and western blot. RESULTS: The expression level of ZEB2 protein was significantly increased in glioma tissues compared to normal brain tissues (P<0.001. In addition, high levels of ZEB2 protein were positively correlated with pathology grade classification (P = 0.024 of glioma patients. Knockdown of ZEB2 by siRNA suppressed cell proliferation, migration and invasion, as well as induced cell apoptosis in glioma cells. Furthermore, ZEB2 downregulation was accompanied by decreased expression of CDK4/6, Cyclin D1, Cyclin E, E2F1, and c-myc, while p15 and p21 were upregulated. Lowered expression of ZEB2 enhanced E-cadherin levels but also inhibited β-Catenin, Vimentin, N-cadherin, and Snail expression. Several apoptosis-related regulators such as Caspase-3, Caspase-6, Caspase-9, and Cleaved-PARP were activated while PARP was inhibited after ZEB2 siRNA treatment. CONCLUSION: Overexpression of ZEB2 is an unfavorable factor that may facilitate glioma progression. Knockdown ZEB2 expression by siRNA suppressed cell proliferation, migration, invasion and promoted cell apoptosis in glioma cells.

  14. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling.

    Science.gov (United States)

    Chen, Sheng; Zhang, Min; Xing, Lili; Wang, Yue; Xiao, Yongtao; Wu, Yeming

    2015-01-01

    The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on the proliferation, migration and invasion of neuroblastoma (NB) cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR), Western blotting and immunohistochemistry (IHC) to detect the expression of HIF-1α and components of the sonic hedgehog (SHH) signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1α in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1α was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1α knockdown, which was mediated by small interfering RNAs (siRNAs) targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1α inhibition. Finally, the pro-migration and proliferative effects of HIF-1α could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1α in NB promotes proliferation, migration and invasiveness via SHH signaling.

  15. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling.

    Directory of Open Access Journals (Sweden)

    Sheng Chen

    Full Text Available The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α on the proliferation, migration and invasion of neuroblastoma (NB cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR, Western blotting and immunohistochemistry (IHC to detect the expression of HIF-1α and components of the sonic hedgehog (SHH signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1α in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1α was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1α knockdown, which was mediated by small interfering RNAs (siRNAs targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1α inhibition. Finally, the pro-migration and proliferative effects of HIF-1α could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1α in NB promotes proliferation, migration and invasiveness via SHH signaling.

  16. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Raufman, Jean-Pierre, E-mail: jraufman@medicine.umaryland.edu [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States); Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  17. Osteopontin knockdown suppresses non-small cell lung cancer cell invasion and metastasis

    Institute of Scientific and Technical Information of China (English)

    SUN Bing-sheng; YOU Jian; LI Yue; ZHANG Zhen-fa; WANG Chang-li

    2013-01-01

    Background Osteopontin (OPN) was identified as one of the leading genes that promote the metastasis of malignant tumor.However,the mechanism by which OPN mediates metastasis in non-small cell lung cancer (NSCLC) remains unknown.The aim of the study is to investigate the biological significance and the related molecular mechanism of OPN expression in lung cancer cell line.Methods Lentiviral-mediated RNA interference was applied to inhibit OPN expression in metastatic human NSCLC cell line (A549).The invasion,proliferation,and metastasis were evaluated OPN-silenced in A549 cells in vitro and in vivo.The related mechanism was further investigated.Results Interestingly,OPN knockdown significantly suppressed the invasiveness of A549 cells,but had only a minor effect on the cellular migration and proliferation.Moreover,we demonstrated that OPN knockdown significantly reduced the levels of matrix metalloproteinase (MMP)-2 and urokinase plasminogen activator (uPA),and led to an obviousinhibition of both in vitro invasion and in vivo lung metastasis of A549 cells (P <0.001).Conclusions Our data demonstrate that OPN contributes to A549 cell metastasis by stimulating cell invasion,independent of cellular migration and proliferation.OPN could be a new treatment target of NSCLC.

  18. Nifedipine promotes the proliferation and migration of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Dong-Qing Guo

    Full Text Available Nifedipine is widely used as a calcium channel blocker (CCB to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn't exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3. Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3-Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.

  19. Ex vivo non-invasive assessment of cell viability and proliferation in bio-engineered whole organ constructs.

    Science.gov (United States)

    Ren, Xi; Tapias, Luis F; Jank, Bernhard J; Mathisen, Douglas J; Lanuti, Michael; Ott, Harald C

    2015-06-01

    Decellularized organ scaffolds allow whole organ regeneration and study of cell behavior in three-dimensional culture conditions. Cell viability within the bio-engineered organ constructs is an essential parameter reflecting the performance of participating cells during long-term ex vivo culture, and is a prerequisite for further functional performance. Resazurin-based redox metabolic assays have been used to monitor cell viability in both two- and three-dimensional cell cultures. Here we developed a method for monitoring cell viability and proliferation in bio-engineered organ constructs using a resazurin perfusion assay. This method allows non-invasive, repetitive and rapid estimation of viable cell numbers during long-term ex vivo culture. As a proof-of-principle, we assessed the performance of two different endothelial sources and the impact of different perfusion programs on endothelial viability after re-endothelialization of decellularized lung scaffolds. The resazurin-based perfusion assay revealed changes in endothelial viability and proliferation during long-term ex vivo culture, which was consistent with histological assessment at different time points. Finally, we showed that this method could be used for assessment of proliferation and cytotoxicity after pharmacological treatment on a three-dimensional non-small cell lung cancer culture model.

  20. 吉非替尼和NS398对前列腺癌PC-3M细胞增殖和侵袭力影响的研究%Effects of gefitinib and NS-398 on the proliferation and invasion ability of prostate cancer cell line ;PC-3 in vitro

    Institute of Scientific and Technical Information of China (English)

    朱佳庚; 吴宏飞; 林建中

    2014-01-01

    Objective To observe the effects and possible mechanism of epidermal growth factor receptor specific inhibitor gefitinib and cyclooxygenase-2 specific inhibitor NS-398 on the proliferation and invasion ability of prostate cancer cell line PC-3M in vitro. Methods Cell proliferation was assayed by using MTT method.The invasion ability was examined by Transwell assay. The mRNA and protein expression of MMP-9 and VEGF was detected by quantitative real-time reverse transcription-polymerase chain reaction(qRT-PCR), and Western blotting respectively. Results MTT analyses revealed that gefitinib and NS-398 combination markedly induced decrease in cell viability compared to either drug(P<0.05). Additionally, the two drugs combination showed a greater suppression in the invasion ability (P<0.01). Also, we found that the combination induced more profound decrease in the expression level of MMP-9 and VEGF mRNA and protein (P<0.01). Conclusions The results suggest that gefitinib and NS-398 combination can significantly suppress PC-3M cells proliferation and invasion ability. VEGF and MMP-9 gene down-regulation may be involved in this progress.%目的:应用表皮生长因子受体(EGFR)特异性阻断剂吉非替尼(Gefitinib)和环氧化酶2(COX-2)特异性阻断剂NS398单独或联合作用于前列腺癌PC-3M细胞,观察对细胞增殖和侵袭能力的影响及可能机制研究。方法采用四甲基偶氮唑蓝法(MTT)和 Transwell 检测Gefitinib和NS398应用对细胞增殖和侵袭能力的影响,应用实时荧光定量聚合酶链反应(qRT-PCR)和Western blot法检测药物应用前后基质金属蛋白酶9(MMP-9)、表皮生长因子(VEGF)基因和蛋白表达水平的变化。结果 MTT结果显示Gefitinib或NS398都可抑制PC-3M细胞增殖(P<0.05),两者联合应用作用更明显(P<0.01),Transwell结果表明两种阻断剂都能在一定程度上抑制细胞侵袭能力(P<0.05)

  1. GPR171 expression enhances proliferation and metastasis of lung cancer cells

    Science.gov (United States)

    Dho, So Hee; Lee, Kwang-Pyo; Jeong, Dongjun; Kim, Chang-Jin; Chung, Kyung-Sook; Kim, Ji Young; Park, Bum-Chan; Park, Sung Sup; Kim, Seon-Young; Kwon, Ki-Sun

    2016-01-01

    G protein-coupled receptors (GPCRs) are among the most significant therapeutic targets and some of them promote the growth and metastasis of cancer. Here, we show that an increase in the levels of GPR171 is crucial for lung cancer tumor progression in vitro and in vivo. Immunostaining of clinical samples indicated that GPR171 was overexpressed in 46.8% of lung carcinoma tissues. Depletion of GPR171 with an anti-GPR171 antibody decreased proliferation of lung carcinoma cells and attenuated tumor progression in a mouse xenograft model. Knockdown of GPR171 also inhibited migration and invasion of the lung cancer cell lines. Notably, inhibition of GPR171 synergistically enhanced the tumoricidal activity of an epidermal growth factor receptor (EGFR) inhibitor in lung cancer cells. These results indicate that GPR171 blockade is a promising antineoplastic strategy and provide a preclinical rationale for combined inhibition of GPR171 and EGFR. PMID:26760963

  2. DIXDC1 activates the Wnt signaling pathway and promotes gastric cancer cell invasion and metastasis.

    Science.gov (United States)

    Tan, Cong; Qiao, Fan; Wei, Ping; Chi, Yayun; Wang, Weige; Ni, Shujuan; Wang, Qifeng; Chen, Tongzhen; Sheng, Weiqi; Du, Xiang; Wang, Lei

    2016-04-01

    DIXDC1 (Dishevelled-Axin domain containing 1) is a DIX (Dishevelled-Axin) domain-possessing protein that promotes colon cancer cell proliferation and increases the invasion and migration ability of non-small-cell lung cancer via the PI3K pathway. As a positive regulator of the Wnt/β-catenin pathway, the biological role of DIXDC1 in human gastric cancer and the relationship between DIXDC1 and the Wnt pathway are unclear. In the current study, the upregulation of DIXDC1 was detected in gastric cancer and was associated with advanced TNM stage cancer, lymph node metastasis, and poor prognosis. We also found that the overexpression of DIXDC1 could promote the invasion and migration of gastric cancer cells. The upregulation of MMPs and the downregulation of E-cadherin were found to be involved in the process. DIXDC1 enhanced β-catenin nuclear accumulation, which activated the Wnt pathway. Additionally, the inhibition of β-catenin in DIXDC1-overexpressing cells reversed the metastasis promotion effects of DIXDC1. These results demonstrate that the expression of DIXDC1 is associated with poor prognosis of gastric cancer patients and that DIXDC1 promotes gastric cancer invasion and metastasis through the activation of the Wnt pathway; E-cadherin and MMPs are also involved in this process. © 2015 Wiley Periodicals, Inc.

  3. Knockdown of RAGE inhibits growth and invasion of gastric cancer cells

    Directory of Open Access Journals (Sweden)

    X.C. Xu

    2013-11-01

    Full Text Available The receptor for advanced glycation endproducts (RAGE is an oncogenic trans-membranous receptor, which is overexpressed in multiple human cancers. However, the role of RAGE in gastric cancer is still elusive. In this study, we investigated the expression and molecular mechanisms of RAGE in gastric cancer cells. Forty cases of gastric cancer and corresponding adjacent non-cancerous tissues (ANCT were collected, and the expression of RAGE was assessed using immunohistochemistry (IHC in biopsy samples. Furthermore, RAGE signaling was blocked by constructed recombinant small hairpin RNA lentiviral vector (Lv-shRAGE used to transfect into human gastric cancer SGC-7901 cells. The expression of AKT, proliferating cell nuclear antigen (PCNA and matrix metallopeptidase-2 (MMP-2 was detected by Real-time PCR and Western blot assays. Cell proliferative activities and invasive capability were respectively determined by MTT and Transwell assays. Cell apoptosis and cycle distribution were analyzed by flow cytometry. As a consequence, RAGE was found highly expressed in cancer tissues compared with the ANCT (70.0% vs 45.0%, P=0.039, and correlated with lymph node metastases (P=0.026. Knockdown of RAGE reduced cell proliferation and invasion of gastric cancer with decreased expression of AKT, PCNA and MMP-2, and induced cell apoptosis and cycle arrest. Altogether, upregulation of RAGE expression is associated with lymph node metastases of gastric cancer, and blockade of RAGE signaling suppresses growth and invasion of gastric cancer cells through AKT pathway, suggesting that RAGE may represent a potential therapeutic target for this aggressive malignancy.

  4. Invasive oral cancer stem cells display resistance to ionising radiation.

    Science.gov (United States)

    Gemenetzidis, Emilios; Gammon, Luke; Biddle, Adrian; Emich, Helena; Mackenzie, Ian C

    2015-12-22

    There is a significant amount of evidence to suggest that human tumors are driven and maintained by a sub-population of cells, known as cancer stem cells (CSC). In the case of head and neck cancer, such cells have been characterised by high expression levels of CD44 cell surface glycoprotein, while we have previously shown the presence of two diverse oral CSC populations in vitro, with different capacities for cell migration and proliferation. Here, we examined the response of oral CSC populations to ionising radiation (IR), a front-line measure for the treatment of head and neck tumors. We show that oral CSC initially display resistance to IR-induced growth arrest as well as relative apoptotic resistance. We propose that this is a result of preferential activation of the DNA damagerepair pathway in oral CSC with increased activation of ATM and BRCA1, elevated levels of DNA repair proteins RAD52, XLF, and a significantly faster rate of DNA double-strand-breaks clearance 24 hours following IR. By visually identifying CSC sub-populations undergoing EMT, we show that EMT-CSC represent the majority of invasive cells, and are more radio-resistant than any other population in re-constructed 3D tissues. We provide evidence that IR is not sufficient to eliminate CSC in vitro, and that sensitization of CD44hi/ESAlow cells to IR, followed by secondary EMT blockade, could be critical in order to reduce primary tumor recurrence, but more importantly to be able to eradicate cells capable of invasion and distant metastasis.

  5. Integrin-linked kinase in gastric cancer cell attachment, invasion and tumor growth

    Institute of Scientific and Technical Information of China (English)

    Gang Zhao; Li-Li Guo; Jing-Yong Xu; Hua Yang; Mei-Xiong Huang; Gang Xiao

    2011-01-01

    AIM: To investigate the effects of integrin-linked kinase (ILK) on gastric cancer cells both in vitro and in vivo . METHODS: ILK small interfering RNA (siRNA) was transfected into human gastric cancer BGC-823 cells and ILK expression was monitored by real-time quantitative polymerase chain reaction, Western blotting analysis and immunocytochemistry. Cell attachment, proliferation, invasion, microfilament dynamics and the secretion of vascular endothelial growth factor (VEGF) were also measured. Gastric cancer cells treated with ILK siRNA were subcutaneously transplanted into nude mice and tumor growth was assessed. RESULTS: Both ILK mRNA and protein levels were significantly down-regulated by ILK siRNA in human gastric cancer cells. This significantly inhibited cell attachment, proliferation and invasion. The knockdown of ILK also disturbed F-actin assembly and reduced VEGF secretion in conditioned medium by 40% (P < 0.05). Four weeks after injection of ILK siRNA-transfected gastric cancer cells into nude mice, tumor volume and weight were significantly reduced compared with that of tumors induced by cells treated with non-silencing siRNA or by untreated cells (P < 0.05). CONCLUSION: Targeting ILK with siRNA suppresses the growth of gastric cancer cells both in vitro and in vivo . ILK plays an important role in gastric cancer progression.

  6. Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells

    Indian Academy of Sciences (India)

    Zhan Shi; Ding Wu; Run Tang; Xiang Li; Renfu Chen; Song Xue; Chengjing Zhang; Xiaoqing Sun

    2016-06-01

    The high mobility group protein A2 (HMGA2) has been demonstrated as an architectural transcription factor that is associated with pathogenesis of many malignant cancers, however, its role in prostate cancer cells remains largely unknown. To explore whether HMGA2 participates in the development and progression of prostate cancer, small interfering RNA (siRNA) targeted on human HMGA2 was transfected to suppress the HMGA2 expression in prostate cancer PC3 and DU145 cells, and then we examined the cellular biology changes after decreased the expression of HMGA2. Our results showed that knockdown of HMGA2 markedly inhibited cell proliferation, this reduced cell proliferation was due to the promotion of cell apoptosis as the Bcl-xl was decreased, whereas Bax was up-regulated. In addition, we found that HMGA2 knockdown resulted in reduction of cell migration and invasion, as well as repressed the expression of matrix metalloproteinases (MMPs) and affected the occurrence of epithelial-mesenchymal transition (EMT) in both cell types. We further found that decreased HMGA2 expression inhibited the transforming growth factor-β (TGF-β)/Smad signaling pathway in cancer cells. In conclusion, our data indicated that HMGA2 was associated with apoptosis, migration and invasion of prostate cancer, which might be a promising therapeutic target for prostate cancer.

  7. Inhibition of periostin gene expression via RNA interference suppressed the proliferation, apoptosis and invasion in U2OS cells

    Institute of Scientific and Technical Information of China (English)

    LIU Chang; HUANG Si-jian; QIN Ze-lian

    2010-01-01

    Background Periostin originally designated osteoblast-specific factor 2 (OSF-2) is frequently found to be highly expressed in various types of human cancer cell lines in vitro and human cancer tissues in vivo. We proposed that periostin was a key factor during the process of proliferation and invasion in cancer cells. We investigated the effect of periostin on the function of human osteosarcoma cell line (U2OS), such as proliferation, apoptosis, invasion and the associated signal pathway.Methods A human PGCsi/U6 promoter-driven DNA template was adopted to induce short hairpin RNA (shRNA)-triggered RNA interference (RNAi) to block periostin gene expression in the cell line U2OS. U2OS cells were divided into three groups: cells transfected with phosphate buffered saline as control group (the U2OS group), cells transfected with pGCsi as negative control group (the NC group) and cells transfected with periostin/pGCsi as experimental group (the pGCsi-periostin group). Then, transfection efficiency of cell was observed under fluorescent microscope. The expressions of periostin and the related genes in cells were detected by reverse transcription polymerase chain reaction and Western Blotting. Cell viability was determined using the methyl-thiazolyl tetrazolium bromide (MTT) quantitative colorimetric assay. The invasion and migration capability of cells were tested by transwell plates with or without extracellular matrix gel. Furthermore, the changes of cell cycle and apoptosis were analyzed by flow cytometry.Results The transfection efficiency of periostin/pGCsi to U2OS cells was about 70%-80%. When compared with the NC group, the levels of mRNA and protein of periostin in the pGCsi-periostin group decreased by 82% (F=564.71, P<0.001) and 58% (F=341.51, P <0.001 ), respectively. Meantime, the earlier apoptosis value increased by 417 (F=28.69,P <0.001). The percentage of S phase pGCsi-periostin cells decreased by 21% (F=47.00, P <0.001), however, that of G0-G1

  8. 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.

  9. Gene profiles between non-invasive and invasive colon cancer using laser microdissection and polypeptide analysis

    Institute of Scientific and Technical Information of China (English)

    Jin-Shui Zhu; Hua Guo; Ming-Quan Song; Guo-Qiang Chen; Qun Sun; Qiang Zhang

    2008-01-01

    AIM: To explore the expression of differential gene expression profiles of target cell between non-invasive submucosal and invasive advanced tumor in colon carcinoma using laser microdissection (LMD) in combination with polypeptide analysis.METHODS: Normal colon tissue samples from 20 healthy individuals and 30 cancer tissue samples from early non-invasive colon cancer cells were obtained. The cells from these samples were used LMD independently after P27-based amplification. aRNA from advanced colon cancer cells and metastatic cancer cells of 40 cases were applied to LMD and polypeptide analysis, semiquantitative reverse transcribed polymerase chain reaction (RT-PCR) and immunohistochemical assays were used to verify the results of microarray and further identify differentially expressed genes in non-invasive early stages of colon cancer.RESULTS: Five gene expressions were changed in colon carcinoma cells compared with that of controls. Of the five genes, three genes were downregulated and two were upregulated in invasive submucosal colon carcinoma compared with non-invasive cases. The results were confirmed at the level of aRNA and gene expression. Five genes were further identified as differentially expressed genes in the majority of cases (50%, 25/40) in progression of colon cancer, and their expression patterns of which were similar to tumor suppressor genes or oncogenes.CONCLUSION: This study suggested that combined use of polypeptide analysis might identify early expression profiles of five differential genes associated with the invasion of colon cancer. These results reveal that this gene may be a marker of submucosal invasion in early colon cancer.

  10. Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells

    Directory of Open Access Journals (Sweden)

    Lei Dai

    2017-01-01

    Full Text Available To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

  11. Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells

    Science.gov (United States)

    Dai, Lei; Wang, Gang

    2017-01-01

    To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

  12. Decreased stathmin-1 expression inhibits trophoblast proliferation and invasion and is associated with recurrent miscarriage.

    Science.gov (United States)

    Tian, Fu-Ju; Qin, Chuan-Mei; Li, Xiao-Cui; Wu, Fan; Liu, Xiao-Rui; Xu, Wang-Ming; Lin, Yi

    2015-10-01

    Fetal trophoblasts invade endometrium and establish a complex interaction with the maternal microenvironment during early pregnancy. However, the molecular mechanisms regulating trophoblast migration and invasion at the maternal-fetal interface remain poorly understood. Immunohistochemistry and immunoblotting have shown that stathmin-1 (STMN1) was down-regulated significantly in placental villi tissue and trophoblasts from patients with recurrent miscarriage. In vitro, overexpression of STMN1 promoted human trophoblast proliferation, migration, and invasion, whereas knockdown of STMN1 inhibited these processes. In addition, knockdown of STMN1 down-regulated N-cadherin and up-regulated E-cadherin in trophoblasts, whereas E-cadherin was up-regulated and N-cadherin was down-regulated in recurrent miscarriage villi tissue. Knockdown of STMN1 attenuated cytoplasmic-nuclear translocation of β-catenin and in turn down-regulated trophoblast matrix metalloproteases. Furthermore, tumor necrosis factor-α (TNF-α) down-regulated STMN1 expression, and serum TNF-α expression correlated inversely with trophoblast STMN1 levels. Interestingly, M1 macrophage-derived TNF-α reduced trophoblast migration and invasion, and an anti-TNF-α antibody reversed this effect. Collectively, this study indicated that STMN1 may play a key role in regulating trophoblast invasion, and that impaired STMN1 expression may lead to abnormal trophoblast invasion and result in recurrent miscarriage.

  13. OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo

    DEFF Research Database (Denmark)

    Iglesias-Gato, Diego; Chuan, Yin-Choy; Jiang, Ning;

    2015-01-01

    BackgroundUbiquitination is a highly dynamic and reversible process with a central role in cell homeostasis. Deregulation of several deubiquitinating enzymes has been linked to tumor development but their specific role in prostate cancer progression remains unexplored.MethodsRNAi screening was used...... to investigate the role of the ovarian tumor proteases (OTU) family of deubiquitinating enzymes on the proliferation and invasion capacity of prostate cancer cells. RhoA activity was measured in relation with OTUB1 effects on prostate cancer cell invasion. Tumor xenograft mouse model with stable OTUB1 knockdown...

  14. miR-214 down-regulates ARL2 and suppresses growth and invasion of cervical cancer cells.

    Science.gov (United States)

    Peng, Ruiqing; Men, Jianlong; Ma, Rui; Wang, Qian; Wang, Yang; Sun, Ying; Ren, Jing

    2017-03-11

    Increasing evidence has shown that miRNAs are implicated in carcinogenesis and can function as oncogenes or tumor suppressor genes in human cancers. In this study, we confirmed that miR-214 is frequently down-regulated in cervical cancer compared with normal cervical tissues. Ectopic expression of miR-214 suppressed proliferation, migration and invasion of HeLa and C33A cervical cancer cells. Bioinformatics analysis revealed that ADP ribosylation factor like 2 (ARL2) was a potential target of miR-214 and was remarkably up-regulated in cervical cancer. Knockdown of ARL2 markedly inhibited cervical cancer cell proliferation, migration and invasion, similarly to over-expression of miR-214, indicating that ARL2 may function as an oncogene in cervical cancer. In conclusion, our study revealed that miR-214 acts as a tumor suppressor via inhibiting proliferation, migration and invasion of cervical cancer cells through targeting ARL2, and that both miR-214 and ARL2 may serve as prognostic or therapeutic targets for cervical cancer.

  15. A synthetic dl-nordihydroguaiaretic acid (Nordy, inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model.

    Directory of Open Access Journals (Sweden)

    Xiaojun Yang

    Full Text Available The zebrafish (Danio rerio and their transparent embryos represent a promising model system in cancer research. Compared with other vertebrate model systems, we had previously shown that the zebrafish model provides many advantages over mouse or chicken models to study tumor invasion, angiogenesis, and tumorigenesis. In this study, we systematically investigated the biological features of glioma stem cells (GSCs in a zebrafish model, such as tumor angiogenesis, invasion, and proliferation. We demonstrated that several verified anti-angiogenic agents inhibited angiogenesis that was induced by xenografted-GSCs. We next evaluated the effects of a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy", which revealed anti-tumor activity against human GSCs in vitro by establishing parameters through studying its ability to suppress angiogenesis, tumor invasion, and proliferation. Furthermore, our results indicated that Nordy might inhibit GSCs invasion and proliferation through regulation of the arachidonate 5-lipoxygenase (Alox-5 pathway. Moreover, the combination of Nordy and a VEGF inhibitor exhibited an enhanced ability to suppress angiogenesis that was induced by GSCs. By contrast, even following treatment with 50 µM Nordy, there was no discernible effect on zebrafish embryonic development. Together, these results suggested efficacy and safety of using Nordy in vivo, and further demonstrated that this model should be suitable for studying GSCs and anti-GSC drug evaluation.

  16. Identification of NDRG1-regulated genes associated with invasive potential in cervical and ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Gang, E-mail: zhaog69@sjtu.edu.cn [Department of Pathology, The First People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin (China); Chen, Jiawei, E-mail: jiaweichen2000@gmail.com [Department of Pathology, The First People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Deng, Yanqiu [Pathophysiology Department, Tianjin Medical University, Tianjin (China); Gao, Feng [Department of Pathology, The First People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Zhu, Jiwei [Basic Medical College, Harbin Medical University, Harbin (China); Feng, Zhenzhong; Lv, Xiuhong [Department of Pathology, The First People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Zhao, Zheng [SAS Headquarters, S6013, 600 Research Drive, Cary, NC (United States)

    2011-04-29

    Highlights: {yields} NDRG1 was knockdown in cervical and ovarian cancer cell lines by shRNA technology. {yields} NDRG1 knockdown resulted in increased cell invasion activities. {yields} Ninety-six common deregulated genes in both cell lines were identified by cDNA microarray. {yields} Eleven common NDRG1-regulated genes might enhance cell invasive activity. {yields} Regulation of invasion by NDRG1 is an indirect and complicated process. -- Abstract: N-myc downstream regulated gene 1 (NDRG1) is an important gene regulating tumor invasion. In this study, shRNA technology was used to suppress NDRG1 expression in CaSki (a cervical cancer cell line) and HO-8910PM (an ovarian cancer cell line). In vitro assays showed that NDRG1 knockdown enhanced tumor cell adhesion, migration and invasion activities without affecting cell proliferation. cDNA microarray analysis revealed 96 deregulated genes with more than 2-fold changes in both cell lines after NDRG1 knockdown. Ten common upregulated genes (LPXN, DDR2, COL6A1, IL6, IL8, FYN, PTP4A3, PAPPA, ETV5 and CYGB) and one common downregulated gene (CLCA2) were considered to enhance tumor cell invasive activity. BisoGenet network analysis indicated that NDRG1 regulated these invasion effector genes/proteins in an indirect manner. Moreover, NDRG1 knockdown also reduced pro-invasion genes expression such as MMP7, TMPRSS4 and CTSK. These results suggest that regulation of invasion and metastasis by NDRG1 is a highly complicated process.

  17. PPARγ inhibits ovarian cancer cells proliferation through upregulation of miR-125b

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Shuang, E-mail: luoshuangsch@163.com [Department of Obstetrics and Gynecology, Suining Central Hospital, Suining (China); Wang, Jidong [Department of Gynecology and Obsterics, Jinan Central Hospital, Jinan (China); Ma, Ying [Department of Otorhinolaryngolgy, Suining Central Hospital, Suining (China); Yao, Zhenwei [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Pan, Hongjuan [Department of Gynecology and Obsterics, Zhongshan Hospital, Wuhan (China)

    2015-06-26

    miR-125b has essential roles in coordinating tumor proliferation, angiogenesis, invasiveness, metastasis and chemotherapy recurrence. In ovarian cancer miR-125b has been shown to be downregulated and acts as a tumor suppressor by targeting proto-oncogene BCL3. PPARγ, a multiple functional transcription factor, has been reported to have anti-tumor effects through inhibition of proliferation and induction of differentiation and apoptosis by targeting the tumor related genes. However, it is unclear whether miR-125b is regulated by PPARγ in ovarian cancer. In this study, we demonstrated that the miR-125b downregulated in ovarian cancer tissues and cell lines. Ligands-activated PPARγ suppressed proliferation of ovarian cancer cells and this PPARγ-induced growth inhibition is mediated by the upregulation of miR-125b. PPARγ promoted the expression of miR-125b by directly binding to the responsive element in miR-125b gene promoter region. Thus, our results suggest that PPARγ can induce growth suppression of ovarian cancer by upregulating miR-125b which inhibition of proto-oncogene BCL3. These findings will extend our understanding of the function of PPARγ in tumorigenesis and miR-125b may be a therapeutic intervention of ovarian cancer. - Highlights: • miR-125b is down-regulated in ovarian cancer tissues and cells. • PPARγ upregulates miR-125b and downregulates its target gene BCL3 expression. • Silence of miR-125b attenuates PPARγ-mediated growth suppression of ovarian cancer cells. • PPARγ promotes the transcription of miR-125b via binding to PPARE in miR-125b gene promoter region.

  18. Perspectives of Nanotechnology in Minimally Invasive Therapy of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Yamin Yang

    2013-01-01

    Full Text Available Breast cancer, the most common type of cancer among women in the western world, affects approximately one out of every eight women over their lifetime. In recognition of the high invasiveness of surgical excision and severe side effects of chemical and radiation therapies, increasing efforts are made to seek minimally invasive modalities with fewer side effects. Nanoparticles (<100 nm in size have shown promising capabilities for delivering targeted therapeutic drugs to cancer cells and confining the treatment mainly within tumors. Additionally, some nanoparticles exhibit distinct properties, such as conversion of photonic energy into heat, and these properties enable eradication of cancer cells. In this review, current utilization of nanostructures for cancer therapy, especially in minimally invasive therapy, is summarized with a particular interest in breast cancer.

  19. Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells

    Directory of Open Access Journals (Sweden)

    Hou Xiaohua

    2010-02-01

    Full Text Available Abstract Background Heparanase facilitates the invasion and metastasis of cancer cells, and is over-expressed in many kinds of malignancies. Our studies indicated that heparanase was frequently expressed in advanced gastric cancers. The aim of this study is to determine whether silencing of heparanase expression can abolish the malignant characteristics of gastric cancer cells. Methods Three heparanase-specific small interfering RNA (siRNAs were designed, synthesized, and transfected into cultured gastric cancer cell line SGC-7901. Heparanase expression was measured by RT-PCR, real-time quantitative PCR and Western blot. Cell proliferation was detected by MTT colorimetry and colony formation assay. The in vitro invasion and metastasis of cancer cells were measured by cell adhesion assay, scratch assay and matrigel invasion assay. The angiogenesis capabilities of cancer cells were measured by tube formation of endothelial cells. Results Transfection of siRNA against 1496-1514 bp of encoding regions resulted in reduced expression of heparanase, which started at 24 hrs and lasted for 120 hrs post-transfection. The siRNA-mediated silencing of heparanase suppressed the cellular proliferation of SGC-7901 cells. In addition, the in vitro invasion and metastasis of cancer cells were attenuated after knock-down of heparanase. Moreover, transfection of heparanase-specific siRNA attenuated the in vitro angiogenesis of cancer cells in a dose-dependent manner. Conclusions These results demonstrated that gene silencing of heparanase can efficiently abolish the proliferation, invasion, metastasis and angiogenesis of human gastric cancer cells in vitro, suggesting that heparanase-specific siRNA is of potential values as a novel therapeutic agent for human gastric cancer.

  20. Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells.

    Science.gov (United States)

    Xu, Hui; Qian, Mingping; Zhao, Bingkun; Wu, Chenyang; Maskey, Niraj; Song, Hongming; Li, Dengfeng; Song, Jialu; Hua, Kaiyao; Fang, Lin

    2017-03-01

    RAB1A acts as an oncogene in various cancers, and emerging evidence has verified that RAB1A is an mTORC1 activator in hepatocellular and colorectal cancer, but the role of RAB1A in breast cancer remains unclear. In this investigation, RAB1A siRNA was successfully transfected in MDA-MB-231 and BT-549 human triple-negative breast cancer cells, and verified by real‑time quantitative polymerase chain reaction and western blotting. Then, MTT cell proliferation, colony formation, cell invasion and wound healing assays were performed to characterize the function of RAB1A in the breast cancer cell lines. Downregulation of RAB1A inhibited cellular growth, cell migration, cell invasion and cell epithelial-mesenchymal transition. Furthermore, compared with NC siRNA transfected cells, RAB1A siRNA transfected breast cancer cells inhibited the phosphorylation of S6K1, the effector molecular of mTORC1. Collectively, our data suggested that RAB1A acts as an oncogene by regulating cellular proliferation, growth, invasion and metastasis via activation of mTORC1 pathway in triple-negative breast cancer.

  1. RNA干扰下调HE4基因表达对人卵巢癌SK-OV-3细胞增殖和侵袭的影响%Effect of HE4 gene silenced by siRNA on the proliferation and invasiveness of ovarian cancer cell SK-OV-3

    Institute of Scientific and Technical Information of China (English)

    房青; 王在; 游嘉; 詹雪梅; 杨爱莲; 魏继红; 房昭

    2014-01-01

    目的应用 RNA 干扰技术下调人附睾蛋白 HE4基因表达水平,观察 HE4对人卵巢癌 SK-OV-3细胞增殖和侵袭能力的影响。  方法化学合成3对 HE4特异性小分子干扰 RNA ( siRNA ),脂质体法转染人卵巢癌细胞系 SK-OV-3( HE4-siRNA 组),同时以非特异序列 siRNA 转染的SK-OV-3细胞(阴性对照组)和正常培养的 SK-OV-3细胞(正常对照组)为对照,于转染后48 h,采用实时荧光定量 PCR 技术(RT-qPCR)和 Western blot 方法分别检测HE4 mRNA 及蛋白表达水平。采用 CCK8试剂盒检测卵巢癌细胞增殖活性的变化,穿膜小室模型测定 HE4对细胞侵袭能力的影响。  结果与正常对照组相比,HE4-siRNA 转染卵巢癌SK-OV-3细胞48 h 后,HE4 mRNA 的表达水平显著下降,仅为正常对照组的12.7%(P0.05)。HE4-siRNA 下调卵巢癌 SK-OV-3细胞 HE4表达后,细胞增殖受到明显抑制,细胞增殖活性仅为正常对照组的60%,阴性对照组细胞增殖未见明显变化。体外侵袭实验显示,HE4-siRNA 组穿膜细胞数为每视野(21.8±2.86)个,显著低于正常对照组(187.4±11.17)个(P 0.05)。  结论 HE4特异性 siRNA 能成功下调 SK-OV-3细胞中HE4基因的表达,显著降低卵巢癌细胞增殖和侵袭能力, HE4有可能成为人卵巢癌侵袭转移防治的重要靶点。%Objective To investigate the effect of HE4 gene knocked down by small interfering RNA (siRNA) on proliferation and invasiveness of ovarian cancer cell SK-OV-3. Methods 3 pairs of synthetic siRNAs targeted HE4 gene were transiently transfected into SK-OV-3 cells by liposomal method (HE4-siRNA group), siRNA of scrambled sequence were transfected at the same time as a negative control, and normal cultured SK-OV-3 without any transfection were used as normal control. HE4 expression level in SK-OV-3 cells was determined using real-time quantitative PCR method and Western blot. CCK8 assay was

  2. Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion.

    Science.gov (United States)

    Zhao, Lanfu; Wang, Yuan; Xue, Yafei; Lv, Wenhai; Zhang, Yufu; He, Shiming

    2015-11-01

    Glioblastoma (GBM) is the most prevalent malignant primary brain tumor in adults and exhibits a spectrum of aberrantly aggressive phenotype. Tumor cell proliferation and invasion are critically regulated by chemokines and their receptors. Recent studies have shown that the chemokine CCL5 and its receptor CCR5 play important roles in tumor invasion and metastasis. Nonetheless, the roles of the CCR5 in GBM still remain unclear. The present study provides the evidence that the chemokine receptor CCR5 is highly expressed and associated with poor prognosis in human GBM. Mechanistically, CCL5-CCR5 mediates activation of Akt, and subsequently induces proliferation and invasive responses in U87 and U251 cells. Moreover, down-regulation of CCR5 significantly inhibited the growth of glioma in U87 tumor xenograft mouse model. Finally, high CCR5 expression in GBM is correlated with increased p-Akt expression in patient samples. Together, these findings suggest that the CCR5 is a critical molecular event associated with gliomagenesis.

  3. Cell migration or cytokinesis and proliferation? – Revisiting the “go or grow” hypothesis in cancer cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Garay, Tamás; Juhász, Éva; Molnár, Eszter [2nd Department of Pathology, Semmelweis University, Budapest (Hungary); Eisenbauer, Maria [Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna (Austria); Czirók, András [Department of Biological Physics, Eötvös University, Budapest (Hungary); Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS (United States); Dekan, Barbara; László, Viktória; Hoda, Mir Alireza [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); Döme, Balázs [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); National Korányi Institute of TB and Pulmonology, Budapest (Hungary); Tímár, József [2nd Department of Pathology, Semmelweis University, Budapest (Hungary); MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest (Hungary); Klepetko, Walter [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); Berger, Walter [Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna (Austria); Hegedűs, Balázs, E-mail: balazs.hegedus@meduniwien.ac.at [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest (Hungary)

    2013-12-10

    The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The “go or grow” hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive. - Highlights: • We investigated the “go or grow” hypothesis in human cancer cells in vitro. • Proliferation and migration positively correlate in melanoma and lung cancer cells. • Duration of cytokinesis and migration shows inverse correlation. • Increased FAK activation is present in highly motile melanoma cells.

  4. Cancer specificity of promoters of the genes controlling cell proliferation.

    Science.gov (United States)

    Kashkin, Kirill; Chernov, Igor; Stukacheva, Elena; Monastyrskaya, Galina; Uspenskaya, Natalya; Kopantzev, Eugene; Sverdlov, Eugene

    2015-02-01

    Violation of proliferation control is a common feature of cancer cells. We put forward the hypothesis that promoters of genes involved in the control of cell proliferation should possess intrinsic cancer specific activity. We cloned promoter regions of CDC6, POLD1, CKS1B, MCM2, and PLK1 genes into pGL3 reporter vector and studied their ability to drive heterologous gene expression in transfected cancer cells of different origin and in normal human fibroblasts. Each promoter was cloned in short (335-800 bp) and long (up to 2.3 kb) variants to cover probable location of core and whole promoter regulatory elements. Cloned promoters were significantly more active in cancer cells than in normal fibroblasts that may indicate their cancer specificity. Both versions of CDC6 promoters were shown to be most active while the activities of others were close to that of BIRC5 gene (survivin) gene promoter. Long and short variants of each cloned promoter demonstrated very similar cancer specificity with the exception of PLK1-long promoter that was substantially more specific than its short variant and other promoters under study. The data indicate that most of the important cis-regulatory transcription elements responsible for intrinsic cancer specificity are located in short variants of the promoters under study. CDC6 short promoter may serve as a promising candidate for transcription targeted cancer gene therapy.

  5. Correlation of microRNA-124 expression in cervical cancer tissue with cancer cell growth and invasion

    Institute of Scientific and Technical Information of China (English)

    Yi Zhu

    2016-01-01

    Objective:To study the correlation of microRNA-124 expression in cervical cancer tissue with cancer cell growth and invasion.Methods: A total of 56 cases of cervical cancer tissue samples and 60 cases of normal cervical tissue samples were selected for study, and microRNA-124 expression levels as well as protein content of proliferation, apoptosis and invasion genes in cervical tissue samples were determined.Results: The relative expression level of miR-124 in cervical cancer tissue was significantly lower than that in normal cervical tissue and the higher the FIGO staging, the lower the relative expression level of miR-124; cervical cancer tissue with different miR-124 expression was divided into group A-D according to quartile, there were differences in the protein content of cyclinD1, CDK4, CDK6, Prdx4, TNFAIP8, Piwil2, p16, p27, Caspase-3, Ezrin, CD44v6, E-cadherin andβ-catenin in cervical cancer tissue of group A, B, C and D, and the lower the relative expression level of miR-124, the higher the protein content of cyclinD1, CDK4, CDK6, Prdx4, TNFAIP8, Piwil2 as well as Ezrin and CD44v6, and the lower the protein content of p16, p27, Caspase-3 as well as E-cadherin andβ-catenin.Conclusions: microRNA-124 shows a trend of lower expression in cervical cancer tissue and is closely related to the excessive proliferation, insufficient apoptosis and invasive growth of cancer cells.

  6. LAPTM4B Down Regulation Inhibits the Proliferation, Invasion and Angiogenesis of HeLa Cells In Vitro

    Directory of Open Access Journals (Sweden)

    Fanling Meng

    2015-09-01

    Full Text Available Background/Aims: LAPTM4B (lysosome-associated protein transmembrane 4 beta is a novel oncogene with important functions in aggressive human carcinomas, including cervical cancer. However, the specific functions and internal molecular mechanisms associated with this gene in the context of cervical cancer remain unclear. Methods: In this study, we explored the effects and mechanisms of LAPTM4B on tumor growth, metastasis and angiogenesis in vitro by depletion of LAPTM4B in Hela cell. RNA interference was used to induce down regulation of LAPTM4B gene expression in Hela cells. The motility, migration potential, and proliferation of the Hela cells were measured by flow cytometry, Transwell migration assays, wound healing assays, and Cell Counting Kit-8 assays. In addition, the cell cycle analysis utilized fluorescence-activated cell sorting. Results: In this study, RNAi-mediated LAPTM4B knockdown inhibited cell growth and angiogenesis. In vitro, HeLa cells with down regulated LAPTM4B also exhibited decreased migration and invasion activity as well as significantly reduced CDK12, HIF-1α, MMP-2, MMP-9 and VEGF expression. LAPTM4B blockade significantly decreased cord lengths and branch points in a tube formation assay. Conclusions: These results suggested that LAPTM4B inactivation could be a novel therapeutic target for cervical cancer.

  7. An Analytical Approach Differentiates Between Individual and Collective Cancer Invasion

    Directory of Open Access Journals (Sweden)

    Elad Katz

    2011-01-01

    Full Text Available Tumour cells employ a variety of mechanisms to invade their environment and to form metastases. An important property is the ability of tumour cells to transition between individual cell invasive mode and collective mode. The switch from collective to individual cell invasion in the breast was shown recently to determine site of subsequent metastasis. Previous studies have suggested a range of invasion modes from single cells to large clusters. Here, we use a novel image analysis method to quantify and categorise invasion. We have developed a process using automated imaging for data collection, unsupervised morphological examination of breast cancer invasion using cognition network technology (CNT to determine how many patterns of invasion can be reliably discriminated. We used Bayesian network analysis to probabilistically connect morphological variables and therefore determine that two categories of invasion are clearly distinct from one another. The Bayesian network separated individual and collective invading cell groups based on the morphological measurements, with the level of cell-cell contact the most discriminating morphological feature. Smaller invading groups were typified by smoother cellular surfaces than those invading collectively in larger groups. Interestingly, elongation was evident in all invading cell groups and was not a specific feature of single cell invasion as a surrogate of epithelial-mesenchymal transition. In conclusion, the combination of cognition network technology and Bayesian network analysis provides an insight into morphological variables associated with transition of cancer cells between invasion modes. We show that only two morphologically distinct modes of invasion exist.

  8. RNA interference targeting CD147 inhibits the proliferation, invasiveness, and metastatic activity of thyroid carcinoma cells by down-regulating glycolysis.

    Science.gov (United States)

    Huang, Peng; Chang, Shi; Jiang, Xiaolin; Su, Juan; Dong, Chao; Liu, Xu; Yuan, Zhengtai; Zhang, Zhipeng; Liao, Huijun

    2015-01-01

    A high rate of glycolytic flux, even in the presence of oxygen, is a key metabolic hallmark of cancer cells. Lactate, the end product of glycolysis, decreases the extracellular pH and contributes to the proliferation, invasiveness and metastasis of tumor cells. CD147 play a crucial role in tumorigenicity, invasion and metastasis; and CD147 also interacts strongly and specifically with monocarboxylate transporter1 (MCT1) that mediates the transport of lactate. The objective of this study was to determine whether CD147 is involved, via its association with MCT1 to transport lactate, in glycolysis, contributing to the progression of thyroid carcinoma. The expression levels of CD147 in surgical specimens of normal thyroid, nodular goiter (NG), well-differentiated thyroid carcinoma (WDTC), and undifferentiated thyroid carcinoma (UDTC) were determined using immunohistochemical techniques. The effects of CD147 silencing on cell proliferation, invasiveness, metastasis, co-localization with MCT1, glycolysis rate and extracellular pH of thyroid cancer cells (WRO and FRO cell lines) were measured after CD147 was knocked-down using siRNA targeting CD147. Immunohistochemical analysis of thyroid carcinoma (TC) tissues revealed significant increases in signal for CD147 compared with normal tissue or NG, while UDTC expressed remarkably higher levels of CD147 compared with WDTC. Furthermore, silencing of CD147 in TC cells clearly abrogated the expression of MCT1 and its co-localization with CD147 and dramatically decreased both the glycolysis rate and extracellular pH. Thus, cell proliferation, invasiveness, and metastasis were all significantly decreased by siRNA. These results demonstrate in vitro that the expression of CD147 correlates with the degree of dedifferentiation of thyroid cancer, and show that CD147 interacts with MCT1 to regulate tumor cell glycolysis, resulting in the progression of thyroid carcinoma.

  9. Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion

    Institute of Scientific and Technical Information of China (English)

    Xia Mu; Yao Chen; Shuihai Wang; Xiang Huang; Huazhen Pan; Ming Li

    2009-01-01

    Vascular endothelial growth factor-correlated chemo-kine 1 (VCC-1), a novel chemokine, is hypothesized to be associated with carcinogenesis. VCC-1 is expressed in hepatocellular carcinoma (HCC) cells, but its func-tion remains unknown. To investigate the molecular effects of VCC-1 on HCC cells, the HCC cell line SMMC7721 was stably transfected with the recombi-nant plasmid pcDNA3.1/VCC-1. Our data demonstrated that overexpression of VCC-1 in SMMC7721 cells sig-nificantly enhanced the cellular proliferation, invasive ability, and tumor growth, when compared with both empty vector control cells and parental cells. These results strongly suggest that VCC-1 plays an important role in SMMC7721 invasion and tumor growth, and indicate that VCC-1 may serve as a potential biomarker for anti-HCC therapies.

  10. NDRG1 Controls Gastric Cancer Migration and Invasion through Regulating MMP-9.

    Science.gov (United States)

    Chang, Xiaojing; Xu, Xiaoyang; Xue, Xiaoying; Ma, Jinguo; Li, Zhenhua; Deng, Peng; Chen, Jing; Zhang, Shuanglong; Zhi, Yu; Dai, Dongqiu

    2016-10-01

    The purpose of this study is to detect the clinical significance of NDRG1 and its relationship with MMP-9 in gastric cancer metastatic progression. 101 cases of gastric cancer specimens were utilized to identify the protein expression of NDRG1 and MMP-9 by immunohistochemistry, their clinical significance was also analyzed. The suppression by siRNA-NDRG1 was employed to detect the role of NDRG1 in gastric cancer progression and its relationship with MMP-9. NDRG1 expression was correlated inversely with the degree of tumor cell differentiation (p 0.05). Furthermore, cell proliferation and invasion effect were remarkably enhanced when NDRG1 was silencing, but MMP-9 expression was increased. NDRG1 silencing enhances gastric cancer cells progression through upregulating MMP-9. It suggests that NDRG1 may inhibit the metastasis of gastric cancer via regulating MMP-9.

  11. Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp [Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan); Haniu, Hisao [Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We examined the correlation between PPAR{gamma} expression and cell proliferation. Black-Right-Pointing-Pointer PPAR{gamma} overexpression reduces cell viability. Black-Right-Pointing-Pointer We show the synergistic effect of cell growth inhibition by a PPAR{gamma} agonist. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPAR{gamma} is expressed at considerable levels in human colon cancer cells. This suggests that PPAR{gamma} expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPAR{gamma} expression in 4 human colon cancer cell lines, HT-29, LOVO, DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPAR{gamma} mRNA and protein in these cells were in the order HT-29 > LOVO > Caco-2 > DLD-1. We also found that PPAR{gamma} overexpression promoted cell growth inhibition in PPAR{gamma} lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPAR{gamma} expression and the cells' sensitivity for proliferation.

  12. Inhibition of RUNX2 transcriptional activity blocks the proliferation, migration and invasion of epithelial ovarian carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Zhi-Qiang Wang

    Full Text Available Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT primary cultures derived from serous epithelial ovarian cancer (EOC patients, when compared to primary cultures derived from matched primary (prior to CT tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

  13. Inhibition of RUNX2 transcriptional activity blocks the proliferation, migration and invasion of epithelial ovarian carcinoma cells.

    Science.gov (United States)

    Wang, Zhi-Qiang; Keita, Mamadou; Bachvarova, Magdalena; Gobeil, Stephane; Morin, Chantale; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Trinh, Xuan Bich; Bachvarov, Dimcho

    2013-01-01

    Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from serous epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

  14. Raddeanin A induces human gastric cancer cells apoptosis and inhibits their invasion in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Gang [Department of Oncology, Nanjing University of Chinese Medicine, Nanjing (China); Zou, Xi [Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China); Zhou, Jin-Yong [Laboratory Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China); Sun, Wei [Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China); Wu, Jian [Laboratory Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China); Xu, Jia-Li [Department of Oncology, Nanjing University of Chinese Medicine, Nanjing (China); Wang, Rui-Ping, E-mail: ruipingwang61@hotmail.com [Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China)

    2013-09-20

    Highlights: •Raddeanin A is a triterpenoid saponin in herb medicine Anemone raddeana Regel. •Raddeanin A can inhibit 3 kinds of gastric cancer cells’ proliferation and invasion. •Caspase-cascades’ activation indicates apoptosis induced by Raddeanin A. •MMPs, RECK, Rhoc and E-cad are involved in Raddeanin A-induced invasion inhibition. -- Abstract: Raddeanin A is one of the triterpenoid saponins in herbal medicine Anemone raddeana Regel which was reported to suppress the growth of liver and lung cancer cells. However, little was known about its effect on gastric cancer (GC) cells. This study aimed to investigate its inhibitory effect on three kinds of different differentiation stage GC cells (BGC-823, SGC-7901 and MKN-28) in vitro and the possible mechanisms. Proliferation assay and flow cytometry demonstrated Raddeanin A’s dose-dependent inhibitory effect and determined its induction of cells apoptosis, respectively. Transwell assay, wounding heal assay and cell matrix adhesion assay showed that Raddeanin A significantly inhibited the abilities of the invasion, migration and adhesion of the BGC-823 cells. Moreover, quantitative real time PCR and Western blot analysis found that Raddeanin A increased Bax expression while reduced Bcl-2, Bcl-xL and Survivin expressions and significantly activated caspase-3, caspase-8, caspase-9 and poly-ADP ribose polymerase (PARP). Besides, Raddeanin A could also up-regulate the expression of reversion inducing cysteine rich protein with Kazal motifs (RECK), E-cadherin (E-cad) and down-regulate the expression of matrix metalloproteinases-2 (MMP-2), MMP-9, MMP-14 and Rhoc. In conclusion, Raddeanin A inhibits proliferation of human GC cells, induces their apoptosis and inhibits the abilities of invasion, migration and adhesion, exhibiting potential to become antitumor drug.

  15. MicroRNA-144 inhibits hepatocellular carcinoma cell proliferation, invasion and migration by targeting ZFX

    Indian Academy of Sciences (India)

    HONGBIN BAO; XINGUO LI; HENGLI LI; HONGLI XING; BINGHUI XU; XIANFENG ZHANG; ZHAOMING LIU

    2017-03-01

    MicroRNA 144 (miR-144), a small non-coding RNA, is frequently dysregulated in human several tumour progression,but its role and the underlying mechanisms in hepatocellular carcinoma (HCC) is poorly investigated. In thepresent study, the expression of miR-144 was firstly analysed in datasets derived from GSE21362 and TCGA, andthen detected in HCC tissues and cell lines by quantitative RT-PCR (qRT-PCR) analysis. MiR-144 was shown to besignificantly down-regulated in HCC tissues and cell lines. Subsequently, overexpression of miR-144 was transfectedinto HCC cell lines so as to investigate its biological function, including MTT, colony formation, and transwell assays.Gain of function assay revealed miR-144 remarkably inhibited cell proliferation, migration and invasion. In addition,bioinformatical analysis and luciferase reporter assay identified ZFX as a novel target of miR-144 in HCC cells, asconfirmed by qRT-PCR and Western blot. Furthermore, ZFX was found to be significantly up-regulated usingOncomine database analysis. Loss of function assay further indicated knockdown of ZFX had similar effects ofmiR-144-mediated HCC cell proliferation and invasion. Therefore, miR-144 has been demonstrated to act as a tumoursuppressor in HCC cell growth and motility by directly targeting ZFX, which implicates its potential applications inthe development of HCC treatment.

  16. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells.

    Science.gov (United States)

    Olaso, E; Ikeda, K; Eng, F J; Xu, L; Wang, L H; Lin, H C; Friedman, S L

    2001-11-01

    Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.

  17. LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

    Science.gov (United States)

    Leve, Fernanda; Peres-Moreira, Rubem J.; Binato, Renata; Abdelhay, Eliana; Morgado-Díaz, José A.

    2015-01-01

    Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell

  18. The thioredoxin system in breast cancer cell invasion and migration.

    Science.gov (United States)

    Bhatia, Maneet; McGrath, Kelly L; Di Trapani, Giovanna; Charoentong, Pornpimol; Shah, Fenil; King, Mallory M; Clarke, Frank M; Tonissen, Kathryn F

    2016-08-01

    Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

  19. The thioredoxin system in breast cancer cell invasion and migration

    Directory of Open Access Journals (Sweden)

    Maneet Bhatia

    2016-08-01

    Full Text Available Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1 in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1 expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

  20. Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism.

    Directory of Open Access Journals (Sweden)

    Liang-Dong Li

    Full Text Available Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application.

  1. BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion

    Directory of Open Access Journals (Sweden)

    Michalski Christoph W

    2007-12-01

    Full Text Available Abstract Background Bone gamma-carboxyglutamate protein (BGLAP; osteocalcin is a small, highly conserved molecule first identified in the mineralized matrix of bone. It has been implicated in the pathophysiology of various malignancies. In this study, we analyzed the expression and role of BGLAP in the normal human pancreas, chronic pancreatitis (CP, and pancreatic ductal adenocarcinoma (PDAC using quantitative RT-PCR, immunohistochemistry, immunocytochemistry and enzyme immunoassays, as well as cell proliferation and invasion assays. Gene silencing was carried out using specific siRNA molecules. Results Compared to the normal pancreas, BGLAP mRNA and protein levels were not significantly different in CP and PDAC tissues. BGLAP was faintly present in the cytoplasm of normal acinar cells but was strongly expressed in the cytoplasm and nuclei of tubular complexes and PanIN lesions of CP and PDAC tissues. Furthermore, BGLAP expression was found in the cancer cells in PDAC tissues as well as in 4 cultured pancreatic cancer cell lines. TNFalpha reduced BGLAP mRNA and protein expression levels in pancreatic cancer cell lines. In addition, BGLAP silencing led to reduction of both cell growth and invasion in those cells. Conclusion BGLAP is expressed in pancreatic cancer cells, where it potentially increases pancreatic cancer cell growth and invasion through autocrine and/or paracrine mechanisms.

  2. Estrogen receptors and cell proliferation in breast cancer.

    Science.gov (United States)

    Ciocca, D R; Fanelli, M A

    1997-10-01

    Most of the actions of estrogens on the normal and abnormal mammary cells are mediated via estrogen receptors (ERs), including control of cell proliferation; however, there are also alternative pathways of estrogen action not involving ERs. Estrogens control several genes and proteins that induce the cells to enter the cell cycle (protooncogenes, growth factors); estrogens also act on proteins directly involved in the control of the cell cycle (cyclins), and moreover, estrogens stimulate the response of negative cell cycle regulators (p53, BRCA1). The next challenge for researchers is elucidating the integration of the interrelationships of the complex pathways involved in the control of cell proliferation. This brief review focuses on the mechanisms of estrogen action to control cell proliferation and the clinical implications in breast cancer. (Trends Endocrinol Metab 1997;8:313-321). (c) 1997, Elsevier Science Inc.

  3. 沉默乙酰肝素酶基因对人卵巢癌SKOV3细胞增殖、侵袭能力的影响%Silencing heparanase suppresses proliferation and invasion in ovarian cancer SKOV3 cells

    Institute of Scientific and Technical Information of China (English)

    赵玲; 杨鹰

    2011-01-01

    Objective To explore the effect of silencing heparanase gene by RNA short hairpin on the proliferation and invasion in human ovarian cancer cell line SKOV3. Methods After shRNA lentiviral vectors targeting heparanase gene was constructed, they were transfected into SKOV3 cells. Experimental transfection groups included the interference sequences HPA shRNA-1 group, HPA shRNA-2, and HPA shRNA-3 group, and the untransfected group amd blank transfection group served as control. After transfection, the interference efficiency was observed though fluorescence quantitative PCR and Western blotting to detect the expression of heparanase at mRNA and protein levels. Flow cytometry was employed to test cell cycle changes, cell counting kit-8 (CCK-8) for the detection of cell proliferation, and matrix gel invasion assays for the detection of cell invasion ability. Results After shRNA lentiviral vectors were transfected into SKOV3 cells, HPA expression was significantly decreased at mRNA and protein levels in the HPA-shRNA-1 sequence and the HPA-shRNA-2 sequence groups (P < 0. 05), whereas the expression levels of HPA-shRNA-3 sequence group was not decreased, indicating it was an ineffective sequence. In the SKOV3 cells transfected with effective sequences HPA-shRNA-1 and HPA-shRNA-2, the cell percentage of G1 phase was decreased, the proliferation (OD index) was significantly decreased and transmembrane cell number was increasingly decreased. There was a significantly difference between the experimental groups and untransfected and blank transfection groups respectively (P < 0.05). Conclusion Silencing HPA by RNA interference inhibits heparanase expression, and suppresses cell proliferation and invasion efficiently, which may be correlated with the downregulation of HPA gene and protein.%目的 观察沉默乙酰肝素酶(heparanase,HPA)基因对人卵巢癌SKOV3细胞的增殖及侵袭能力的影响.方法 构建针对HPA基因的shRNA慢病毒载体,感染人卵巢癌SKOV3

  4. 磁性纳米顺铂微球联合磁流体热疗对卵巢癌skov-3细胞增殖、凋亡及侵袭的影响%Effects of magnetic nano-cisplatin microspheres combined with magnetic fluid hyperthermia on the proliferation, apoptosis and invasion of skov-3 cell line of ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    徐云钊; 奚庆华; 张玉泉

    2013-01-01

    Objective To investigate the effects of magnetic nano-cisplatin microspheres combined with magnetic fluid hyperthermia on the proliferation,apoptosis and invasion of skov-3 cell line of ovarian cancer and the mechanism.Methods The logarithmic growth phase skov-3 cells were divided into five groups:the control group,naked drug group (cisplatin 5μmol/L),nano drug group (cisplatin 5 μmol/L + Fe304 magnetic nano-cisplatin microspheres lg/L),magnetic thermochemotherapy group (Fe304 magnetic nano-cisplatin microspheres 1 g/L) and magnetic heating group (Fe304 magnetic nanoparticles 1 g/L).Cells in the control group,naked drug group and nano drug group were cultured in the incubator for 24 h.Cells in the magnetic thermochemotherapy group and magnetic heating group were treated by magnetic fluid hyperthermia under the electromagnetic field for 24 h.The proliferation was measured by MTT; the levels of CD44v6,MMP-2 mRNA expression were measured by RT-PCR; the invasive ability of cells was detected by transwell test; and the apoptotic rate was detected by flow cytometry (FCM).Results Compared with the control group,inhibitory rate of cell proliferation,apoptosis rate and invasion inhibition rate in the remaining 4 groups were increased (all P < 0.05).There were no statistical significant differences in the expression of MMP-2,CD44v6 mRNA between nano drug group and control group (P >0.05).MMP-2,CD44v6 mRNA expression of magnetic heating group,naked drug group and magnetic thermochemotherapy group was decreased gradually (P < 0.05 or P < 0.01).There were statistically significant differences in MMP-2 and CD44v6 mRNA expression between the nano drug group,magnetic heating group,naked drug group and magnetic thermoche-motherapy group (all P < 0.05).Conclusion Magnetic nano-cisplatin microspheres combined with magnetic fluid hyperthermia can not only enhance the inhibitory effects of proliferation and invasion,but also induce the apoptosis,which is associated with the

  5. HIPK2 downregulates vimentin and inhibits breast cancer cell invasion.

    Science.gov (United States)

    Nodale, Cristina; Sheffer, Michal; Jacob-Hirsch, Jasmine; Folgiero, Valentina; Falcioni, Rita; Aiello, Aurora; Garufi, Alessia; Rechavi, Gideon; Givol, David; D'Orazi, Gabriella

    2012-02-15

    Vimentin, a mesenchymal marker, is frequently overexpressed in epithelial carcinomas undergoing epithelial to mesenchymal transition (EMT), a condition correlated with invasiveness and poor prognosis. Therefore, vimentin is a potential molecular target for anticancer therapy. Emerging studies in experimental models underscore the functions of homeodomain-interacting protein kinase 2 (HIPK2) as potential oncosuppressor by acting as transcriptional corepressor or catalytic activator of molecules involved in apoptosis and response to antitumor drugs. However, an involvement of HIPK2 in limiting tumor invasion remains to be elucidated. This study, by starting with a microarray analysis, demonstrates that HIPK2 downregulates vimentin expression in invasive, vimentin-positive, MDA-MB-231 breast cancer cells and in the non-invasive MCF7 breast cancer cells subjected to chemical hypoxia, a drive for mesenchymal shift and tumor invasion. At functional level, vimentin downregulation by HIPK2 correlates with inhibition of breast tumor cell invasion. Together, these data show that vimentin is a novel target for HIPK2 repressor function and that HIPK2-mediated vimentin downregulation can contribute to inhibition of breast cancer cells invasion that might be applied in clinical therapy.

  6. Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity.

    Science.gov (United States)

    Li, Dawei; Sun, Xing; Yan, Dongwang; Huang, Jianfeng; Luo, Qiongzhen; Tang, Huamei; Peng, Zhihai

    2012-10-01

    Piwi-like protein 2 (Piwil2) has recently emerged as a putative oncogene which is amplified in several human malignancies. However, the role of Piwil2 in colon cancer remains poorly understood. The aim of this study was to investigate the clinical and pathological significance of Piwil2, and the possible role in the proliferation and metastasis of colon cancer. Primary colon cancer paired with adjacent normal colon tissue and lymph node metastasis (LNM) lesions in 66 patients' tissue microarrays (TMA) were used to determine the expression of Piwil2. Knocked down Piwil2 expression in SW620 and SW480 colon cancer cell lines was performed to evaluate the role of Piwil2 in cell proliferation, invasion, metastasis in vitro and tumorigenicity in vivo. The possible roles of Piwil2 in the regulation of a 2 kb matrix metallopeptidase 9 (MMP9) promoter fragment and on the regulation of apoptotic pathways were evaluated by using a luciferase reporter construct and Western blots, respectively. Significantly higher expression levels of Piwil2 were observed in primary colon cancer tissue and in LNM in comparison with normal colon mucosa. Piwil2 expression significantly correlated with more aggressive clinical and pathological parameters with poorer five-year metastasis-free survival and overall survival. Piwil2 silencing significantly reduced cancer cell proliferation, colony formation ability and increased apoptosis in vitro and inhibited tumor growth in vivo. Piwil2 knockdown also attenuated migration and invasion of colon cancer cells via modulation of MMP9 transcriptional activities. Our results indicate that Piwil2 moderates the proliferation and metastasis potential of colon cancer.

  7. MiR-100 Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion and Enhances Chemosensitivity by Targeting IGFIR.

    Science.gov (United States)

    Liu, Yang; Zhu, Shu-Tao; Wang, Xiao; Deng, Jun; Li, Wei-Hua; Zhang, Peng; Liu, Bing-Shan

    2016-10-01

    MicroRNAs are highly conserved noncoding RNA that negatively modulate protein expression at a posttranscriptional and/or translational level. MicroRNAs play an important role in the development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-100 was downregulated in many cancers; however, the role of miR-100 in human osteosarcoma has not been totally elucidated. In this study, we demonstrate that the expression of miR-100 was significantly downregulated in human osteosarcoma tissues compared to the adjacent tissues. Enforced expression of miR-100 inhibited cell proliferation, migration, and invasion abilities of osteosarcoma cells, U-2OS, and MG-63. Additionally, miR-100 also sensitized osteosarcoma cells to cisplatin and promoted apoptosis. Furthermore, overexpression of miR-100 decreased the expression of insulin-like growth factor I receptor and inhibited PI3K/AKT and MAPK/ERK signaling. In human clinical specimens, insulin-like growth factor I receptor was inversely correlated with miR-100 in osteosarcoma tissues. Collectively, our results demonstrate that miR-100 is a tumor suppressor microRNA and indicate its potential application for the treatment of osteosarcoma in future.

  8. Alterations in integrin expression modulates invasion of pancreatic cancer cells.

    LENUS (Irish Health Repository)

    Walsh, Naomi

    2009-01-01

    BACKGROUND: Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. METHODS: In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. RESULTS: Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin beta1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. CONCLUSION: Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma.

  9. Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5

    Institute of Scientific and Technical Information of China (English)

    Xiao-dong SUN; LIU Jun ZHOU; Xing-juan SHl; Xiao-ou SUN; You-guang LUO; Xiao-jing WU; Chang-fu YAO; Hai-yang YU; Deng-wen; LI Min

    2011-01-01

    The mitotic kinesin Eg5 plays a critical role in bipolar spindle assembly,and its inhibitors have shown impressive anticancer activity in preclinical studies.This study was undertaken to investigate the effect of dimethylenastron,a specific inhibitor of Eg5,on the migration and invasion of pancreatic cancer cells.Methods:Human pancreatic cancer cell lines PANC1,EPP85,BxPC3,CFPAC1,and AsPAC1 were used.Eg5 expression was examined using immunofluorescence microscopy.Cell migration and invasion were analyzed with wound healing and transwell assays.Cell pro-liferation was examined using sulforhodamine B and MTT assays.The binding of dimethylenastron to Eg5 was analyzed with a molecular modeling study,and the ADP release rate was examined with the MANT-ADP reagent.Results:Eg5 expression was 9-16-fold up-regulated in the 5 pancreatic cancer cell lines.Treatment of PANC1 pancreatic cancer cells with dimethylenastron (3 and 10 μmol/L) for 24 h suppressed the migratory ability of the cancer cells in a concentration-dependent manner.The invasion ability of the cancer cells was also reduced by the treatment.However,treatment of PANC1 cells with dimeth-ylenastron (3 and 10 μmol/L) for 24 h had no detectable effect on their proliferation,which was inhibited when the cancer cells were treated with the drug for 72 h.Molecular modeling study showed that dimethylenastron could allosterically inhibit the motor domain ATPase of Eg5 by decreasing the rate of ADP release.Conclusion:Dimethylenastron inhibits the migration and invasion of PANC1 pancreatic cancer cells,independent of suppressing the cell proliferation.The findings provide a novel insight into the mechanisms of targeting Eg5 for pancreatic cancer chemotherapy.

  10. Downregulation of LIMK1–ADF/cofilin by DADS inhibits the migration and invasion of colon cancer

    Science.gov (United States)

    Su, Jian; Zhou, Yujuan; Pan, Zhibing; Shi, Ling; Yang, Jing; Liao, Aijun; Liao, Qianjin; Su, Qi

    2017-01-01

    This study aimed to explore whether the downregulation of LIM kinase 1 (LIMK1)-actin depolymerization factor (ADF, also known as destrin)/cofilin by diallyl disulfide (DADS) inhibited the migration and invasion of colon cancer. Previous studies have shown that silencing LIMK1 could significantly enhance the inhibitory effect of DADS on colon cancer cell migration and invasion, suggesting that LIMK1 was a target molecule of DADS, which needed further confirmation. This study reported that LIMK1 and destrin were highly expressed in colon cancer and associated with poor prognosis of patients with colon cancer. Also, the expression of LIMK1 was positively correlated with the expression of destrin. The overexpression of LIMK1 significantly promoted colon cancer cell migration and invasion. DADS obviously inhibited migration and invasion by suppressing the phosphorylation of ADF/cofilin via downregulation of LIMK1 in colon cancer cells. Furthermore, DADS-induced suppression of cell proliferation was enhanced and antagonized by the knockdown and overexpression of LIMK1 in vitro and in vivo, respectively. Similar results were observed for DADS-induced changes in the expression of vimentin, CD34, Ki-67, and E-cadherin in xenografted tumors. These results indicated that LIMK1 was a potential target molecule for the inhibitory effect of DADS on colon cancer cell migration and invasion. PMID:28358024

  11. Cell polarity signaling in the plasticity of cancer cell invasiveness.

    Science.gov (United States)

    Gandalovičová, Aneta; Vomastek, Tomáš; Rosel, Daniel; Brábek, Jan

    2016-05-03

    Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.

  12. MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2.

    Science.gov (United States)

    Xia, Ying; Gao, Yan

    2014-05-09

    MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3'-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.

  13. Effects and Significance of SDF-1/CXCR4 in Proliferation, Migration and Invasion of Colorectal Cancer Cell Line SW480%SDF-1/CXCR4对大肠癌细胞株SW480增殖、迁移及侵袭的影响及意义

    Institute of Scientific and Technical Information of China (English)

    袁丽倩; 郑淑芳

    2014-01-01

    目的:探讨基质细胞衍生因子-1(SDF-1)及其特异性受体CXC趋化因子受体4(CXCR4)对大肠癌细胞SW480增殖、迁移及侵袭能力的影响及意义。方法取对数生长期大肠癌细胞SW480分为对照组(未经任何处理)、SDF-1组(加入100μg/L SDF-1)、SDF-1+AMD3100混合组(向细胞中加入1 mg/L AMD3100,孵育2 h后加入100μg/L SDF-1)、AMD3100组(加入1 mg/L AMD3100)。免疫组化法检测SW480细胞中CXCR4蛋白表达情况;RT-PCR法检测SW480细胞中CXCR4 mRNA的表达情况,以及外源性SDF-1和AMD3100作用后CXCR4 mRNA表达水平的变化;MTT增殖实验、Transwell迁移及侵袭实验分别检测SDF-1以及AMD3100对SW480细胞增殖、迁移及侵袭能力的影响。结果 SW480细胞中CXCR4蛋白呈阳性表达(阳性率80%)。SW480细胞中有CXCR4 mRNA的表达,100μg/L SDF-1促使CXCR4 mRNA表达水平进一步上调,且能被1 mg/L AMD3100阻断。SDF-1组细胞增殖活性(0.847±0.039)高于对照组(0.624±0.011)和SDF-1+AMD3100混合组(0.607±0.016),AMD3100组(0.456±0.032)低于对照组和SDF-1+AMD3100混合组(F=108.030,P<0.05)。Transwell小室迁移及侵袭实验中SDF-1组穿膜细胞数(个:98.7±5.8、33.7±6.2)均多于对照组(21.0±2.2、6.1±2.3)、SDF-1+AMD3100混合组(18.5±8.4、8.5±2.8)和AMD3100组(12.1±3.2、2.1±1.0),后3组间比较差异无统计学意义。结论 SDF-1/CXCR4生物轴可促进大肠癌细胞SW480的增殖、迁移及侵袭。%Objective To discuss the influence and significance of stromal cell-derived factor 1 (SDF-1) and its specific receptor CXC chemokine receptor 4 (CXCR4) in proliferation, migration and invasion ability of SW480 colorectal cancer cells. Methods The colorectal cancer cell line SW480 in logarithmic phase was divided into four groups:control group (with no any processing), SDF-1 group (added 100μg/L SDF-1), SDF-1+1 mg/L AMD3100 mixed group (added 1 mg/L AMD3100 for 2 hours, then added 100

  14. Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis

    Science.gov (United States)

    Xia, Shujun; Wang, Chuandong; Postma, Emily Louise; Yang, Yanhua; Ni, Xiaofeng; Zhan, Weiwei

    2017-01-01

    Lymph node metastasis (LNM) is common in papillary thyroid cancer (PTC), and is an indicator of recurrence. The detailed molecular mechanism of LNM in PTC has not been well described. This study aimed to investigate the role of fibronectin 1 in PTC LNM and its clinical relevance. The expression of fibronectin 1 was confirmed in PTC tissues and cell lines. A correlation analysis was conducted and a receiver-operating characteristic curve obtained. The effect of fibronectin 1 on the proliferation of PTC cell lines was performed using a colony-formation assay and Cell Counting Kit 8. Cell-cycle analysis was performed with a flow-cytometry assay. Migration and invasion ability were evaluated by transwell and wound-healing assays. Fibronectin 1 was overexpressed in metastasized PTC. Overexpressed fibronectin 1 was positively correlated with PTC LNM. Receiver-operating characteristic analysis showed that the diagnostic accuracy of fibronectin 1 was 81.1%, with sensitivity of 80% and specificity of 82%. Overexpression of fibronectin 1 promoted proliferation, migration, and invasion in PTC. Fibronectin 1 plays a critical role in PTC metastasis by modulating the proliferation, migration, and invasion ability of PTC cells, and it is a valuable diagnostic biomarker for predicting PTC LNM. PMID:28367057

  15. RPM peptide conjugated bioreducible polyethylenimine targeting invasive colon cancer.

    Science.gov (United States)

    Lee, Yeong Mi; Lee, Duhwan; Kim, Jihoon; Park, Hansoo; Kim, Won Jong

    2015-05-10

    CPIEDRPMC (RPM) peptide is a peptide that specifically targets invasive colorectal cancer, which is one of the leading causes of cancer-related deaths worldwide. In this study, we exploited RPM peptide as a targeting ligand to produce a novel and efficient gene delivery system that could potentially be used to treat invasive colon cancer. In order to achieve enhanced specificity to colon cancer cells, the RPM peptide was conjugated to a bioreducible gene carrier consisting of a reducible moiety of disulfide-crosslinked low molecular weight polyethylenimine, IR820 dye, and polyethylene glycol. Here, we examined the physiochemical properties, cytotoxicity, in vitro transfection efficiency, and in vivo biodistribution of the RPM-conjugated polyplex. Our results showed that the RPM-conjugated gene carrier formed a compact polyplex with pDNA that had low toxicity. Furthermore, the RPM-conjugated polymer not only had higher cellular uptake in invasive colon cancer than the non-targeted polymer, but also showed enhanced transfection efficiency in invasive colon cancer cells in vitro and in vivo.

  16. Inhibitory effect of maple syrup on the cell growth and invasion of human colorectal cancer cells.

    Science.gov (United States)

    Yamamoto, Tetsushi; Uemura, Kentaro; Moriyama, Kaho; Mitamura, Kuniko; Taga, Atsushi

    2015-04-01

    Maple syrup is a natural sweetener consumed by individuals of all ages throughout the world. Maple syrup contains not only carbohydrates such as sucrose but also various components such as organic acids, amino acids, vitamins and phenolic compounds. Recent studies have shown that these phenolic compounds in maple syrup may possess various activities such as decreasing the blood glucose level and an anticancer effect. In this study, we examined the effect of three types of maple syrup, classified by color, on the cell proliferation, migration and invasion of colorectal cancer (CRC) cells in order to investigate whether the maple syrup is suitable as a phytomedicine for cancer treatment. CRC cells that were administered maple syrup showed significantly lower growth rates than cells that were administered sucrose. In addition, administration of maple syrup to CRC cells caused inhibition of cell invasion, while there was no effect on cell migration. Administration of maple syrup clearly inhibited AKT phosphorylation, while there was no effect on ERK phosphorylation. These data suggest that maple syrup might inhibit cell proliferation and invasion through suppression of AKT activation and be suitable as a phytomedicine for CRC treatment, with fewer adverse effects than traditional chemotherapy.

  17. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

    Directory of Open Access Journals (Sweden)

    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  18. RNA interference targeting raptor inhibits proliferation of gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, William Ka Kei; Lee, Chung Wa [Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Cho, Chi Hin [Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Chan, Francis Ka Leung [Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Yu, Jun, E-mail: junyu@cuhk.edu.hk [Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Sung, Joseph Jao Yiu, E-mail: joesung@cuhk.edu.hk [Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China)

    2011-06-10

    Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G{sub 0}/G{sub 1}-phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D{sub 3} and p21{sup Waf1}, which stabilizes cyclin D/cdk4 complex for G{sub 1}-S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.

  19. Voltage-Gated Ion Channels in Cancer Cell Proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Rao, Vidhya R.; Perez-Neut, Mathew [Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago 2160 S. 1st Ave, Maywood, IL 60153 (United States); Kaja, Simon [Department of Ophthalmology and Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO 64108 (United States); Gentile, Saverio, E-mail: sagentile@luc.edu [Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago 2160 S. 1st Ave, Maywood, IL 60153 (United States)

    2015-05-22

    Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K{sup +}, Ca{sup ++}, Cl{sup −}, Na{sup +}. Traditionally, voltage-gated ion channels (VGIC) are known to play fundamental roles in controlling rapid bioelectrical signaling including action potential and/or contraction. However, several investigations have revealed that these classes of proteins can also contribute significantly to cell mitotic biochemical signaling, cell cycle progression, as well as cell volume regulation. All these functions are critically important for cancer cell proliferation. Interestingly, a variety of distinct VGICs are expressed in different cancer cell types, including metastasis but not in the tissues from which these tumors were generated. Given the increasing evidence suggesting that VGIC play a major role in cancer cell biology, in this review we discuss the role of distinct VGIC in cancer cell proliferation and possible therapeutic potential of VIGC pharmacological manipulation.

  20. In vitro invasion efficiency and intracellular proliferation rate comprise virulence-related phenotypic traits of Neospora caninum

    Directory of Open Access Journals (Sweden)

    Regidor-Cerrillo Javier

    2011-02-01

    Full Text Available Abstract In this study, we examined the in vitro invasion and proliferation capacities of the Nc-Liv and ten Spanish Neospora caninum isolates (Nc-Spain 1 H - Nc-Spain 10. The invasion rate was determined as the number of tachyzoites that completed their internalisation into MARC-145 cells at 2, 4, and 6 h post-inoculation (pi. The proliferation rate was evaluated by determining the doubling time during the exponential proliferation period. Significant differences in the invasion rates of these isolates were detected at 2 and 4 h pi (P P = 0.0016, ANOVA test. Tachyzoite yield, which combines invasion and proliferation data, was also assessed and confirmed marked differences between the highly and less prolific isolates. Interestingly, a direct correlation between the invasion rates and tachyzoite yields, and the severity of the disease that was exhibited by infected pregnant mice in previous works could be established for the isolates in this study (Spearman's coefficient > 0.62, P

  1. [CCR7 silence by siRNA inhibits proliferation, invasion and promotes apoptosis of human MG63 osteosarcoma cells].

    Science.gov (United States)

    Zhang, Richun; Zhang, Hongtao; E, Zhen; Ma, Qiong; Yan, Shiju; Zhang, Enwei; Ma, Bao'an

    2016-12-01

    Objective To investigate the effect of siRNA-mediated chemokine receptor 7 (CCR7) silence on the proliferation, migration, invasion and apoptosis of human MG-63 osteosarcoma cells. Methods The study designed and synthesized siRNA targeting CCR7 (CCR7-siRNA). After MG63 cells were transfected with CCR7-siRNA, the expression of CCR7 was identified by Western blotting; cell apoptosis was detected by annexinV-FITC/PI double staining combined with flow cemetery; cell proliferation was tested by MTT assay; and cell migration and invasion abilities were examined by Transwell(TM) migration/invasion assays. Results CCR7 expression in MG63 cells was significantly inhibited after transfected with CCR7-siRNA. At the same time, cell proliferation, migration and invasion abilities were distinctly suppressed, and cell apoptosis rate increased. Conclusion Down-regulating CCR7 expression in MG63 cells could apparently inhibit cell proliferation, migration and invasion abilities of MG63 cells, and also induce cell apoptosis.

  2. Effect of miRNA-6841-3p on proliferation, migration and invasion of human cervical cancer cells%Hsa-miR-6841-3 p对宫颈癌细胞系Caski增殖及侵袭转移的影响

    Institute of Scientific and Technical Information of China (English)

    裴桂华; 殷复粉; 王宁; 孙欣; 于啸; 孙业武; 于风胜; 王言奎

    2016-01-01

    Objective:To explore the effect of microRNA-6841-3p ( miRNA-6841-3p) on the biological behavior of human cervical cancer cells. Methods:The cervical cancer cell line Caski was transiently transfected with miRNA-6841-3 p mimics and miRNA-6841-3 p inhibi-tor by riboFECT CP. The expression of trefoil factor 3 (TFF3) and miRNA-6841-3p in human cervical cancer cell line Caski were detected by real-time fluorescent quantitative polymerase chain reaction (RT-PCR). Cell proliferation was evaluated using the cell counting Kit-8(CCK-8) assay. Invasion was measured by transwell chamber assays. The wound healing model was used to represent the migrationability. Results:The CaSki cells transfected with miRNA. miR-NA-6841-3 p mRNA expression in cells transfected with miRNA-6841-3 p mimics was signifi-cantly higher than that in negative control cells(P<0. 01). miRNA-6841-3p mRNA expression in cells transfected with miRNA-6841-3 p inhibitor was significantly lower than that in negative control cells (P<0. 01). However,the TFF3 mRNA expression in the mimics transfected cells decreased significantly. The overexpression of miRNA-6841-3p inhibited the viability,and inva-sion and migration abilities,as shown in the cells transfected with the miRNA-6841-3p mimics ( P<0 . 05 ) . Conclusion:Overexpression of miRNA-6841-3 p had an inhibitory effect on cell proliferation,and markedly inhibited invasion and migration of Caskicells in vitro and in vivo.%目的::探讨 miRNA-6841-3 p 对宫颈癌细胞生物学行为的影响。方法:将miRNA-6841-3 p模拟物、miRNA-6841-3 p抑制物转染至宫颈癌细胞系Caski。实时荧光定量PCR检测宫颈癌细胞系Caski转染后miRNA-6841-3 p mRNA以及其预测靶基因TFF3的转录表达。 CCK-8法检测细胞增殖能力。 Transwell小室检测细胞体外侵袭转移能力。划痕实验检测细胞迁移能力。结果:实时荧光定量PCR显示, miRNA-6841-3 p模拟物转染组与miRNA-6841-3 p 模拟物对照组相比, mi

  3. Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products.

    Science.gov (United States)

    Harikumar, Kuzhuvelil B; Sung, Bokyung; Tharakan, Sheeja T; Pandey, Manoj K; Joy, Beena; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B

    2010-05-01

    Agents that are safe, affordable, and efficacious are urgently needed for the prevention of chronic diseases such as cancer. Sesamin, a lipid-soluble lignan, is one such agent that belongs to a class of phytoestrogens, isolated from sesame (Sesamum indicum), and has been linked with prevention of hyperlipidemia, hypertension, and carcinogenesis through an unknown mechanism. Because the transcription factor NF-kappaB has been associated with inflammation, carcinogenesis, tumor cell survival, proliferation, invasion, and angiogenesis of cancer, we postulated that sesamin might mediate its effect through the modulation of the NF-kappaB pathway. We found that sesamin inhibited the proliferation of a wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas, and lung. Sesamin also potentiated tumor necrosis factor-alpha-induced apoptosis and this correlated with the suppression of gene products linked to cell survival (e.g., Bcl-2 and survivin), proliferation (e.g., cyclin D1), inflammation (e.g., cyclooxygenase-2), invasion (e.g., matrix metalloproteinase-9, intercellular adhesion molecule 1), and angiogenesis (e.g., vascular endothelial growth factor). Sesamin downregulated constitutive and inducible NF-kappaB activation induced by various inflammatory stimuli and carcinogens, and inhibited the degradation of IkappaBalpha, the inhibitor of NF-kappaB, through the suppression of phosphorylation of IkappaBalpha and inhibition of activation of IkappaBalpha protein kinase, thus resulting in the suppression of p65 phosphorylation and nuclear translocation, and NF-kappaB-mediated reporter gene transcription. The inhibition of IkappaBalpha protein kinase activation was found to be mediated through the inhibition of TAK1 kinase. Overall, our results showed that sesamin may have potential against cancer and other chronic diseases through the suppression of a pathway linked to the NF-kappaB signaling.

  4. Drug resistance in cancer: molecular evolution and compensatory proliferation.

    Science.gov (United States)

    Friedman, Ran

    2016-03-15

    Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.

  5. Influence of BMSCs-derived exosome on proliferation and invasion of mouse breast cancer cells 4 T1 and the mechanism%BMSCs 来源的外泌体对小鼠乳腺癌细胞4 T1增殖、侵袭的影响及机制探讨

    Institute of Scientific and Technical Information of China (English)

    王丹丹; 陈建中; 亢春彦

    2015-01-01

    目的:观察骨髓间充质干细胞(BMSCs)来源的外泌体(exosome)对小鼠乳腺癌细胞4T1增殖、侵袭的影响,并探讨其可能机制。方法将小鼠乳腺癌细胞4T1随机分为3组,4T1+vehicle组仅加入400μL无血清培养基,4T1+exosome组加入400μL由无血清培养基配置的exosome,4T1+exosome+磷脂酰肌醇3激酶( PI3K)/Akt信号通路阻断剂( Y294002)组加入400μL终浓度为5μmol/mL Y294002及400μg/mL exosome的培养基。分别采用MTT法、细胞划痕实验、Western blotting法检测各组细胞增殖、迁移和侵袭能力以及PI3K/Akt信号通路相关蛋白。结果4T1+exosome组、4T1+vehicle组、4T1+exosome+Y294002组细胞增殖抑制率分别为0.713%±0.050%、0.401%±0.030%、0.459%±0.800%,4T1+exosome组分别与4T1+vehicle组、4T1+exosome+Y294002组比较,P均<0.05。4T1+exosome组、4T1+vehicle组、4T1+exosome+Y294002组细胞迁移距离分别为(388.0±36.1)、(295.0±34.2)、(275.0±63.5)μm,4T1+exosome组分别与4T1+vehicle组、4T1+exosome+Y294002组比较,P均<0.05。4T1+exosome组p-AKT、β-catenin OD值分别为0.30±0.11、0.30±0.08,4T1+vehicle组分别为1.10±0.41、0.70±0.08,4T1+exosome+Y294002组分别为0.40±0.13、0.30±0.07,4T1+exosome组分别与4T1+vehicle组、4T1+exosome+Y294002组比较,P均<0.05。结论 BMSCs来源的exosome能够增加小鼠乳腺癌细胞4T1的增殖、迁移及侵袭能力,其机制可能与上调PI3K/Akt信号通路有关。%Objective To observe the influence of bone marrow mesenchymal stem cells ( BMSCs)-derived exosome on the proliferation and invasion of mouse breast cancer cells 4T1 and to investigate the mechanism.Methods The mouse breast cancer cells 4T1 were randomly divided into three groups:4T1+vehicle group, 4T1+exosome group and 4T1+exosome+Y294002 (an

  6. Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo

    Institute of Scientific and Technical Information of China (English)

    Adarsh Shankar; Robert A. Knight; Stephen Brown; Ali S. Arbab; Sanath Kumar; Asm Iskander; Nadimpalli RS Varma; Branislava Janic; Ana deCarvalho; Tom Mikkelsen; Joseph A. Frank; Meser M. Ali

    2014-01-01

    Tumor cellproliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n= 8), or underwent no radiation (n= 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 ± 15)%compared with (25 ± 12)%in the nonirradiated group (P=0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance fol owing radiation therapy for GBM.

  7. Human decorin regulates proliferation and migration of human lung cancer A549 cells

    Institute of Scientific and Technical Information of China (English)

    LIANG Shuo; XU Jin-fu; CAO Wei-jun; LI Hui-ping; HU Cheng-ping

    2013-01-01

    Background Decorin is a small leucine-rich proteoglycan and it plays an important role in regulation of cell growth and migration in various tumor cell lines.Decorin was found down-regulated in non-small cell lung cancer tissue and may be involved in regulation of lung cancer development.Methods In this study,lentivirus-mediated RNA interference and over expression were employed to change the expression levels of decorin in lung cancer A549 cells.We tested the cell cycle of A549 cells and the expression of transforming growth factor (TGF)-β1,cyclin D1,epidermal growth factor receptor (EGFR),P53,and P21.Results We found that up-regulation of decorin could inhibit proliferation,block cell cycle at G1 and decrease invasive activity of A549 cells.Moreover,we also show that up-regulation of decorin induced significant decreases of TGF-β1,cyclin D1 expression,phosphorylation of EGFR,and increases of P53 and P21 expression.Opposite results were observed in A549 cells with down-regulation of decorin.Conclusion Our results suggest that decorin is a key regulator involved in proliferation and migration ofA549 cells.

  8. Current therapeutic strategies for invasive and metastatic bladder cancer

    Directory of Open Access Journals (Sweden)

    Vishnu P

    2011-07-01

    Full Text Available Prakash Vishnu, Jacob Mathew, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Bladder cancer is one of the most common cancers in Europe, the United States, and Northern African countries. Muscle-invasive bladder cancer is an aggressive epithelial tumor, with a high rate of early systemic dissemination. Superficial, noninvasive bladder cancer can most often be cured; a good proportion of invasive cases can also be cured by a combined modality approach of surgery, chemotherapy, and radiation. Recurrences are common and mostly manifest as metastatic disease. Those with distant metastatic disease can sometime achieve partial or complete remission with combination chemotherapy.Recent developments: Better understanding of the biology of the disease has led to the incorporation of molecular and genetic features along with factors such as tumor grade, lympho-vascular invasion, and aberrant histology, thereby allowing identification of ‘favorable’ and ‘unfavorable’ cancers which helps a more accurate informed and objective selection of patients who would benefit from neoadjuvant and adjuvant chemotherapy. Gene expression profiling has been used to find molecular signature patterns that can potentially be predictive of drug sensitivity and metastasis. Understanding the molecular pathways of invasive bladder cancer has led to clinical investigation of several targeted therapeutics such as anti-angiogenics, mTOR inhibitors, and anti-EGFR agents.Conclusion: With improvements in the understanding of the biology of bladder cancer, clinical trials studying novel and targeted agents alone or in combination with chemotherapy have increased the armamentarium for the treatment of bladder cancer. Although the novel biomarkers and gene expression profiles have been shown to provide important predictive and prognostic information and are anticipated to be incorporated in clinical decision-making, their exact utility

  9. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect.

    Directory of Open Access Journals (Sweden)

    Marta Solinas

    Full Text Available In the present study, we found that CBD inhibited U87-MG and T98G cell proliferation and invasiveness in vitro and caused a decrease in the expression of a set of proteins specifically involved in growth, invasion and angiogenesis. In addition, CBD treatment caused a dose-related down-regulation of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and decreased hypoxia inducible factor HIF-1α expression in U87-MG cells. Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways. As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.

  10. The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion

    Science.gov (United States)

    Keita, Mamadou; Bachvarova, Magdalena; Morin, Chantale; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Trinh, Xuan Bich; Bachvarov, Dimcho

    2013-01-01

    Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis. PMID:23442798

  11. Results of radiotherapy on ureteric obstruction in muscle-invasive bladder cancer

    DEFF Research Database (Denmark)

    Honnens De Lichtenberg, Mette; Miskowiak, J; Rolff, H

    1995-01-01

    To evaluate the effect of radiotherapy on ureteric obstruction due to muscle-invasive bladder cancer.......To evaluate the effect of radiotherapy on ureteric obstruction due to muscle-invasive bladder cancer....

  12. Limitations of Colposcopy in Early Invasive Cervical Cancer Detection

    OpenAIRE

    Grubišić, Goran

    2007-01-01

    Colposcopy is a key element in the diagnostic chain required to reduce cervical cancer mortality but it has limitations in the diagnosis of malignant disease. In the Republic of Croatia the Croatian Society for Colposcopy and Cervical Pathology started constructing guidelines for early detection, therapy and follow-up of patients with early invasive cervical cancer in order to achieve the best possible results in diagnosis, therapy and follow-up. From 2001 to 2006 Croatian society ...

  13. Phosphatase of regenerating liver-3-signal transducer and activators of transcription 3-miR-21 sighal pathway promotes proliferation and invasion of colon cancer cells%肝再生磷酸酶-3-信号传导和转录激活子3-微小RNA21信号通路促进结肠癌细胞增殖侵袭的研究

    Institute of Scientific and Technical Information of China (English)

    张建龙; 张育超; 孙健; 何传超; 褚忠华

    2012-01-01

    目的 观察肝再生磷酸酶-3-信号传导和转录激活子3-微小RNA21(PRL-3-STAT3miR-21)信号通路对结肠癌细胞增殖侵袭的作用.方法 构建稳定转染PRL-3基因和空白对照质粒的结肠癌细胞株LoVo-PRL-3和LoVo-VC,用荧光实时定量聚合酶链反应(RT-qPCR)检测稳转细胞株中miR-21的表达并在瞬时转染PRL-3的SW480及CaCO2细胞中进行验证.用Western blot法对PRL-3调控STAT3的表达进行检测,在LoVo-PRL-3细胞中对STAT3进行RNA干扰,检测miR-21的表达,在稳转细胞株中转染miR-21或对其进行敲除,用细胞计数试剂盒(CCK-8)、Transwell实验对细胞的增殖侵袭能力的变化进行研究.结果 LoVo-PRL-3细胞在72、96 h的增殖能力以及在Transwell实验24 h后的侵袭能力要强于对照组LoVo-VC细胞(P<0.01).在结肠癌细胞株LoVo-PRL-3中pSTAT3、miR-21的表达明显上调,干扰STAT3可以抑制miR-21的表达(P<0.05).在LoVo-VC细胞中过表达miR-21促进了细胞的增殖侵袭(P<0.01),而在LoVo-PRL-3细胞中敲除miR-21抑制了细胞的增殖侵袭(P<0.05).结论 PRL-3-STAT3-miR-21信号通路在结肠癌细胞增殖侵袭中起促进作用.%Objective To explore the effect of phosphatase of regenerating liver-3-signal transducer and activators of transcription 3-microRNA-21 (PRL-3-STAT3-miR-21) signal pathway on proliferation and invasion of colon cancer cellsMethods We stablely transfected PRL-3 expressing plasmid and empty plasmid into LoVo colon cancer cells and established two cell lines:LoVo-PRL-3 and LoVo-VC.We used quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) to detect the expression of miR-21 in LoVo cells.We also performed transient transfection of PRL-3 into SW480 and CACO2 cells to validate the expression of miR-21.Western blotting was used to detect the effect of PRL-3 on the expression of STAT3.RNA interference was used to knocked down STAT3 in LoVo-PRL-3 cells,after that miR-21 expression was

  14. Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhan, Yu; Abi Saab, Widian F.; Modi, Nidhi; Stewart, Amanda M. [Department of Biological Sciences, The University of Toledo, 2801 W. Bancroft, Toledo, OH 43606 (United States); Liu, Jinsong [Department of Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Chadee, Deborah N., E-mail: deborah.chadee@utoledo.edu [Department of Biological Sciences, The University of Toledo, 2801 W. Bancroft, Toledo, OH 43606 (United States)

    2012-08-15

    Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. -- Highlights: Black-Right-Pointing-Pointer Ovarian cancer cell lines have high levels of total and phosphorylated MLK3. Black-Right-Pointing-Pointer MLK3 is required for MMP expression and activity in ovarian cancer cells. Black-Right-Pointing-Pointer MLK3 is required for invasion of SKOV3 and HEY1B ovarian cancer cells. Black-Right-Pointing-Pointer MLK3-dependent regulation of MMP-2 and MMP-9 activities requires ERK and JNK.

  15. Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development.

    Directory of Open Access Journals (Sweden)

    Ville Härmä

    Full Text Available The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D growth conditions using non-transformed prostate epithelial cells (EP156T, an androgen-sensitive prostate cancer cell line (LNCaP, and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.

  16. Inhibition of cell proliferation, migration and invasion of B16-F10 melanoma cells by α-mangostin

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    Beninati, Simone, E-mail: beninati@bio.uniroma2.it [Department of Biology, University “Tor Vergata”, Rome (Italy); Oliverio, Serafina [Department of Biology, University “Tor Vergata”, Rome (Italy); Cordella, Martina [Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome (Italy); Rossi, Stefania; Senatore, Cinzia [Regina Elena National Cancer Institute, Rome (Italy); Liguori, Immacolata; Lentini, Alessandro; Piredda, Lucia [Department of Biology, University “Tor Vergata”, Rome (Italy); Tabolacci, Claudio [Department of Biology, University “Tor Vergata”, Rome (Italy); Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome (Italy)

    2014-08-08

    Highlights: • We studied the anticancer potential of a new emerging molecule, α-mangostin (α-M). • We provide first evidences on the effects of α-M on transglutaminase activity. • We deeply examined the antimetastatic effects of α-M through many in vitro assays. • Proteomic analysis revealed that α-M promotes a reorganization at cellular level. - Abstract: In this study, we have evaluated the potential antineoplastic effects of α-mangostin (α-M), the most representative xanthone in Garcinia mangostana pericarp, on melanoma cell lines. This xanthone markedly inhibits the proliferation of high-metastatic B16-F10 melanoma cells. Furthermore, by deeply analyzing which steps in the metastatic process are influenced by xanthone it was observed that α-M strongly interferes with homotypic aggregation, adhesion, plasticity and invasion ability of B16-F10 cells, probably by the observed reduction of metalloproteinase-9 activity. The antiproliferative and antimetastatic properties of α-M have been established in human SK-MEL-28 and A375 melanoma cells. In order to identify pathways potentially involved in the antineoplastic properties of α-M, a comparative mass spectrometry proteomic approach was employed. These findings may improve our understanding of the molecular mechanisms underlying the anti-cancer effects of α-M on melanoma.

  17. Role of Seprase in Breast Cancer Invasion

    Science.gov (United States)

    1998-09-01

    ctin Nvas si~paratcd frorn free (𔃻ýI1 by get I tra - iwtvdopodWa prateolysis )f e.TtraceLlular mnatrix~ tion osmAg sa. excellulose GS colunin (Pi.erce...invadopodia. MMP-2 is secreted istry of proteinas :. in tumor invasion. Physicl Revs 73, as a soluble enzyme that can be found within the 161-45, oytoplasm

  18. Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling.

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    Sliva, D; Jedinak, A; Kawasaki, J; Harvey, K; Slivova, V

    2008-04-22

    The antitumour activity of a medicinal mushroom Phellinus linteus (PL), through the stimulation of immune system or the induction of apoptosis, has been recently described. However, the molecular mechanisms responsible for the inhibition of invasive behaviour of cancer cells remain to be addressed. In the present study, we demonstrate that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer cells. The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27(Kip1) expression. Phellinus linteus also suppressed invasive behaviour of MDA-MB-231 cells by the inhibition of cell adhesion, cell migration and cell invasion through the suppression of secretion of urokinase-plasminogen activator from breast cancer cells. In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells. These effects are mediated by the inhibition of serine-threonine kinase AKT signalling, because PL suppressed phosphorylation of AKT at Thr(308) and Ser(473) in breast cancer cells. Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.

  19. Global existence for a degenerate haptotaxis model of cancer invasion

    Science.gov (United States)

    Zhigun, Anna; Surulescu, Christina; Uatay, Aydar

    2016-12-01

    We propose and study a strongly coupled PDE-ODE system with tissue-dependent degenerate diffusion and haptotaxis that can serve as a model prototype for cancer cell invasion through the extracellular matrix. We prove the global existence of weak solutions and illustrate the model behavior by numerical simulations for a two-dimensional setting.

  20. Morphological instability and cancer invasion: a 'splashing water drop' analogy

    Directory of Open Access Journals (Sweden)

    Delsanto Pier P

    2007-01-01

    Full Text Available Abstract Background Tissue invasion, one of the hallmarks of cancer, is a major clinical problem. Recent studies suggest that the process of invasion is driven at least in part by a set of physical forces that may be susceptible to mathematical modelling which could have practical clinical value. Model and conclusion We present an analogy between two unrelated instabilities. One is caused by the impact of a drop of water on a solid surface while the other concerns a tumor that develops invasive cellular branches into the surrounding host tissue. In spite of the apparent abstractness of the idea, it yields a very practical result, i.e. an index that predicts tumor invasion based on a few measurable parameters. We discuss its application in the context of experimental data and suggest potential clinical implications.

  1. Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis.

    Science.gov (United States)

    Jiang, Guosong; Wu, Amy D; Huang, Chao; Gu, Jiayan; Zhang, Liping; Huang, Haishan; Liao, Xin; Li, Jingxia; Zhang, Dongyun; Zeng, Xingruo; Jin, Honglei; Huang, Haojie; Huang, Chuanshu

    2016-07-01

    Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1-FOXO1-MMP-2 axis. Cancer Prev Res; 9(7); 567-80. ©2016 AACR.

  2. Invasion and metastasis ability of renal cancer cell strains 786-0: under the influence of miR-141.

    Science.gov (United States)

    Xu, Y; Lv, L N; Guo, Z Y; Zhang, W

    2016-01-01

    This study aimed to explore the invasion and metastasis ability of miR-141 in 786-0 renal cancer tissue cells, as well as identify the key function of endogenous miR-141 in adjustment and control of malignant activities of renal cancer. The renal cancer cell strain with overexpression of miR-141 and its control renal cancer cell line were constructed; methyl thiazolyl tetrazolium (MTT) assay was adopted to measure proliferation of renal cancer cells; Transwell assay was performed to measure the invasion and metastasis ability of cells; MTT assay and fluorescence activated cell sorting (FACS) were used for measurement of cell apoptosis and drug susceptibility. Results indicated that the expression of miR-141 in 786-0 cells could be significantly increased 400-fold by slow viruses that contained miR-141; moreover, c omprehensive functions showed that miR-141 inhibited the invasion and metastasis ability of renal cancer cells to a great extent (p less than 0.001), partially inhibited cell growth (p less than 0.05) and also induced cell cycle to be arrested in G0/G1 as well as reducing the number of cells in S phase (DNA replicative phase). Moreover, miR-141 could not induce morphologic changes of renal cancer cells, had no direct stimulating effect on cell apoptosis and could not improve the drug susceptibility of renal cancer cells to drugs such as cis-Dichlorodiamineplatinum (DDP), 5-fluorouracil (5-FU) and tumor-related apoptosis-inducing ligand (TRAIL). In conclusion, miR-141 can be considered an important cancer suppressor gene of renal cancer by inhibiting proliferation and metastasis of renal cancer cells.

  3. Curcumin affects -hydrazino liposomal nanoparticles on breast cancer cell proliferation, apoptosis,invasion and migration%联氨基姜黄素脂质体纳米颗粒对乳腺癌细胞增殖、凋亡、侵袭和迁移的影响

    Institute of Scientific and Technical Information of China (English)

    任玉国; 张凤梅; 王敏; 田文霞; 伦立民

    2016-01-01

    Objective:To study the effect of linking amino liposomal curcumin nanoparticles(HC -NPs)on breast cancer cells and its mechanism.Methods:Prepared the HC -NPs,cultured human breast cancer MDA -MB -231 cells in logarithmic growth phase cells for the study,and cells were divided into control group and the experimental group.The control group was not with special treatment,the experimental group were given NPs.HC -NPs processing and measuring the rate of cell growth inhibition,transitional healing rate and determine associated protein CyclinD1, Bcl -2,the expression of Bax,Survivin,MMP -9,p -STAT3.Results:HC -NPs treated human breast cancer MDA-MB -231,compared with liposomal nanoparticles load (NPs)in the control group,significantly inhibited cell pro-liferation in the experimental group than the control group(P <0.05).Apoptosis rate was higher in the experimental group(P <0.05).There were significant differences in cell cycle measurement(P <0.05).HC -NPs role in human breast cancer MDA -MB -231 cells after 24h,cell cycle arrest in G2 .Invasion and migration compared with the con-trol group(P <0.05).HC -NPs invasion and migration group was significantly lower than the control group.MMP -9 was significantly reduced and relatively lower than the control group,while Bax increased significantly higher.Con-clusion:The effect of HC -NPs on breast cancer cells was related with down JAK/STAT signaling pathway.%目的:研究联氨基姜黄素脂质体纳米颗粒(HC -NPs)对乳腺癌细胞的抑制作用及其机制。方法:制备 HC -NPs,培养人乳腺癌 MDA -MB -231细胞。以对数生长期的细胞为研究对象。分成对照组和实验组,对照组及实验组分别予以脂质体纳米颗粒空载(NPs)、HC -NPs 处理。测定细胞生长抑制率、移行愈合率,并测定相关蛋白 CyclinD1、Bcl -2、Bax、Survivin、MMP -9、p -STAT3的表达情况。结果:HC -NPs 处理人乳腺癌 MDA -MB -231后,与 NPs 对

  4. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells.

    Directory of Open Access Journals (Sweden)

    Andrej Udelnow

    Full Text Available BACKGROUND: Omeprazole has recently been described as a modulator of tumour chemoresistance, although its underlying molecular mechanisms remain controversial. Since pancreatic tumours are highly chemoresistant, a logical step would be to investigate the pharmacodynamic, morphological and biochemical effects of omeprazole on pancreatic cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Dose-effect curves of omeprazole, pantoprazole, gemcitabine, 5-fluorouracil and the combinations of omeprazole and 5-fluorouracil or gemcitabine were generated for the pancreatic cancer cell lines MiaPaCa-2, ASPC-1, Colo357, PancTu-1, Panc1 and Panc89. They revealed that omeprazole inhibited proliferation at probably non-toxic concentrations and reversed the hormesis phenomena of 5-fluorouracil. Electron microscopy showed that omeprazole led to accumulation of phagophores and early autophagosomes in ASPC-1 and MiaPaCa-2 cells. Signal changes indicating inhibited proliferation and programmed cell death were found by proton NMR spectroscopy of both cell lines when treated with omeprazole which was identified intracellularly. Omeprazole modulates the lysosomal transport pathway as shown by Western blot analysis of the expression of LAMP-1, Cathepsin-D and β-COP in lysosome- and Golgi complex containing cell fractions. Acridine orange staining revealed that the pump function of the vATPase was not specifically inhibited by omeprazole. Gene expression of the autophagy-related LC3 gene as well as of Bad, Mdr-1, Atg12 and the vATPase was analysed after treatment of cells with 5-fluorouracil and omeprazole and confirmed the above mentioned results. CONCLUSIONS: We hypothesise that omeprazole interacts with the regulatory functions of the vATPase without inhibiting its pump function. A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death. This may circumvent common resistance mechanisms of

  5. Invasive ductal breast cancer metastatic to the sigmoid colon

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    Zhou Xiao-cong

    2012-11-01

    Full Text Available Abstract The most common sites of breast cancer metastasis are the bone, lung, liver and brain. However, colonic metastases from breast cancer are very rare in the clinic. We describe an unusual case of sigmoid colonic metastasis from invasive ductal breast cancer. With this report, we should increase the clinical awareness that any patient with a colorectal lesion and a history of malignancy should be considered to have a metastasis until proven otherwise. Early diagnosis is very important, which enables prompt initiation of systemic treatment, such as chemotherapy, endocrine therapy or both, thus avoiding unnecessary radical surgical resection and improving the prognosis.

  6. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Tae Mogami

    Full Text Available Ovarian clear cell adenocarcinoma (CCC is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++-binding annexin A4 (ANXA4 protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  7. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

    Science.gov (United States)

    Mogami, Tae; Yokota, Naho; Asai-Sato, Mikiko; Yamada, Roppei; Koizume, Shiro; Sakuma, Yuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Takano, Yasuo; Hirahara, Fumiki; Miyagi, Yohei; Miyagi, Etsuko

    2013-01-01

    Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++)-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  8. Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling.

    Science.gov (United States)

    Fu, Qianfeng; Jiang, Yuling; Zhang, Daxin; Liu, Xiuli; Guo, Junfeng; Zhao, Jinlong

    2016-07-01

    Valosin-containing protein (VCP) was previously shown to exhibit high expression in colorectal cancer (CRC) tissues as compared with that in normal tissues; however, the role of VCP in human CRC cells has remained to be elucidated. Two colorectal cancer cell lines HCT116 and RKO were used in the experiment. We introduced lentiviral constructs expressing VCP to infect RKO cells and lenti-shRNA targeting VCP into HCT116 cells, respectively. Cell proliferation, invasion, apoptosis, and cell cycle arrest were subsequently examined by MTT assay, transwell chamber assay, flow cytometry, and western blot analysis, respectively. Furthermore, a subcutaneous tumor mouse model and lung metastasis model was used to investigate the effects of VCP on the growth and metastasis of CRC cells in vivo. VCP knockdown was shown to inhibit cell proliferation, chemoresistance and invasion, and induce apoptosis in the HCT116 CRC cells, whereas VCP over-expression suppressed apoptosis and chemoresponse, promoted proliferation and invasion of the RKO CRC cells. In addition, in the subcutaneous tumor and lung metastasis mouse model, VCP knockdown in HCT116 cells suppressed carcinogenesis and metastasis in vivo. The findings of the present study indicated that VCP is very important for the proliferation and metastasis of CRC; therefore, targeting VCP and its downstream targets may represent novel therapies for the treatment of CRC.

  9. Proliferation and Polarity in Breast Cancer: Untying the GordianKnot

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hong; Radisky, Derek C.; Bissell, Mina J.

    2005-05-09

    Epithelial cancers are associated with genomic instability and alterations in signaling pathways that affect proliferation, apoptosis, and integrity of tissue structure. Overexpression of a number of oncogenic protein kinases has been shown to malignantly transform cells in culture and to cause tumors in vivo, but the interconnected signaling events induced by transformation still awaits detailed dissection. We propose that the network of cellular signaling pathways can be classified into functionally distinct branches, and that these pathways are rewired in transformed cells and tissues after they lose tissue-specific architecture to favor tumor expansion and invasion. Using three-dimensional (3D) culture systems, we recently demonstrated that polarity and proliferation of human mammary epithelial cancer cells were separable consequences of signaling pathways downstream of PI3 kinase.These, and results from a number of other laboratories are beginning to provide insight into how different signaling pathways may become interconnected in normal tissues to allow homeostasis, and how they are disrupted during malignant progression.

  10. Effects of Curcumin on Invasion and Metastasis in the Human Cervical Cancer Cells Caski

    Institute of Scientific and Technical Information of China (English)

    Fang XU; Xiao-ling MU; Jing ZHAO

    2009-01-01

    Objective: To explore the effects of curcumin on invasion and metastasis in the human cervical cancer cells Caski.Methods: Caski cells were treated with 10, 25, 50μmol/L curcumin for 24, 48, 72 h. Proliferation of Caski cells was measured with MTT assay. When treated with 50μmol/L curcumin for 72 h, the expressions of MMP-2, MT1-MMP and NF-κB of cells were detected by Western-blot, and invasion and metastasis of Caski cells were evaluated with transwell chamber.Results: After being treated with 10μmol/L, 25μmol/L, 50μmol/L curcumin for 24, 48 and 72 h, the proliferation of Caski cells was inhibited in a dose-and time-dependent manner. The expression of MMP-2, MT1-MMP and NF-κB were decreased when being treated with 50μmol/L curcumin for 72 h. After treatment with 50μmol/L curcumin, in invasion assay, the number of cells in curcumin treated group to migrate to filter coated with Matrigel was reduced compared with control group(P<0.05). Meanwhile, in migration assay, the number of cells in curcumin treated group to migrate to filter was also decreased compared with control group (P<0.05).Conclusion: Curcumin could affect the invasion and metastasis of the human cervical cancer cells Caski. Inhibiting the expression of MMP-2, MT1-MMP and NF-κB was probably one of its molecular mechanisms.

  11. Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features

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    de Weger Roel A

    2009-06-01

    Full Text Available Abstract Background Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3 is a pro-apoptotic member of the Bcl-2 family induced under hypoxia. Low or absent expression has recently been described in human tumors, including gastrointestinal tumors, resulting in poor prognosis. Little is known about BNIP3 expression in invasive breast cancer. The aim of the present study was to investigate the expression of BNIP3 in invasive breast cancer at the mRNA and protein level in correlation with the hypoxic response and clinicopathological features. Methods In 40 cases of invasive breast cancer, BNIP3 mRNA in situ hybridization was performed on frozen sections with a digoxigenin labeled anti-BNIP3 probe. Paraffin embedded sections of the same specimens were used to determine protein expression of BNIP3, Hypoxia Inducible Factor 1 alpha (HIF-1α and its downstream targets Glucose Transporter 1 (Glut-1 and Carbonic Anhydrase (CAIX by immunohistochemistry. Results BNIP3 mRNA was expressed in 16/40 (40% of the cases and correlated with BNIP3 protein expression (p = 0.0218. Neither BNIP3 protein nor mRNA expression correlated with expression of HIF-1α expression or its downstream targets. Tumors which showed loss of expression of BNIP3 had significantly more often lymph node metastases (82% vs 39%, p = 0.010 and showed a higher mitotic activity index (p = 0.027. BNIP3 protein expression was often nuclear in normal breast, but cytoplasmic in tumor cells. Conclusion BNIP3 expression is lost in a significant portion of invasive breast cancers, which is correlated with poor prognostic features such as positive lymph node status and high proliferation, but not with the hypoxic response.

  12. Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

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    Kari T. Syvänen

    2014-05-01

    Full Text Available Neoadjuvant chemotherapy (NAC in muscle-invasive bladder cancer was introduced several years ago. Despite the evidence supporting its use in clinical practice, only a minority of patients who undergo radical cystectomy receive preoperative chemotherapy. In addition, recommendations and methods to detect patients who would benefit the most from NAC are still unclear. The European Association of Urology (EAU guidelines panel on muscle-invasive and metastatic bladder cancer recommends the use of cisplatin-based NAC for T2-T4a, cN0 M0 bladder cancer if the patient has a performance status ≥2 and if the renal function is not impaired, but the American Urological Association, for example, does not have any guideline recommendations on this topic at all. In this review we describe the current literature supporting NAC in association with radical cystectomy in muscle-invasive urothelial carcinoma of the bladder. Evidence acquisition was made searching the Medline database for original articles published before 1st February 2014, with search terms: “neoadjuvant chemotherapy”, “radical cystectomy”, and “invasive bladder cancer”.

  13. Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil.

    Science.gov (United States)

    Zhang, Rui; Xu, Lei-Bo; Yue, Xiu-Jing; Yu, Xian-Huan; Wang, Jie; Liu, Chao

    2013-03-01

    The Bmi1 gene has been reported to play important roles in cancer initiation and progression. The aim of this study was to investigate the effects of RNA interference (RNAi)-mediated silencing of Bmi1 gene expression on the proliferation and invasiveness of hepatocellular carcinoma (HCC) cells and on the efficacy of chemotherapy in HCC patients. The Bmi1 gene was silenced by Bmi1-siRNA (small interfering RNA) in the human HCC cell lines HepG2 and Bel-7402, and the gene expression levels were assayed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The proliferation and migration of Bmi1-silenced tumor cells and their sensitivity to 5-FU treatment were determined by Cell Counting Kit-8 (CCK-8), transwell assays and 4',6-diamidino-2-phenylindole (DAPI) staining and flow cytometry, respectively. Bmi1-siRNA inhibited the Bmi1 expression at both the mRNA and protein levels in HCC cells. Proliferation and migration of HCC cells treated with Bmi1-siRNA was significantly lower compared to that of the control cells. Moreover, Bmi1 gene silencing increased the percentage of apoptotic cells treated by 5-FU and decreased the IC50 values of 5-FU to a greater extent. Downregulation of the Bmi1 gene by RNAi can inhibit the proliferation and invasivesness of HCC cells and increase their sensitivity to 5-FU treatment.

  14. Emerging roles of exosomes in cancer invasion and metastasis.

    Science.gov (United States)

    Soung, Young Hwa; Nguyen, Thalia; Cao, Hans; Lee, Janet; Chung, Jun

    2016-01-01

    Recent evidence has indicated that nano-sized vesicles called "exosomes" mediate the interaction between cancer cells and their microenvironment and play a critical role in the development of cancers. Exosomes contain cargo consisting of proteins, lipids, mRNAs, and microRNAs that can be delivered to different types of cells in nascent as well as distant locations. Cancer cell-derived exosomes (CCEs) have been identified in body fluids such as urine, plasma, and saliva from patients with cancer. Although their content depends on tumor type and stage, CCEs merit consideration as prognostic and diagnostic markers, as vehicles for drug delivery, and as potential therapeutic targets because they could transport various oncogenic elements. In this review, we summarize recent advances regarding the role of CCEs in cancer invasion and metastasis, as well as its potential clinical applications.

  15. c-Yes enhances tumor migration and invasion via PI3K/AKT pathway in epithelial ovarian cancer.

    Science.gov (United States)

    Jin, Yunfeng; Huang, Menghui; Wang, Yingying; Yi, Changying; Deng, Yan; Chen, Yannan; Jiang, Lifei; Wang, Juan; Shen, Qin; Liu, Rong; QinghuaXi

    2016-08-01

    Overexpression of c-Yes has been noted to correlation with several human cancers. However, the effects of c-Yes on epithelial ovarian cancer (EOC) development remain unclear. The aim of this study is going to prove the effects of c-Yes and related mechanisms in proliferation, metastasis and invasion of EOC. Immunohistochemical analysis was performed in 119 human EOC samples, and the data was correlated with clinic pathologic features. Furthermore, western blot analysis is performed for c-Yes in EOC samples and cell lines to evaluate their protein levels and molecular interaction. Kaplan-Meier survival analysis shows that the strong expression of c-Yes exhibited a significant correlation with poor prognosis in human EOC (PYes by shRNA inhibited the ability of migration and invasion in EOC cells via the PI3K/AKT pathway. In a word, these results suggested that c-Yes plays an important role in migration and invasion of EOC.

  16. ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity.

    Science.gov (United States)

    Jin, Feng; Irshad, Shazia; Yu, Wei; Belakavadi, Madesh; Chekmareva, Marina; Ittmann, Michael M; Abate-Shen, Cory; Fondell, Joseph D

    2013-07-01

    MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.

  17. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Lu, Su [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Tang, Huamei, E-mail: tanghuamei@gmail.com [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Peng, Zhihai, E-mail: zhihai.peng@hotmail.com [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China)

    2014-06-27

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.

  18. 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells.

    Science.gov (United States)

    Kim, Sun Young; Lee, Ik-Soo; Moon, Aree

    2013-05-25

    Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231 cells with IC50 values of 18.1, 4.6, and 6.7 μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231 cells. Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC.

  19. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Kelemen, Linda E; Wang, Qinggang;

    2011-01-01

    BACKGROUND: We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1.......0-1.2, P(trend) = 0.11). There was no evidence for statistical heterogeneity in ORs across the studies. CONCLUSIONS: Although rs2660753 is a strong prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study...

  20. Amygdalin-mediated inhibition of non-small cell lung cancer cell invasion in vitro.

    Science.gov (United States)

    Qian, Liyu; Xie, Bo; Wang, Yaguo; Qian, Jun

    2015-01-01

    Lung cancer is a common malignant tumor claiming the highest fatality worldwide for a long period of time. Unfortunately, most of the current treatment methods are still based on the characteristics of cancer cells in the primary lesion and the prognosis is often much poorer in patients with metastatic cancers. Amygdalin, a natural product of glycosides and lots of evidence shows that amygdalin can inhibit the proliferation of some kinds of cancer cells. In this study, we first obtained the highly metastatic NSCLC cell lines H1299/M and PA/M and further treated these cells with amygdalin. We found that the in vitro proliferability of H1299/M and PA/M was inhibited, but such inhibition required higher concentration of amygdalin. When lower concentration of amygdalin was used for the experiments, we observed that the in vitro invasive and migration capacities of H1299/M and PA/M were significantly inhibited. These results strongly suggested that amygdalin was likely to have anti-metastatic NSCLC effect. This study offers information of the role of amygdalin that may be useful as a therapeutic target in lung tumors.

  1. Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells.

    Science.gov (United States)

    Qin, Yuan; Zhang, Qiang; Lee, Shan; Zhong, Wei-Long; Liu, Yan-Rong; Liu, Hui-Juan; Zhao, Dong; Chen, Shuang; Xiao, Ting; Meng, Jing; Jing, Xue-Shuang; Wang, Jing; Sun, Bo; Dai, Ting-Ting; Yang, Cheng; Sun, Tao; Zhou, Hong-Gang

    2015-12-01

    The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.

  2. ROLE OF PANCREATIC STELLATE CELLS AND GALECTIN-3 ON PROLIFERATION AND INFILTRATION OF HUMAN PANCREATIC CANCER CELL LINE SW1990

    Institute of Scientific and Technical Information of China (English)

    JIANG Hai-biao; XU Ming; WANG Xing-peng

    2008-01-01

    Objective To investigate the role of pancreatic stellate cells (PSCs) and galectin-3 (GAL-3)on the proliferation and infiltration of pancreatic cancer cell line SW1990. Methods Human pancreatic cancercell line SW1990 and PSCs were cultured in vitro. Supernatant of cultured PSCs and SW1990 cells was collected.Expressions of GAL-3 in SW1990 cells and PSCs were detected by ELISA, RT-PCR and Western blot. Theproliferation of those cultured PSCs and SW1990 cells were measured by MTT assay and flowcytometry. Infiltrationof SW1990 cells was detected by cell infiltration kit. Results SW1990 cells expressed GAL-3 and the expressionwas up-regulated by the supernatant fluid of cultured PSCs. PSCs did not express GAL-3. SW1990 cells couldstimulate the proliferation of PSCs via GAL-3. GAL-3 antibody could inhibit SW1990 cells proliferation andinfiltration, which indicated that supernatant of PSCs might stimulate the proliferation of SW1990 cells through theinteraction with GAL-3 protein. The supernatant fluid of PSCs could enhance the invasiveness of SW1990 cellsthrough the interaction with GAL-3. Conclusion GAL-3 and PSCs was involved in the proliferation andinfiltration process of pancreatic cancer.

  3. Effects of Genistein and Daidzein on the Proliferation,Invasion, Migration and Adhesion of Melanoma Cells

    Institute of Scientific and Technical Information of China (English)

    张勇; 谢莉萍; 王洪钟; 王锋; 余旭亚; 陈朝银; 张荣庆

    2002-01-01

    Our previous studies demonstrated that genistein and daidzein were able to change several membrane characteristics of human colon tumor (HCT) cells. As the condition of the membrane plays important roles in tumor progression, evidence led to the hypothesis that genistein and daidzein had an inhibitive effect on the metastasis of malignant cells. To validate this hypothesis, we employed a highly metastatic melanoma cell line (murine K1735M2) to study the effects of genistein and daidzein on the metastatic events of K1735M2. Studies show that genistein (30 -μmol/L) and daidzein (30 -μmol/L) have an obvious inhibitive effect on the proliferation of K1735M2. In addition, genistein and daidzein markedly inhibit the invasion of K1735M2 cells into a collagen I gel matrix and also inhibit migration through a polycarbonate filter. The inhibitive effect of genistein on migration is dose-dependent. These results support the hypothesis and imply that genistein and daidzein might be potential chemopreventive agents for melanoma treatment.

  4. Inhibition of CXCR4 activity with AMD3100 decreases invasion of human colorectal cancer cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Ji-Kun Li; Liang Yu; Yun Shen; Li-Sheng Zhou; Yi-Cheng Wang; Jian-Hai Zhang

    2008-01-01

    AIM: To investigate the effect and mechanism of blockade of the CXC chemokine receptor-4 (CXCR4) signaling pathway by AMD3100, a small non-peptide CXCR4 inhibitor, on invasion and metastasis of colorectal cancer cells in vitro.METHODS: Human colorectal cancer cell line SW480 was treated with AMD3100 at different final concentrations.3-(4,5-dimethylthiazole-2-yl)-2.5-dipheny-ltetrazolium bromide (MTT) assay was used to detect the effect of AMD3100 on cell proliferation. The invasion ability of SW480 cells was determined by cell invasion assay kit.In the presence of AMD3100, the CXCL12-mediated migratory response of SW480 cells was tested by classical chemotaxis assays. RT-PCR analysis and Western blotting were used to detect the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2)and -9 (MMP-9) in SW480 cells.RESULTS: Cell viability was significantly suppressed by AMD3100 in a dose-dependent manner. AMD3100 (100and 1000 ng/mL) significantly inhibited the invasion ability of SW480 cells. Treatment with AMD3100markedly reduced the expression of VEGF and MMP-9but not MMP-2 in SW480 cells.CONCLUSION: The CXCL12/CXCR4 system is an important mediator of proliferation and invasion of CXCR4-expressing colorectal cancer cells, AMD3100inhibited invasion and metastasis activity of the colorectal cancer cell line SW480 through down-regulation of VEGF and MMP-9 expression.

  5. 钙调蛋白依赖性蛋白激酶Ⅱ对前列腺癌PC3细胞增殖、侵袭及上皮-间充质转化的影响%Effects of calcium/calmodulin dependent protein kinase Ⅱ on proliferation, invasion and epithelia-mesenchymal transition of prostate cancer PC3 cells

    Institute of Scientific and Technical Information of China (English)

    彭璇; 陈晖; 王敏; 刘修恒

    2015-01-01

    Objective To observe the effects of inactivation of calcium/calmodulin dependent protein kinase Ⅱ (CaMK Ⅱ) on proliferation, invasion and epithelia-mesenchymal transition related signaling pathway in prostate cancer PC3 cells.Methods The activity of CaMK Ⅱ in PC3 cells was suppressed by KN93, a pharmacological inhibitor.MTT assay was used to detect the inhibition rate of PC3 cells and the invasion ability of PC3 cells was examined using Transwell invasion chambers.The protein expression of phosphorylated CaMK Ⅱ (p-CaMK Ⅱ), nuclear factor κB (NF-κB), zinc finger transcription factor (Snail), and Raf kinase inhibitory protein (RKIP) was measured by Western blotting.Results After treatment with KN93 for 24 h, the protein expression of p-CaMK Ⅱ PC3 cells treated with 5, 10, 20 μmol/L KN93 (0.453 ± 0.070, 0.368 ± 0.076, and 0.308 ± 0.011) was significantly decreased as compare with control group (0.596 ± 0.028) (P < 0.05 or 0.01), 40 μmol/L KN93 almost completely inhibited p-CaMK Ⅱ protein expression.The inhibition rate of PC3 cells treated with KN93 for 24 h was (6.88±1.79)%, (12.92 ±2.74)%, (17.88 ±2.86)% and (31.23 ±4.24)%, and (16.53 ±2.45) %, (29.02 ± 1.74) %, (40.52 ± 1.98) % and (52.26 ± 3.51) % for 48 h respectively.The number of the invasion PC3 cells in control and KN93 groups was (149 ± 17), (97 ± 7), (59 ± 9),(51 ±7), and (24 ± 3)/high magnification mirror (HP) respectively.The number of invasion cells in KN93 groups was significantly decreased when compared with control group (P < 0.01).The protein expression of NF-κB p65 had no significant difference between control and KN93 groups (P > 0.05), but p-NF-κB p65 was down-regulated in KN93 groups (0.483 ± 0.052, 0.490 ± 0.064, 0.432 ± 0.057,and 0.341 ±0.008) when compared with control group (0.597 ±0.020, P <0.05 or 0.01).As compared with control group (0.716 ±0.046), Snail protein expression in PC3 cells treated with 5, and 10 μmol/L KN93 (0

  6. Ellagic Acid Inhibits Bladder Cancer Invasiveness and In Vivo Tumor Growth

    Directory of Open Access Journals (Sweden)

    Claudia Ceci

    2016-11-01

    Full Text Available Ellagic acid (EA is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A, an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376 by in vitro proliferation tests (measuring metabolic and foci forming activity, invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1, an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.

  7. Effect of S1P5 on proliferation and migration of human esophageal cancer cells

    OpenAIRE

    Hu, Wei-Min; Li, Li; Jing, Bao-Qian; Zhao, Yong-Sheng; Wang, Chao-Li; Feng, Li; Xie, Yong-En

    2010-01-01

    AIM: To investigate the sphingosine 1-phosphate (S1P) receptor expression profile in human esophageal cancer cells and the effects of S1P5 on proliferation and migration of human esophageal cancer cells.

  8. Cancer proliferation and therapy: the Warburg effect and quantum metabolism

    Directory of Open Access Journals (Sweden)

    Tuszynski Jack A

    2010-01-01

    Full Text Available Abstract Background Most cancer cells, in contrast to normal differentiated cells, rely on aerobic glycolysis instead of oxidative phosphorylation to generate metabolic energy, a phenomenon called the Warburg effect. Model Quantum metabolism is an analytic theory of metabolic regulation which exploits the methodology of quantum mechanics to derive allometric rules relating cellular metabolic rate and cell size. This theory explains differences in the metabolic rates of cells utilizing OxPhos and cells utilizing glycolysis. This article appeals to an analytic relation between metabolic rate and evolutionary entropy - a demographic measure of Darwinian fitness - to: (a provide an evolutionary rationale for the Warburg effect, and (b propose methods based on entropic principles of natural selection for regulating the incidence of OxPhos and glycolysis in cancer cells. Conclusion The regulatory interventions proposed on the basis of quantum metabolism have applications in therapeutic strategies to combat cancer. These procedures, based on metabolic regulation, are non-invasive, and complement the standard therapeutic methods involving radiation and chemotherapy

  9. Long non-coding RNA MALAT-1 is downregulated in preeclampsia and regulates proliferation, apoptosis, migration and invasion of JEG-3 trophoblast cells.

    Science.gov (United States)

    Chen, Haiying; Meng, Tao; Liu, Xuemin; Sun, Manni; Tong, Chunxiao; Liu, Jing; Wang, He; Du, Juan

    2015-01-01

    Long non-coding RNA (lncRNA), as a newly identified subset of the transcriptome, has been implicated in a variety of physiological and pathological processes. Metastasis associated lung adenocarcinoma transcript-1 (MALAT-1), a lncRNA that was initially detected in the metastatic lung cancer, was reported to be overexpressed in placenta previa increta/percreta (I/P), which is caused by excessive trophoblast invasion. However, the role of MALAT-1 in the regulation of trophoblast behavior is not fully understood. In this study, we first examined the expression of MALAT-1 in the placentas from the patients with preeclampsia, the pathology of which is associated with inadequate trophoblast invasion, and found that the expression of MALAT-1 was downregulated in the preeclamptic placentas as compared to the normal placentas. We further investigated the function of MALAT-1 in JEG-3 trophoblast cell line using short interfering RNA (siRNA) against MALAT-1 transcripts. Silencing of MALAT-1 in JEG-3 cells suppressed proliferation and induced cell cycle arrest at G0/G1 phase. Reduced expression of MALAT-1 by RNA interference resulted in enhanced apoptosis in JEG-3 cells, accompanied with elevated levels of the pro-apoptotic proteins including cleaved caspase-3, cleaved caspase-9 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1). Moreover, the migration rate and the invasiveness of JEG-3 cells were suppressed when MALAT-1 was downregulated. In summary, our results suggest that MALAT-1 may play an important role in the regulation of proliferation, cell cycle, apoptosis, migration and invasion of trophoblast cells, and under-expression of MALAT-1 during early placentation may be involved in the pathogenesis of preeclampsia.

  10. Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation.

    Science.gov (United States)

    Brahmbhatt, Meera; Gundala, Sushma R; Asif, Ghazia; Shamsi, Shahab A; Aneja, Ritu

    2013-01-01

    Dietary phytochemicals offer nontoxic therapeutic management as well as chemopreventive intervention for slow-growing prostate cancers. However, the limited success of several single-agent clinical trials suggest a paradigm shift that the health benefits of fruits and vegetables are not ascribable to individual phytochemicals, rather may be ascribed to synergistic interactions among them. We recently reported growth-inhibiting and apoptosis-inducing properties of ginger extract (GE) in in vitro and in vivo prostate cancer models. Nevertheless, the nature of interactions among the constituent ginger biophenolics, viz. 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogoal, remains elusive. Here we show antiproliferative efficacy of the most-active GE biophenolics as single-agents and in binary combinations, and investigate the nature of their interactions using the Chou-Talalay combination index (CI) method. Our data demonstrate that binary combinations of ginger phytochemicals synergistically inhibit proliferation of PC-3 cells with CI values ranging from 0.03 to 0.88. To appreciate synergy among phytochemicals present in GE, the natural abundance of ginger biophenolics was quantitated using LC-UV/MS. Interestingly, combining GE with its constituents (in particular, 6-gingerol) resulted in significant augmentation of GE's antiproliferative activity. These data generate compelling grounds for further preclinical evaluation of GE alone and in combination with individual ginger biophenols for prostate cancer management.

  11. SUZ12 Depletion Suppresses the Proliferation of Gastric Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yingjun Cui

    2013-05-01

    Full Text Available Background/Aims: SUZ12 and EZH2 are two main components of polycomb repressive complex 2 (PRC2 that is known to be of great importance in tumorigenesis. EZH2 has been reported to play a vital role in pathogenesis of human cancer. However, whether SUZ12 has equivalent roles in tumorigenesis has not been demonstrated. Here, we investigated a possible role of SUZ12 for the proliferation of gastric cancer cells. Methods: Western-blot analysis was used to detected the levels of SUZ12, H3K27me3, EZH2 and p27 in ten gastric cell lines. SUZ12 was depleted by RNA interference. Cell cycle was detected by flow cytometry. Luciferase assays was to analyze whether miR-200b directly regulate SUZ12. Results: We found that SUZ12 depletion mediated by RNA interference (RNAi led to a reduction of gastric cell numbers and arrested the cell cycle at G1/S point. As an important G1/S phase inhibitory gene, p27 is re-induced to some extent by SUZ12 knockdown. Furthermore, we demonstrated that SUZ12 was directly downregulated by miR-200b. Conclusion: We provide evidence suggesting that SUZ12 may be a potential therapeutic target for gastric cancer.

  12. Evaluation of aqueous extracts of Taraxacum officinale on growth and invasion of breast and prostate cancer cells.

    Science.gov (United States)

    Sigstedt, Sophia C; Hooten, Carla J; Callewaert, Manika C; Jenkins, Aaron R; Romero, Anntherese E; Pullin, Michael J; Kornienko, Alexander; Lowrey, Timothy K; Slambrouck, Severine Van; Steelant, Wim F A

    2008-05-01

    Ethnotraditional use of plant-derived natural products plays a significant role in the discovery and development of potential medicinal agents. Plants of the genus Taraxacum, commonly known as dandelions, have a history of use in Chinese, Arabian and Native American traditional medicine, to treat a variety of diseases including cancer. To date, however, very few studies have been reported on the anti-carcinogenic activity of Taraxacum officinale (TO). In the present study, three aqueous extracts were prepared from the mature leaves, flowers and roots, and investigated on tumor progression related processes such as proliferation and invasion. Our results show that the crude extract of dandelion leaf (DLE) decreased the growth of MCF-7/AZ breast cancer cells in an ERK-dependent manner, whereas the aqueous extracts of dandelion flower (DFE) and root (DRE) had no effect on the growth of either cell line. Furthermore, DRE was found to block invasion of MCF-7/AZ breast cancer cells while DLE blocked the invasion of LNCaP prostate cancer cells, into collagen type I. Inhibition of invasion was further evidenced by decreased phosphorylation levels of FAK and src as well as reduced activities of matrix metalloproteinases, MMP-2 and MMP-9. This study provides new scientific data on TO and suggests that TO extracts or individual components present in the extracts may be of value as novel anti-cancer agents.

  13. Triptolide inhibits the migration and invasion of human prostate cancer cells via Caveolin-1/CD147/MMPs pathway.

    Science.gov (United States)

    Yuan, Shiqi; Wang, Liping; Chen, Xixi; Fan, Bo; Yuan, Qingmin; Zhang, Han; Yang, Deyong; Wang, Shujing

    2016-12-01

    Prostate cancer (PCa) is the second most common type of carcinoma and the 5th leading cause of cancer-related death in males. Triptolide, is a main and effective component of Tripterygium wilfordii Hook F, which exerts an broad-spectrum anti-malignant tumor function. However, the effect of triptolide on migration and invasion of human prostate cancer cells is still poorly understood. In this study, we demonstrated that triptolide significantly inhibited the proliferation, migration and invasion of prostate cancer cells in a time- and dose-dependent manner. Caveolin-1 (Cav-1) is regarded as a major structural protein of caveolae and participated in lipid transport, signal transduction and tumor progression. Triptolide treatment inhibited the expression of tumor promoter Cav-1 and reduced CD147 and MMPs activities at both mRNA and protein levels. Meanwhile, triptolide treatment combined with Cav-1 knockdown in PCa cells enhanced the effects of anti-migration and anti-invasion, and those effects were restored following Cav-1-rescued. Together, our research indicates that triptolide represses the migration and invasion through Cav-1/CD147/MMPs pathway in PCa cells, which gives a better understanding of triptolide in clinical aggressive prostate cancer therapy.

  14. Interleukin-8 associates with adhesion, migration, invasion and chemosensitivity of human gastric cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wen-Xia Kuai; Qiong wang; Xiao-Zhong Yang; Yao Zhao; Ren Yu; Xiao-Jun Tang

    2012-01-01

    AIM:To investigate the relationship between Interleukin-8 (IL-8) and proliferation,adhesion,migration,invasion and chemosensitivity of gastric cancer (GC) cells.METHODS:The IL-8 cDNA was stably transfected into human GC cell line MKN-45 and selected IL-8-secreting transfectants.The expression of IL-8 in human GC cell line KATO-Ⅲ was inhibited by RNA interference.The expressions of mRNA and protein of IL-8 in GC cells were detected by real-time reverse transcriptionpolymerase chain reaction or enzyme-linked immunosorbent assay (ELISA).RESULTS:The overexpression of IL-8 resulted in an increased cell adhesion,migration and invasion,and a significant resistance to oxaliplatin in MKN-45 cells.Inhibition of IL-8 expression with small interfering RNA decreased the adhesion,migration and invasion functions and oxaliplatin resistance in KATO-Ⅲ cells.IL-8 increased NF-кB and Akt activities and adhesion molecules ICAM-1,VCAM-1,and CD44 expression in GC cells.CONCLUSION:Overexpression of IL-8 promotes the adhesion,migration,invasion,and chemoresistance of GC cells,indicating that IL-8 is an important therapeutic target in GC.

  15. Overweight, Obesity and Postmenopausal Invasive Breast Cancer Risk

    Science.gov (United States)

    Neuhouser, Marian. L; Aragaki, Aaron K.; Prentice, Ross L.; Manson, JoAnn E.; Chlebowski, Rowan; Carty, Cara L.; Ochs-Balcom, Heather M.; Thomson, Cynthia A.; Caan, Bette J.; Tinker, Lesley F.; Urrutia, Rachel Peragallo; Knudtson, Jennifer; Anderson, Garnet L.

    2016-01-01

    IMPORTANCE Over ⅔ of U.S. women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. OBJECTIVE To investigate the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women’s Health Initiative (WHI) Clinical Trial. DESIGN The WHI protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer endpoints. SETTING 40 U.S. clinical centers. PARTICIPANTS n=67,142 postmenopausal women aged 50–79 years were enrolled from 1993–1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. MAIN OUTCOMES AND MEASURES Height and weight were measured at baseline and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. RESULTS Women who were overweight and obese had an increased invasive breast cancer risk vs. normal weight women. Risk was greatest for obesity grades 2+3 (BMI>35.0 kg/m2) (hazard ratio [HR] for invasive breast cancer =1.58, 95% CI 1.40–1.79). BMI ≥ 35.0 kg/m2 was strongly associated with risk for ER+/PR+ breast cancers (HR=1.86 95% CI 1.60–2.17), but was not associated with ER− cancers. Obesity grade 2+3 was also associated with advanced disease including larger tumor size (HR=2.12 95%CI 1.67–2.69). (P=0.02), positive lymph nodes (HR=1.89 95%CI 1.46–2.45), (P=0.06), regional/distant stage (HR=1.94, 95%CI 1.52–2.47) (P=0.05) and deaths after breast cancer (HR=2.11 95%CI 1.57–2.84) (P5% of bodyweight over the follow-up period had an increased breast cancer risk (HR=1.36 95% CI 1.1–1.65), but among women already overweight or obese we found no association of weight change (gain or loss

  16. Precursor lesions of invasive breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schreer, Ingrid [Breast Center, University Hospital Kiel, Kiel (Germany)]. E-mail: ischreer@email.uni-kiel.de; Luettges, Jutta [Department of Pathology, University Hospital Kiel, Kiel (Germany)

    2005-04-01

    The increasing application of mammography, mainly in screening programs for the early detection of breast cancer, and the high technical standard of imaging has resulted in the detection of clinically occult breast tumors. Considering that only diagnosis at an early stage will be able to change the prognosis of breast cancer, this diagnostic challenge appears to be the most exciting field in both breast imaging and breast pathology. Especially the precursor lesions need to be diagnosed and defined precisely to understand their prognostic significance. In imaging, the morphologic appearance of precursor lesions is usually neither typical nor pathognomonic. They have to be assessed histologically using percutaneous interventions. Recent molecular studies have demonstrated various genetic alterations in the ductal epithelium, with the earliest onset in atypical ductal hyperplasia. The recent WHO classification, which is based on molecular data and histopathological features, attempts to define in particular the precursor lesions and low grade intraductal carcinomas. The clinical importance of the various grades has to be assessed. Intimate cooperation between diagnostic radiologist and pathologist is essential.

  17. Precursor lesions of invasive breast cancer.

    Science.gov (United States)

    Schreer, Ingrid; Lüttges, Jutta

    2005-04-01

    The increasing application of mammography, mainly in screening programs for the early detection of breast cancer, and the high technical standard of imaging has resulted in the detection of clinically occult breast tumors. Considering that only diagnosis at an early stage will be able to change the prognosis of breast cancer, this diagnostic challenge appears to be the most exciting field in both breast imaging and breast pathology. Especially the precursor lesions need to be diagnosed and defined precisely to understand their prognostic significance. In imaging, the morphologic appearance of precursor lesions is usually neither typical nor pathognomonic. They have to be assessed histologically using percutaneous interventions. Recent molecular studies have demonstrated various genetic alterations in the ductal epithelium, with the earliest onset in atypical ductal hyperplasia. The recent WHO classification, which is based on molecular data and histopathological features, attempts to define in particular the precursor lesions and low grade intraductal carcinomas. The clinical importance of the various grades has to be assessed. Intimate cooperation between diagnostic radiologist and pathologist is essential.

  18. Collective cell migration: Implications for wound healing and cancer invasion

    Directory of Open Access Journals (Sweden)

    Li Li

    2013-07-01

    Full Text Available During embryonic morphogenesis, wound repair and cancer invasion, cells often migrate collectively via tight cell-cell junctions, a process named collective migration. During such migration, cells move as coherent groups, large cell sheets, strands or tubes rather than individually. One unexpected finding regarding collective cell migration is that being a "multicellular structure" enables cells to better respond to chemical and physical cues, when compared with isolated cells. This is important because epithelial cells heal wounds via the migration of large sheets of cells with tight intercellular connections. Recent studies have gained some mechanistic insights that will benefit the clinical understanding of wound healing in general. In this review, we will briefly introduce the role of collective cell migration in wound healing, regeneration and cancer invasion and discuss its underlying mechanisms as well as implications for wound healing.

  19. Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

    Science.gov (United States)

    Issa, Mark E; Berndt, Sarah; Carpentier, Gilles; Pezzuto, John M; Cuendet, Muriel

    2016-09-01

    Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

  20. Treatment of Muscle-Invasive Bladder Cancer in Older Patients.

    Science.gov (United States)

    Skinner, Eila C

    2016-01-01

    Treatment of muscle-invasive bladder cancer in older patients is challenging. Definitive therapy of localized disease requires either surgery or radiation therapy, ideally combined with systemic chemotherapy. However, current population data suggest that less than half of patients older than age 70 are offered such treatments. We will review tools available to assess the fitness of older patients for surgery, alternatives, and tips for perioperative patient treatment.

  1. Deregulated SLC2A1 Promotes Tumor Cell Proliferation and Metastasis in Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Shiyan Yan

    2015-07-01

    Full Text Available Gastric cancer (GC is one of the common reasons of cancer-related death with few biomarkers for diagnosis and prognosis. Solute carrier family 2 (facilitated glucose transporter member 1 protein SLC2A1, also known as glucose transporter type 1 (GLUT1, has been associated with tumor progression, metastasis, and poor prognosis in many human solid tumors. However, little is reported about its clinical significance and biological functions in GC. Here we observed a strong up-regulation of SLC2A1 in patients with GC and found that SLC2A1 was significantly correlated with depth of invasion and clinical stage. Additionally, over-expression of SLC2A1 in GC cells promotes cellular proliferation and metastasis in vitro and enhances tumor growth in vivo as well as enhancement of glucose utilization. Meanwhile, elevated SLC2A1 also contributes to tumor metastasis in vitro. Our results indicate SLC2A1 exhibits a pivotal role in tumor growth, metastasis and glucose metabolism, and also suggest SLC2A1 as a promising target for gastric cancer therapy.

  2. CAP1 (Cyclase-Associated Protein 1) Exerts Distinct Functions in the Proliferation and Metastatic Potential of Breast Cancer Cells Mediated by ERK.

    Science.gov (United States)

    Zhang, Haitao; Zhou, Guo-Lei

    2016-05-13

    The actin-regulating protein CAP1 is implicated in the invasiveness of human cancers. However, the exact role remains elusive and controversial given lines of conflicting evidence. Moreover, a potential role in the proliferative transformation has largely been overlooked. Further establishing the role and dissecting underlying mechanisms are imperative before targeting CAP1 can become a possibility for cancer treatment. Here we report our findings that CAP1 exerts cell type-dependent functions in the invasiveness of breast cancer cells. Depletion of CAP1 in the metastatic MDA-MB-231 and BT-549 cancer cells stimulated the metastatic potential while it actually inhibited it in the non-metastatic MCF-7 cancer cells or in normal cells. Moreover, we demonstrate functions for CAP1 in cancer cell proliferation and anchorage-independent growth, again in a cell context-dependent manner. Importantly, we identify pivotal roles for the ERK-centered signaling in mediating both CAP1 functions. Phosphor mutants of CAP1 at the S307/S309 regulatory site had compromised rescue effects for both the invasiveness and proliferation in CAP1-knockdown cells, suggesting that CAP1 likely mediates upstream cell signals to control both functions. These novel mechanistic insights may ultimately open up avenues for strategies targeting CAP1 in the treatment of breast cancer, tailored for specific types of the highly diverse disease.

  3. Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Yuan Wang

    2014-03-01

    Full Text Available The platelet-derived growth factor-D (PDGF-D was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001, and high level of PDGF-D was correlated with late stage (p = 0.003, deep myometrium invasion (p < 0.001 and lympha vascular space invasion (p = 0.006. In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we

  4. Study on the effect of PDGF-D shRNA on proliferation and invasion of breast cancer SK-BR-3 cells%PDGF-D 稳定沉默后对乳腺癌细胞 SK-BR-3生物学功能的影响

    Institute of Scientific and Technical Information of China (English)

    李红昌; 冯雯; 陈亚峰; 梅怡; 蔡含; 蒋一鸣; 陈腾; 殷佩浩; 奉典旭

    2016-01-01

    of BRCA cells. Methods RT - PCR and Western - blot were used to detect PDGF -D expression profiles in 5 different BrCa cell lines,in order to confirm the target cell line. In vitro,the lentiviral vector was constructed to silence PDGF - D expression in SK - BR - 3 cells. Then,the MTT and soft agar assay were used to detect cell proliferation. Additionally,cell apoptosis and cell migration after knockdown of PDGF - D were measured by the method of flow cytometry and transwell assay respectively. Results The expression of PDGF - D in protein and mRNA level in different cell lines of breast cancer were detected,among which the highly metastatic MDA- MB - 231,SK - BR - 3 cell lines showed higher PDGF - D expression than that in low metastatic MCF7 cell lines( t = 3. 880,P < 0. 05). After PDGF - D gene silencing by the lentivirus vector,the ability of growth and colony formation had been significantly decreased( F = 75. 23, P < 0. 001),together with an induction of apoptosis effect on SK - BR - 3 cells( F = 84. 44,P < 0. 001). Moreover,SK - BR - 3 cells with si-lenced PDGF - D diminished significantly aggressive potential in migration and invasion than other tested cells( F = 155. 9,P < 0. 001). Con-clusion PDGF - D may be closely associated with the proliferation,apoptosis as well as migration of BRCA cells,which indicate that it plays a pivotal role in the development and progression of BRCA.

  5. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Kelemen, Linda E; Wang, Qinggang;

    2011-01-01

    BACKGROUND: We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1...

  6. miR-107 activates ATR/Chk1 pathway and suppress cervical cancer invasion by targeting MCL1.

    Directory of Open Access Journals (Sweden)

    Chengyan Zhou

    Full Text Available MicroRNAs (miRNAs are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRNAs may function as oncogenes or tumor suppressors. Here we showed that miR-107 directly targeted MCL1 and activated ATR/Chk1 pathway to inhibit proliferation, migration and invasiveness of cervical cancer cells. Moreover, we found that MCL1 was frequently up-regulated in cervical cancer, and knockdown of MCL1 markedly inhibited cancer cell proliferation, migration and invasion, whereas ectopic expression of MCL1 significantly enhances these properties. The restoration of MCL1 expression can counteract the effect of miR-107 on the cancer cells. Together, miR-107 is a new regulator of MCL1, and both miR-107 and MCL1 play important roles in the pathogenesis of cervical cancer. We have therefore identified a mechanism for ATR/Chk1 pathway which involves an increase in miR-107 leading to a decrease in MCL1. Correspondingly, our results revealed that miR-107 affected ATR/Chk1 signalling and gene expression, and implicated miR-107 as a therapeutic target in human cervical cancer. We also demonstrated that taxol attenuated migration and invasion in cervical cancer cells by activating the miR-107, in which miR-107 play an important role in regulating the expression of MCL1. Elucidation of this discovered MCL1 was directly regulated by miR-107 will greatly enhance our understanding of the mechanisms responsible for cervical cancer and will provide an additional arm for the development of anticancer therapies.

  7. Wnt blockers inhibit the proliferation of lung cancer stem cells

    Directory of Open Access Journals (Sweden)

    Zhang X

    2015-04-01

    Full Text Available Xueyan Zhang,1* Yuqing Lou,1* Xiaoxuan Zheng,1 Huimin Wang,1 Jiayuan Sun,1 Qianggang Dong,2 Baohui Han1 1Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 2Section of Cancer Stem Cells, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Previous study has confirmed that the occurrence of Wnt pathway activation is associated with risk of non-small-cell lung cancer recurrence. However, whether the pharmacologic blocking of the Wnt signaling pathway could provide therapeutic possibility remains unknown. The aim of the present study was to evaluate the therapeutic functions of the Wnt signaling pathway inhibitor pyrvinium pamoate (PP on lung cancer stem cells (LCSCs in vitro. Methods: Colony formation and sphere culture were performed to enrich LCSCs from three lung cancer cell lines: PC9, SPC-A1, and A549. After confirming stemness by immunofluorescence, PP was employed for cell viability assay by comparison with three other kinds of Wnt signaling inhibitor: salinomycin, ICG-001, and silibinin. The effect of PP on LCSCs was further verified by colony formation assay and gene expression analysis. Results: LCSCs were successfully generated by sphere culture from SPC-A1 and PC9 cells, but not A549 cells. Immunofluorescence assay showed that LCSCs could express pluripotent stem cell markers, including NANOG, Oct4, KLF5, and SOX2, and Wnt signaling pathway molecules ß-catenin and MYC. Half-maximal inhibitory concentrations of PP on SPC-A1, PC9, and A549 were 10 nM, 0.44 nM, and 0.21 nM, respectively, which are much lower than those of salinomycin, ICG-001, and silibinin. Moreover, significantly decreased colony formation and downregulation of pluripotent stem cell signaling pathway were observed in lung cancer cells after treatment with PP. Conclusion: Wnt signaling

  8. Immunophenotyping invasive breast cancer: paving the road for molecular imaging

    Directory of Open Access Journals (Sweden)

    Vermeulen Jeroen F

    2012-06-01

    Full Text Available Abstract Background Mammographic population screening in The Netherlands has increased the number of breast cancer patients with small and non-palpable breast tumors. Nevertheless, mammography is not ultimately sensitive and specific for distinct subtypes. Molecular imaging with targeted tracers might increase specificity and sensitivity of detection. Because development of new tracers is labor-intensive and costly, we searched for the smallest panel of tumor membrane markers that would allow detection of the wide spectrum of invasive breast cancers. Methods Tissue microarrays containing 483 invasive breast cancers were stained by immunohistochemistry for a selected set of membrane proteins known to be expressed in breast cancer. Results The combination of highly tumor-specific markers glucose transporter 1 (GLUT1, epidermal growth factor receptor (EGFR, insulin-like growth factor-1 receptor (IGF1-R, human epidermal growth factor receptor 2 (HER2, hepatocyte growth factor receptor (MET, and carbonic anhydrase 9 (CAIX 'detected' 45.5% of tumors, especially basal/triple negative and HER2-driven ductal cancers. Addition of markers with a 2-fold tumor-to-normal ratio increased the detection rate to 98%. Including only markers with >3 fold tumor-to-normal ratio (CD44v6 resulted in an 80% detection rate. The detection rate of the panel containing both tumor-specific and less tumor-specific markers was not dependent on age, tumor grade, tumor size, or lymph node status. Conclusions In search of the minimal panel of targeted probes needed for the highest possible detection rate, we showed that 80% of all breast cancers express at least one of a panel of membrane markers (CD44v6, GLUT1, EGFR, HER2, and IGF1-R that may therefore be suitable for molecular imaging strategies. This study thereby serves as a starting point for further development of a set of antibody-based optical tracers with a high breast cancer detection rate.

  9. Curcumin inhibits LPA-induced invasion by attenuating RhoA/ROCK/MMPs pathway in MCF7 breast cancer cells.

    Science.gov (United States)

    Sun, Kai; Duan, Xiaoyi; Cai, Hui; Liu, Xiaohong; Yang, Ya; Li, Min; Zhang, Xiaoyun; Wang, Jiansheng

    2016-02-01

    Breast cancer generally shows poor prognosis because of its invasion and metastasis. Lysophosphatidic acid (LPA) induces and aggravates cancer invasion and metastasis by activating its downstream signal pathways. RhoA/ROCK/MMP signaling was found one of the LPA-induced pathways, which may be involved in invasion of breast cancer. Furthermore, we investigated whether this pathway was involved in curcumin's effect against LPA-induced invasion. LPA incubation was used to enhance invasion of MCF-7 breast cancer cells. RhoA expression was knocked-down by siRNA technique. MTT assay was used to evaluate the proliferation. Transwell assay was utilized to investigate the invasion ability of MCF-7 cells. Real-time PCR and Western blotting were used to assess the expressions of RhoA, ROCK1, ROCK2, MMP2 and MMP9 at both translational and transcriptional levels. The RhoA and ROCK activities were also evaluated. LPA incubation significantly boosted invasion rate of MCF-7. RhoA silencing by siRNA dramatically inhibited LPA-enhanced invasion. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by RhoA siRNA transfection. In order to avoid influence of cytotoxicity of curcumin, concentrations below 45 μmol/L were selected to further investigate the mechanism of curcumin's anti-invasion effect. Invasion of LPA-incubated MCF-7 cells was impaired by curcumin in a concentration-dependent manner. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by curcumin in a concentration-dependent manner. In conclusion, RhoA/ROCK/MMPs pathway activation is involved in LPA-induced invasion in MCF-7 cells; curcumin inhibited LPA-induced invasion in MCF-7 cells by attenuating RhoA/ROCK/MMPs pathway.

  10. F-box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin-mediated degradation of forkhead box M1.

    Science.gov (United States)

    Li, Liang-qing; Pan, Dun; Chen, Hui; Zhang, Lin; Xie, Wen-jun

    2016-02-01

    F-box/LRR-repeat protein 2 (FBXL2), a component of Skp-Cullin-F box (SCF) ubiquitin E3 ligase, has been shown to inhibit tumorigenesis by targeting and ubiquitinating several oncoproteins. However, its role in gastric cancer remains poorly understood. Here, by tandem mass spectrometry, we show that FBXL2 interacts with forkhead box M1 (FoxM1) transcription factor. As a result, FBXL2 promotes ubiquitination and degradation of FoxM1 in gastric cancer cells. Furthermore, overexpression of FBXL2 inhibits, while its deficiency promotes cell proliferation and invasion. Expression levels of cell-cycle regulators (Cdc25B and p27), which are down-stream target effectors of FoxM1, are also regulated by FBXL2. Therefore, our results uncover a previous unknown network involving FBXL2 and FoxM1 in the regulation of gastric cancer growth.

  11. Paeonol Inhibits the Proliferation, Invasion, and Inflammatory Reaction Induced by TNF-α in Vascular Smooth Muscle Cells.

    Science.gov (United States)

    Meng, Liang; Xu, Weidong; Guo, Lihong; Ning, Wenqi; Zeng, Xiandong

    2015-11-01

    The aim of this study was to evaluate the effect of paeonol on the proliferation, migration, and inflammation induced by tumor necrosis factor (TNF-α) of rat vascular smooth muscle cells (VSMCs). Primary rat VSMCs were identified by immunofluorescence assay. The inhibition of VSMCs proliferation induced by TNF-α was observed after paeonol treatment in a dose-dependent manner. Treatment with 100 μM paeonol significantly reduced the expression of proliferating cell nuclear antigen (PCNA). On the other hand, transwell assay showed that treatment with paeonol suppressed the invasion of TNF-α-induced VSMCs and the production of inflammation factors stimulated by TNF-α. For apoptosis induced by paeonol, Western blot analysis showed that cleaved caspase-3 and -9 were detected, and pro-apoptotic protein Bax was up-regulated, whereas anti-apoptotic protein Bcl-2 was down-regulated by paeonol in TNF-α-stimulated VSMCs. ELISA analysis data showed that both levels of IL-1β and IL-6 produced by the stimulation of TNF-α were decreased by paeonol in a dose-dependent manner in VSMCs. These results suggest that paeonol can effectively inhibit the proliferation through apoptotic induction through caspase pathway in VSMCs induced by TNF-α. Also, paeonol significantly reduced the invasion and the inflammation stimulated by TNF-α in VSMCs.

  12. Multidetector CT of Locally Invasive Advanced Gastric Cancer: Value of Oblique Coronal Reconstructed Images for the Assessment of Local Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Jin Hee; Kim, Ah Yong; Kim, Hye Jin; Yook, Jeong Hwan; Yu, Eun Sil; Jang, Yoon Jin; Park, Seong Ho; Shin, Yong Moon; Ha, Hyun Kwon [Asan Medical Center, Seoul (Korea, Republic of)

    2010-01-15

    To evaluate the diagnostic value of oblique coronal reconstructed CT images to determine the local invasion of advanced gastric cancer (AGC). Thirty-four consecutive patients, who were suspected to have locally invasive advanced gastric cancer (more than T3 stage) on a preoperative MDCT scan and underwent a diagnostic or curative laparotomy, were enrolled in this study. Two reviewers performed an independent blind review of three series of MDCT images in random order; axial (AXI), conventional coronal (CCI), and oblique coronal (OCI) (parallel to long axis of gastric body and pancreas) images. In assessing the local invasion, the reader's confidence for the local invasion of AGC was graded using a five point scale (1 = definitely negative, 5 = definitely positive: T4). With surgical findings and histopathological proofs as reference standards, the diagnostic performance of the three different plans of CT images was employed for the verification of local invasion of AGC on a preoperative CT scan using the receiver operating characteristic (ROC) method. Agreements between the two reviewers were analyzed using weighted kappa statistics. Results: In 19 out of 34 patients, local invasion was confirmed surgically or histopathologically (13 pancreas invasion, 6 liver invasion, 4 major vascular invasion, 3 colon and mesocolon invasion, and 2 spleen invasion). The diagnostic performance of OCI was superior to AXI or CCI in the local invasion of AGC. The differences in the area under the curve of AXI (0.770 {+-} 0.087, 0.700 {+-} 0.094), CCI (0.884 {+-} 0.058, 0.958 {+-} 0.038), and OCI (0.954 {+-} 0.050, 0.956 {+-} 0.049), were statistically significant for both reviewers. Inter-observer agreement was excellent for OCI ({kappa}= .973), which was greater than CCI (({kappa}= .839), and AXI (({kappa}= .763). On a CT scan, OCI might be a useful imaging technique in evaluating locally invasive advanced gastric cancer.

  13. Clinical significance of telomerase activity in peritoneal lavage fluid from patients with gastric cancer and its relationship with cellular proliferation

    Institute of Scientific and Technical Information of China (English)

    Ming-Xu Da; Xiao-Ting Wu; Tian-Kang Guo; Zi-Guang Zhao; Ting Luo; Kun Qian; Ming-Ming Zhang; Jie Wang

    2007-01-01

    AIM: To evaluate the efficacy of telomerase activity assay and peritoneal lavage cytology (PLC) examination in peritoneal lavage fluid for the prediction of peritoneal metastasis in gastric cancer patients, and to explore the relationship between telomerase activity and proliferating cell nuclear antigen expression.METHODS: Telomeric repeated amplification protocol (TRAP)-enzyme-linked immunosorbent assay (ELISA) was performed to measure the telomerase activity in 60 patients with gastric cancer and 50 with peptic ulcer. PLC analysis of the 60 patients with gastric cancer was used for comparison. The proliferating cell nuclear antigen (PCNA) in gastric carcinoma was immunohistochemically examined.RESULTS: The telomerase activity and PLC positive rate in peritoneal lavage fluid from patients with gastric cancer was 41.7% (25/60), and 25.0% (15/60), respectively. The positive rate of telomerase activity was significantly higher than that of PLC in the group Of pT4 (15/16 vs 9/16, P < 0.05), P1-3 (13/13 vs 9/13, P < 0.05) and diffuse type (22/42 vs 13/42, P < 0.05). The patients with positive telomerase activity, peritoneal metastasis, and serosal invasion had significantly higher levels of average PCNA proliferation index (PI), (55.00 ± 6.59 vs 27.43 ± 7.72, 57.26 ± 10.18 vs 29.15 ± 8.31, and 49.82 ± 6.74 vs 24;65 ± 7.33, respectively, P < 0.05).CONCLUSION: The TRAP assay for telomerase activity is a useful adjunct for cytologic method in the diagnosis of peritoneal micrometastasis and well related to higher proliferating activity of gastric cancer. The results of this study also suggest a promising future therapeutic strategy for treating peritoneal dissemination based on telomerase inhibition.

  14. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  15. Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Zhaohe Niu; Xinhui Li; Bin Hu; Rong Li; Ligang Wang; Lilin Wu; Xingang Wang

    2012-01-01

    Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes.It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models.In this study,we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility,invasion,and growth in vitro and in vivo.MDA-MB-231 cells were transfected with pSuper-siRNA/sClu.Cell survival and proliferation were examined by 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay.The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells.The invasion and migration ability were also dramatically decreased,which was detected by matrigel assays.TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells,resulting in the inhibition of cell growth.We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model.The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB-231/pSuper scramble siRNA cells,and metastasize less to the lungs.These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression.Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy.

  16. Effects of silencing the ATP-binding cassette protein E1 gene by electroporation on the proliferation and migration of EC109 human esophageal cancer cells.

    Science.gov (United States)

    Li, Xiao-Rui; Yang, Liu-Zhong; Huo, Xiao-Qing; Wang, Ying; Yang, Qing-Hui; Zhang, Qing-Qin

    2015-07-01

    In the present study, the gene expression of ATP-binding cassette protein E1 (ABCE1) in the EC109 human esophageal cancer cell line was silenced using electroporation to examine the effect if the ABCE1 gene on the growth migration and cell cycle of cancer cells. The small interference (si)RNA sequence of ABCE1 was designed and synthesized to transfect the EC109 cells by electroporation. The mRNA and protein expression levels of ABCE1 were then detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The analysis of the cell cycle and apoptosis was performed using flow cytometry. The effect of silencing the ABCE1 gene on the proliferation, migration and invasive ability of the EC109 human esophageal cancer cells were assessed using a Cell counting kit-8 (CCK-8) and with proliferation, wound-healing and cell invasion assays. The mRNA and protein expression levels of ABCE1 were significantly lower in the experimental group compared with the control group (Pmigration capacity of the cells in the experimental group was significantly decreased (Pmigration in esophageal cancer and silencing the ABCE1 gene by electroporation can significantly reduce the proliferation, invasion and migration capacity of EC109 cells in vitro.

  17. Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK.

    Science.gov (United States)

    Zhao, Ming; Howard, Erin W; Parris, Amanda B; Guo, Zhiying; Zhao, Qingxia; Yang, Xiaohe

    2017-03-01

    Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however, the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis. Understanding the molecular mechanisms of TNBC etiology remains a significant challenge. In this study, we investigated cellular responses to alcohol in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Our results showed that alcohol at low concentrations (0.025-0.1% v/v) induced cell proliferation, migration, and invasion in 1% FBS-containing medium. Molecular analysis indicated that these phenotypic changes were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation. Likewise, p38 or JNK inhibition attenuated alcohol-induced cell migration and invasion. We revealed that alcohol treatment activated/phosphorylated NF-κB regulators and increased transcription of NF-κB-targeted genes. While examining the role of acetaldehyde, the major alcohol metabolite, in alcohol-associated responses in TNBC cells, we saw that acetaldehyde induced cell migration, invasion, and increased phospho-p38, phospho-JNK, and phospho-IκBα in a pattern similar to alcohol treatment. Taken together, we established that alcohol promotes TNBC cell proliferation, migration, and invasion in vitro. The underlying mechanisms involve the induction of oxidative stress and the activation of NF-κB signaling. In particular, the activation of p38 and JNK plays a pivotal role in alcohol-induced cellular responses. These results will advance our understanding of alcohol-mediated development and promotion of TNBC. © 2016 Wiley Periodicals, Inc.

  18. MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells.

    Science.gov (United States)

    Gu, Jian-Jun; Zhang, Jian-He; Chen, Hong-Jie; Wang, Shou-Sen

    2016-06-01

    MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non‑neoplastic brain specimens. Specifically, higher expression levels of miR‑130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR‑130b interacted with the 3'-untranslated region of peroxisome proliferator‑activated receptor-γ (PPAR‑γ), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR-130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR‑130b in U251 glioma cells restored the expression of PPAR-γ and E-cadherin, and inhibited the expression of β-catenin. Notably, PPAR-γ knockdown abolished the inhibitory effect of miR-130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR‑130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-γ.

  19. Non-invasive actionable biomarkers for metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Jun Luo

    2016-10-01

    Full Text Available In the current clinical setting, many disease management options are available for men diagnosed with prostate cancer. For metastatic prostate cancer, first-line therapies almost always involve agents designed to inhibit androgen receptor (AR signaling. Castration-resistant prostate cancers (CRPCs that arise following first-line androgen deprivation therapies (ADT may continue to respond to additional lines of AR-targeting therapies (abiraterone and enzalutamide, chemotherapies (docetaxel and cabazitaxel, bone-targeting Radium-223 therapy, and immunotherapy sipuleucel-T. The rapidly expanding therapies for CRPC is expected to transform this lethal disease into one that can be managed for prolonged period of time. In the past 3 years, a number of promising biomarkers that may help to guide treatment decisions have been proposed and evaluated, including androgen receptor splice variant-7 (AR-V7, a truncated AR lacking the ligand-binding domain (LBD and mediate constitutively-active AR signaling. Putative treatment selection markers such as AR-V7 may further improve survival benefit of existing therapies and help to accelerate development of new agents for metastatic prostate cancer. In the metastatic setting, it is important to consider compatibility between the putative biomarker with non-invasive sampling. In this review, biomarkers relevant to the setting of metastatic prostate cancer are discussed with respect to a number of key attributes critical for clinical development of non-invasive, actionable markers. It is envisioned that biomarkers for metastatic prostate cancer will continue to be discovered, developed, and refined to meet the unmet needs in both standard-of-care and clinical trial settings.

  20. Upregulation of miR-124 by physcion 8-O-β-glucopyranoside inhibits proliferation and invasion of malignant melanoma cells via repressing RLIP76.

    Science.gov (United States)

    Zhang, Di; Han, Yantao; Xu, Luo

    2016-12-01

    Melanoma is the most malignant type of skin cancer. In recent years, mounting studies have evidenced the involvement of miRNAs in melanoma. One of these miRNAs, miR-124 has been found aberrantly downregulated in a variety of human malignancies. In this study, our results showed that the expression of miR-124 was significantly lower in malignant melanoma tissues and cell lines and miR-124 functioned as a tumor suppressor in melanoma. Moreover, our findings showed that miR-124 exerted anti-tumor effect by directly targeting RLIP76, a stress-inducible non-ABC transporter that plays a crucial role in the development of melanoma. Furthermore, our study also showed that physcion 8-O-β-glucopyranoside, a natural compound from medicinal plant, could inhibit the proliferation and invasion of melanoma cells by targeting miR-124/RLIP76 signaling.

  1. miR-30b inhibits cancer cell growth, migration, and invasion by targeting homeobox A1 in esophageal cancer.

    Science.gov (United States)

    Li, Qing; Zhang, Xuan; Li, Ning; Liu, Qin; Chen, Dongfeng

    2017-02-09

    Emerging evidence has shown that microRNAs (miRNAs) play important roles in tumor development and progression. In particular, miR-30b is thought to be closely related to the migration, invasion, proliferation, communication, and drug resistance of tumor cells. However, the potential value of miR-30b in human esophageal cancer (EC) remains unclear. In this study, we investigated the biological functions of miR-30b and its potential role in EC. The results indicated that the expression levels of miR-30b were decreased in EC tissues and were correlated with invasion classification (P < 0.01), lymph node metastasis (P < 0.01), and pathological stage (P < 0.05). Log-rank tests demonstrated that low expression of miR-30bwas strongly correlated with poor overall survival in patients with EC (P < 0.05). Moreover, overexpression of miR-30b markedly inhibited the growth, migration, and invasion of ECA109 and TE-1 cells by directly downregulating homeobox A1 (HOXA1). When HOXA1 was reintroduced into miR-30b-transfected ECA109 or TE-1 cells, the inhibitory effects of miR-30b on EC cell growth, migration, and invasion were markedly reversed. In conclusion, our findings demonstrated that miR-30b could inhibit tumor cell growth, migration, and invasion by directly targeting HOXA1 in EC cells.

  2. Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Uchino, Keita, E-mail: uchino13@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Hirano, Gen [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Hirahashi, Minako [Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Isobe, Taichi; Shirakawa, Tsuyoshi; Kusaba, Hitoshi; Baba, Eishi [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Tsuneyoshi, Masazumi [Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Akashi, Koichi [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2012-09-10

    There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation. -- Highlights: Black-Right-Pointing-Pointer Nanog maintains pluripotency by regulating embryonic stem cells differentiation. Black-Right-Pointing-Pointer Nanog is expressed in cancer stem cells of human gastrointestinal cancer cells. Black-Right-Pointing-Pointer Nucleotide sequencing revealed that Nanog pseudogene8 but not Nanog was expressed. Black-Right-Pointing-Pointer Nanog pseudogene8 promotes cancer stem cells proliferation. Black-Right-Pointing-Pointer Nanog pseudogene8 is involved in gastrointestinal cancer development.

  3. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  4. Differential effects of miR-34c-3p and miR-34c-5p on SiHa cells proliferation apoptosis, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Lopez, Jesus Adrian [Laboratorio de Terapia Genica, Departamento de Genetica y Biologia Molecular, CINVESTAV, Av. IPN 2508, Mexico 07360 D.F. (Mexico); Alvarez-Salas, Luis Marat, E-mail: lalvarez@cinvestav.mx [Laboratorio de Terapia Genica, Departamento de Genetica y Biologia Molecular, CINVESTAV, Av. IPN 2508, Mexico 07360 D.F. (Mexico)

    2011-06-10

    Highlights: {yields} In this study we examine miR-34c-3p and miR-34c-5p functions in SiHa cells. {yields} We study miRNA effect on cell proliferation, anchorage independent growth, apoptosis, cell motility and invasion. {yields} We find that miR-34c-3p and miR-34c-5p inhibition of proliferation and anchorage independent growth are exclusive to SiHa cells. {yields} miR-34c-3p induces apoptosis and inhibits cell motility and invasion in SiHa cells. {yields} In this study we conclude that miR-34c-3p functions as a tumor suppressor differ from miR-34c-5p. -- Abstract: MicroRNAs (miRNA) regulate expression of several genes associated with human cancer. Here, we analyzed the function of miR-34c, an effector of p53, in cervical carcinoma cells. Expression of either miR-34c-3p or miR-34c-5p mimics caused inhibition of cell proliferation in the HPV-containing SiHa cells but not in other cervical cells irrespective of tumorigenicity and HPV content. These results suggest that SiHa cells may lack of regulatory mechanisms for miR-34c. Monolayer proliferation results showed that miR-34c-3p produced a more pronounced inhibitory effect although both miRNAs caused inhibition of anchorage independent growth at similar extent. However, ectopic expression of pre-miR-34c-3p, but not pre-miR-34c-5p, caused S-phase arrest in SiHa cells triggering a strong dose-dependent apoptosis. A significant inhibition was observed only for miR-34c-3p on SiHa cells migration and invasion, therefore implying alternative regulatory pathways and targets. These results suggest differential tumor suppressor roles for miR-34c-3p and miR-34c-5p and provide new insights in the understanding of miRNA biology.

  5. Imaging Prostate Cancer Invasion with Multi-Nuclear Magnetic Resonance Methods: The Metabolic Boyden Chamber

    Directory of Open Access Journals (Sweden)

    Ulrich Pilatus

    2000-05-01

    Full Text Available The physiological milieu within solid tumors can influence invasion and metastasis. To determine the impact of the physiological environment and cellular metabolism on cancer cell invasion, it is necessary to measure invasion during well-controlled modulation of the physiological environment. Recently, we demonstrated that magnetic resonance imaging can be used to monitor cancer cell invasion into a Matrigel layer [Artemov D, Pilatus U, Chou S, Mori N, Nelson JB, and Bhujwalla ZM. (1999. Dynamics of prostate cancer cell invasion studied in vitro by NMR microscopy. Mag Res Med 42, 277–282.]. Here we have developed an invasion assay (“Metabolic Boyden Chamber” that combines this capability with the properties of our isolated cell perfusion system. Long-term experiments can be performed to determine invasion as well as cellular metabolism under controlled environmental conditions. To characterize the assay, we performed experiments with prostate cancer cell lines preselected for different invasive characteristics. The results showed invasion into, and degradation of the Matrigel layer, by the highly invasive/metastatic line (MatLyLu, whereas no significant changes were observed for the less invasive/metastatic cell line (DU-145. With this assay, invasion and metabolism was measured dynamically, together with oxygen tensions within the cellular environment and within the Matrigel layer. Such a system can be used to identify physiological and metabolic characteristics that promote invasion, and evaluate therapeutic interventions to inhibit invasion.

  6. Invasive Haemophilus influenzae Infection in Patients With Cancer.

    Science.gov (United States)

    Singh, Vivek; Nanjappa, Sowmya; Pabbathi, Smitha; Greene, John N

    2017-01-01

    A major cause of morbidity and mortality in patients with cancer is infection. Since the introduction of the Haemophilus influenzae type b (Hib) vaccine in the United States in the 1990s, invasive H influenzae infection has become less common. We report on 5 patients with cancer and invasive H influenzae infection. A literature review was also performed of the dominant Haemophilus subtype and the clinical features associated with the infection and concomitant cancer. Of the 17 cases found in the literature, had hematological malignancies and 1 case each had thymoma, schwannoma, teratoma, and pancreatic, Merkel cell, pharyngeal, laryngeal, and rectal carcinomas. Two cases occurred with AIDS and Kaposi sarcoma. Pneumonia with bacteremia was seen in 8 cases, whereas pleuritis, neck cellulitis, septic arthritis, meningitis, and mediastinitis were diagnosed in the others. No focus of infection was identified in 2 cases. Nontypable H influenzae (NTHi) occurred in 4 cases, and Hib was isolated in 2 cases; serotyping was not reported in the others. Leukocytosis occurred in 7 cases and lymphopenia in 3; no cases presented with neutropenia. Four isolates were positive for beta-lactamase. Susceptibility data were unavailable in 5 case patients. Among serotyped cases, 67% were of the NTHi strain - a finding consistent with the change in the epidemiology of H influenzae since the introduction of the Hib vaccine.

  7. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    David G. Menter

    2012-01-01

    Full Text Available Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1 are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2, which binds to and activates G-protein-coupled prostaglandin E1-4 receptors (EP1-4. Selectively targeting the COX-2/mPGES-1/PGE2/EP1-4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM. Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1-4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

  8. Inhibiting cell migration and cell invasion by silencing the transcription factor ETS-1 in human bladder cancer.

    Science.gov (United States)

    Liu, Li; Liu, Yuchen; Zhang, Xintao; Chen, Mingwei; Wu, Hanwei; Lin, Muqi; Zhan, Yonghao; Zhuang, Chengle; Lin, Junhao; Li, Jianfa; Xu, Wen; Fu, Xing; Zhang, Qiaoxia; Sun, Xiaojuan; Zhao, Guoping; Huang, Weiren

    2016-05-03

    As one of the members of the ETS gene family, the transcription factor v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays key role in the regulation of physiological processes in normal cells and tumors. In this study, we aimed to investigate the relationship between the transcription factor ETS-1 and malignant phenotypes of bladder cancer. We demonstrated that ETS-1 was up-regulated in human bladder cancer tissue compared to paired normal bladder tissue. In order to evaluate the functional role of ETS-1 in human bladder cancer, vectors expressing ETS-1 shRNA and ETS-1 protein were constructed in vitro and transfected into the human bladder cancer T24 and 5637 cells. Our results showed that the transcription factor ETS-1 could promote cell migration and cell invasion in human bladder cancer, without affecting cell proliferation and apoptosis. In conclusion, ETS-1 plays oncogenic roles through inducing cell migration and invasion in human bladder cancer, and it can be used as a therapeutic target for treating human bladder cancer.

  9. High expression of adenylate cyclase-associated protein 1 accelerates the proliferation, migration and invasion of neural glioma cells.

    Science.gov (United States)

    Bao, Zhen; Qiu, Xiaojun; Wang, Donglin; Ban, Na; Fan, Shaochen; Chen, Wenjuan; Sun, Jie; Xing, Weikang; Wang, Yunfeng; Cui, Gang

    2016-04-01

    Adenylate cyclase-associated protein 1 (CAP1), a conserved member of cyclase-associated proteins was reported to be associated with the proliferation, migration or invasion of the tumors of pancreas, breast and liver, and was involved in astrocyte proliferation after acute Traumatic Brain Injury (TBI). In this study, we sought to investigate the character of CAP1 in the pathological process of human glioma by detecting human glioma specimens and cell lines. 43 of 100 specimens showed high expression of CAP1 via immunohistochemistry. With statistics analysis, we found out the expression level of CAP1 was correlated with the WHO grades of human glioma and was great positively related to Ki-67 (p<0.01). In vitro, silencing CAP1 in U251 and U87MG, the glioma cell lines with the relatively higher expression of CAP1, induced the proliferation of the cells significantly retarded, migration and invasion as well. Obviously, our results indicated that CAP1 participated in the molecular pathological process of glioma indeed, and in a certain sense, CAP1 might be a potential and promising molecular target for glioma diagnosis and therapies in the future.

  10. Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation

    Directory of Open Access Journals (Sweden)

    Hui eZhao

    2015-01-01

    Full Text Available Pregnancy can be defined as a permissible process, where a semi-allogeneic fetus and placenta are allowed to grow and survive within the mother. Similarly, in tumor growth, antigen-specific malignant cells proliferate and evade into normal tissues of the host. The microenvironments of the placenta and tumors are amazingly comparable, sharing similar mechanisms exploited by fetal or cancer cells with regard to surviving in a hypoxic microenvironment, invading tissues via degradation and vasculogenesis, and escaping host attack through immune privilege. Heme oxygease-1 (HO-1 is a stress-response protein that has anti-oxidative, anti-apoptotic, pro-angiogenic, and anti-inflammatory properties. Although a large volume of research has been published in recent years investigating the possible role(s of HO-1 in pregnancy and in cancer development, the molecular mechanisms that regulate these yin-yang processes have still not been fully elucidated. Here, we summarize and compare pregnancy and cancer development, focusing primarily on the function of HO-1 in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Due to the similarities of both processes, a thorough understanding of the molecular mechanisms of each process may reveal and guide the development of new approaches to prevent not only pregnancy disorders; but also, to study cancer.

  11. G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis.

    Directory of Open Access Journals (Sweden)

    Matthew J Billard

    Full Text Available Triple negative breast cancer (TNBC is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine receptor interactions are important modulators of breast cancer metastasis; however, it is now recognized that quantitative surface expression of one important chemokine receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3 is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis.

  12. Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways.

    Directory of Open Access Journals (Sweden)

    Boying Dun

    Full Text Available Mycophenolic acid (MPA is the metabolized product and active element of mycophenolate mofetil (MMF that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA and proteins (PRKCA, AKT, SRC, CD147 and MMP1 with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1. However, a few genes that may promote migration (CYR61 and NOS3 were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.

  13. Effects of homeodomain protein CDX2 expression on the proliferation and migration of lovo colon cancer cells.

    Science.gov (United States)

    Zheng, Jian-bao; Sun, Xue-jun; Qi, Jie; Li, Shou-shuai; Wang, Wei; Ren, Hai-liang; Tian, Yong; Lu, Shao-ying; Du, Jun-kai

    2011-09-01

    The homeobox gene, CDX2, plays a major role in development, especially in the gut, and also functions as a tumor suppressor in the adult colon. In the present study, we investigated the effects of CDX2 expression on the proliferation, migration, and apoptosis of the human colon cancer cell line, Lovo. Lovo cells exogenously expressing CDX2 exhibited no significant differences in the percentage of cells in G1- and S-phase or in apoptosis, as determined by flow cytometry. MTT assay also confirmed that CDX2 expression had no effect on proliferation in these cells. Interestingly, conditioned medium collected from CDX2-overexpressing Lovo cells showed a significant decrease in secretion of MMP-2 and the invasive potential of these cells was significantly inhibited. Collectively, these data suggest that CDX2 may play a critical role in the migration and metastasis of colon carcinoma and over-expression of CDX2 in colon cancer cells markedly inhibits invasion. Based on these results, exogenous expression of CDX2 might be a promising option in the treatment of colon carcinoma.

  14. S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide

    Science.gov (United States)

    Stewart, Rachel L.; Carpenter, Brittany L.; West, Dava S.; Knifley, Teresa; Liu, Lili; Wang, Chi; Weiss, Heidi L.; Gal, Tamas S.; Durbin, Eric B.; Arnold, Susanne M.; O'Connor, Kathleen L.; Chen, Min

    2016-01-01

    S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer. PMID:27127879

  15. Fusicoccin A, a Phytotoxic Carbotricyclic Diterpene Glucoside of Fungal Origin, Reduces Proliferation and Invasion of Glioblastoma Cells by Targeting Multiple Tyrosine Kinases1

    Science.gov (United States)

    Bury, Marina; Andolfi, Anna; Rogister, Bernard; Cimmino, Alessio; Mégalizzi, Véronique; Mathieu, Véronique; Feron, Olivier; Evidente, Antonio; Kiss, Robert

    2013-01-01

    Glioblastoma multiforme (GBM) is a deadly cancer that possesses an intrinsic resistance to pro-apoptotic insults, such as conventional chemotherapy and radiotherapy, and diffusely invades the brain parenchyma, which renders it elusive to total surgical resection. We found that fusicoccin A, a fungal metabolite from Fusicoccum amygdali, decreased the proliferation and migration of human GBM cell lines in vitro, including several cell lines that exhibit varying degrees of resistance to pro-apoptotic stimuli. The data demonstrate that fusicoccin A inhibits GBM cell proliferation by decreasing growth rates and increasing the duration of cell division and also decreases two-dimensional (measured by quantitative video microscopy) and three-dimensional (measured by Boyden chamber assays) migration. These effects of fusicoccin A treatment translated into structural changes in actin cytoskeletal organization and a loss of GBM cell adhesion. Therefore, fusicoccin A exerts cytostatic effects but low cytotoxic effects (as demonstrated by flow cytometry). These cytostatic effects can partly be explained by the fact that fusicoccin inhibits the activities of a dozen kinases, including focal adhesion kinase (FAK), that have been implicated in cell proliferation and migration. Overexpression of FAK, a nonreceptor protein tyrosine kinase, directly correlates with the invasive phenotype of aggressive human gliomas because FAK promotes cell proliferation and migration. Fusicoccin A led to the down-regulation of FAK tyrosine phosphorylation, which occurred in both normoxic and hypoxic GBM cell culture conditions. In conclusion, the current study identifies a novel compound that could be used as a chemical template for generating cytostatic compounds designed to combat GBM. PMID:23544164

  16. Fusicoccin a, a phytotoxic carbotricyclic diterpene glucoside of fungal origin, reduces proliferation and invasion of glioblastoma cells by targeting multiple tyrosine kinases.

    Science.gov (United States)

    Bury, Marina; Andolfi, Anna; Rogister, Bernard; Cimmino, Alessio; Mégalizzi, Véronique; Mathieu, Véronique; Feron, Olivier; Evidente, Antonio; Kiss, Robert

    2013-04-01

    Glioblastoma multiforme (GBM) is a deadly cancer that possesses an intrinsic resistance to pro-apoptotic insults, such as conventional chemotherapy and radiotherapy, and diffusely invades the brain parenchyma, which renders it elusive to total surgical resection. We found that fusicoccin A, a fungal metabolite from Fusicoccum amygdali, decreased the proliferation and migration of human GBM cell lines in vitro, including several cell lines that exhibit varying degrees of resistance to pro-apoptotic stimuli. The data demonstrate that fusicoccin A inhibits GBM cell proliferation by decreasing growth rates and increasing the duration of cell division and also decreases two-dimensional (measured by quantitative video microscopy) and three-dimensional (measured by Boyden chamber assays) migration. These effects of fusicoccin A treatment translated into structural changes in actin cytoskeletal organization and a loss of GBM cell adhesion. Therefore, fusicoccin A exerts cytostatic effects but low cytotoxic effects (as demonstrated by flow cytometry). These cytostatic effects can partly be explained by the fact that fusicoccin inhibits the activities of a dozen kinases, including focal adhesion kinase (FAK), that have been implicated in cell proliferation and migration. Overexpression of FAK, a nonreceptor protein tyrosine kinase, directly correlates with the invasive phenotype of aggressive human gliomas because FAK promotes cell proliferation and migration. Fusicoccin A led to the down-regulation of FAK tyrosine phosphorylation, which occurred in both normoxic and hypoxic GBM cell culture conditions. In conclusion, the current study identifies a novel compound that could be used as a chemical template for generating cytostatic compounds designed to combat GBM.

  17. Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer

    Science.gov (United States)

    Shimada, Hiroshi; Abe, Shyuetsu; Kohno, Takayuki; Satohisa, Seiro; Konno, Takumi; Takahashi, Syunta; Hatakeyama, Tsubasa; Arimoto, Chihiro; Kakuki, Takuya; Kaneko, Yakuto; Takano, Ken-ichi; Saito, Tsuyoshi; Kojima, Takashi

    2017-01-01

    Lipolysis-stimulated lipoprotein receptor (LSR) is a unique molecule of tricellular contacts of normal and cancer cells. We investigated how the loss of LSR induced cell migration, invasion and proliferation in endometrial cancer cell line Sawano. mRNAs of amphiregulin (AREG) and TEA domain family member 1 (TEAD1) were markedly upregulated by siRNA-LSR. In endometrial cancer tissues, downregulation of LSR and upregulation of AREG were observed together with malignancy, and Yes-associated protein (YAP) was present in the nuclei. siRNA-AREG prevented the cell migration and invasion induced by siRNA-LSR, whereas treatment with AREG induced cell migration and invasion. LSR was colocalized with TRIC, angiomotin (AMOT), Merlin and phosphorylated YAP (pYAP). siRNA-LSR increased expression of pYAP and decreased that of AMOT and Merlin. siRNA-YAP prevented expression of the mRNAs of AREG and TEAD1, and the cell migration and invasion induced by siRNA-LSR. Treatment with dobutamine and 2-deoxy-D-glucose and glucose starvation induced the pYAP expression and prevented the cell migration and invasion induced by siRNA-LSR. siRNA-AMOT decreased the Merlin expression and prevented the cell migration and invasion induced by siRNA-LSR. The loss of LSR promoted cell invasion and migration via upregulation of TEAD1/AREG dependent on YAP/pYAP and AMOT/Merlin in human endometrial cancer cells. PMID:28071680

  18. Thermo-chemotherapy Induced miR-218 upregulation inhibits the invasion of gastric cancer via targeting Gli2 and E-cadherin.

    Science.gov (United States)

    Ruan, Qiang; Fang, Zhi-Yuan; Cui, Shu-Zhong; Zhang, Xiang-Liang; Wu, Yin-Bing; Tang, Hong-Sheng; Tu, Yi-Nuo; Ding, Yan

    2015-08-01

    Thermo-chemotherapy has been proven to reduce the invasion capability of cancer cells. However, the molecular mechanism underlying this anti-invasion effect is still unclear. In this study, the role of thermo-chemotherapy in the inhibition of tumor invasion was studied. The results demonstrated that expression of miR-218 was downregulated in gastric cancer tissues, which had a positive correlation with tumor invasion and metastasis. In vitro thermo-chemotherapy increased miR-218 expression in SGC7901 cells and inhibited both proliferation and invasion of cancer cells. Gli2 was identified as a downstream target of miR-218, and its expression was negatively regulated by miR-218. The thermo-chemotherapy induced miR-218 upregulation was also accompanied by increasing of E-cadherin expression. In conclusion, the present study indicates that thermo-chemotherapy can effectively decrease the invasion capability of cancer cells and increase cell-cell adhesion. miR-218 and its downstream target Gli2, as well as E-cadherin, participate in the anti-invasion process.

  19. Silencing of CCR7 inhibits the growth, invasion and migration of prostate cancer cells induced by VEGFC.

    Science.gov (United States)

    Chi, Bao-Jin; Du, Cong-Lin; Fu, Yun-Feng; Zhang, Ya-Nan; Wang, Ru Wen

    2015-01-01

    Early in prostate cancer development, tumor cells express vascular endothelial growth factor C (VEGF-C), a secreted molecule that is important in angiogenesis progression. CC-chemokine receptor 7 (CCR7), another protein involved in angiogenesis, is strongly expressed in most human cancers, where it activated promotes tumor growth as well as favoring tumor cell invasion and migration. The present study aimed to investigate the effect of down-regulating CCR7 expression on the growth of human prostate cancer cells stimulated by VEGFC. The CCR7-specific small interfering RNA (siRNA) plasmid vector was constructed and then transfected into prostate cancer cells. The expression of CCR7 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation, apoptosis, cell cycle distribution and cell migration were assessed following knockdown of CCR7 by RNA interference (RNAi). Western blot analysis was used to identify differentially expressed angiogenesis- and cell cycle-associated proteins in cells with silenced CCR7. The expression levels of CCR7 in prostate cancer cells transfected with siRNA were decreased, leading to a significant inhibition of prostate cancer cell proliferation, migration and invasion induced by VEGFC. Western blot analysis revealed that silencing of CCR7 may inhibit vascular endothelial growth factor, matrix metalloproteinase (MMP)-2 and MMP-9 protein expression. In conclusion, the present study demonstrated that RNAi can effectively silence CCR7 gene expression and inhibit the growth of prostate cancer cells, which indicates that there is a potential of targeting CCR7 as a novel gene therapy approach for the treatment of prostate cancer.

  20. Natural biology and management of nonmuscle invasive bladder cancer

    DEFF Research Database (Denmark)

    Scarpato, Kristen R; Tyson, Mark D; Clark, Peter E

    2016-01-01

    PURPOSE OF REVIEW: This article reviews the natural biology of noninvasive bladder cancer and its management strategies while summarizing the most recent advances in the field. RECENT FINDINGS: Nonmuscle invasive bladder cancer (NMIBC) has a tendency to recur and progress. Risk stratification has...... treatment, especially in refractory high-risk cases, include the addition of intravesical hyperthermia, combination and sequential therapy with existing agents and the use of novel agents such as mycobacterial cell wall extract. New data are emerging regarding the potential role of active surveillance...... in low-risk patients. SUMMARY: NMIBC represents a variety of disease states and continues to pose management challenges. As our understanding of tumor biology improves and technology advances, achieving better outcomes through individualized care may be possible....

  1. A Comprehensive Study of Extramural Venous Invasion in Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    David McClelland

    Full Text Available Colorectal cancer is a common malignancy and a leading cause of cancer related death. Cancer staging following resection is key to determining any adjuvant therapy in those patients with high risk disease. In colorectal cancer, tumour stage and lymph node stage are the main pathological factors which have been considered to influence outcome. Increasing emphasis is now being placed on other factors, especially the presence of extramural venous invasion (EMVI. It is important to understand the relationship of EMVI with other pathological factors and to confirm that in an individual centre that EMVI is being detected at an appropriate rate and is of prognostic significance. This comprehensive study assesses the reporting and prognostic significance of EMVI in a single centre, using prospectively collected data from histopathology reports of a cohort of 2405 patients who underwent surgery for colorectal cancer over a nine year period. Overall, EMVI was reported in 27.9% of colorectal cancer excision specimens. In tumours (n = 1928 that had not received neoadjuvant therapy, the presence of EMVI varied significantly depending on tumour site (χ2 = 12.03, p<0.005, tumour stage (χ2 = 268.188, p<0.001, lymph node stage (χ2 = 294.368, p<0.001 and Dukes' stage (χ2 = 253.753, p<0.001. Multivariate analysis confirmed EMVI as a significant independent prognostic indicator (p<0.001. In conclusion, the presence of EMVI as an independent prognostic indicator is shown and is related to other pathological and prognostic factors. This study emphasises the requirement for the accurate identification of EMVI in colorectal cancer excision specimens and also understanding the relationship of EMVI with other prognostic factors.

  2. Effects of hypoxia on the expression of CCR7 and proliferation, invasiveness of A549 cells

    Directory of Open Access Journals (Sweden)

    Yang LI

    2008-10-01

    Full Text Available Background and objective It has been proven that hypoxia could promote tumor cells invasion and metastasis by different mechanisms, but the relationship between hypoxia and CCR7 have not been reported. The aim of this investigate is to evaluate the effects of hypoxia on the expression of CCR7 and the invasiveness of lung adenocarcinoma A549 cells. Methods A549 cells were incubated at either normoxia (37 ℃, 5%CO2, 21%O2 or hypoxia(37 ℃, 5%CO2, 1%O2 condition for 4 h,12 h, 24 h. The expressions of CCR7 mRNA and protein levels were observed by RT-PCR and Western blotting; Cells invasiveness was measured by matrigel invasion assay. Results RT-PCR and Western blotting showed that the expression of CCR7 was detected in lung adenocarcinoma A549 cells, CCR7 mRNA and protein expression level were increased with culture time along either in normoxia or hypoxia condition; Furthermore,compared with normoxia group, the CCR7 mRNA and protein expression level in hypoxia group was increased (P <0.01.The results of Transwell invasion showed that The number of invasive cells was significantly increased in hypoxia group(t =0.006, P <0.01 and A549 cells invasive ability was inhibited after add anti-CCR7 Ab to culture medium (t =0.09, P <0.01. Conclusion The results suggest that hypoxia plays an important role in the augmentation of the CCR7 expression and invasiveness of A549 cells. Invasion of A549 cells in hypoxia condition correlated with CCR7 expression level.

  3. Targeting MACC1 by RNA interference inhibits proliferation and invasion of bladder urothelial carcinoma in T24 cells.

    Science.gov (United States)

    Xu, Song-Tao; Ding, Xiang; Ni, Qing-Feng; Jin, Shao-Ju

    2015-01-01

    The purpose of this article is to research on whether MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma (BUC). In this study, the expression of MACC1 gene was knocked down by RNA interference (RNAi) in the T24 cell (human BUC cell). The transcription level of MACC1 was detected by RT-PCR. Activities of MACC1, caspase-3, caspase-8, Bax and Met (mesenchymal-epithelial transition factor) protein were measured by Western blot. The cell proliferation and apoptosis were detected by MTT and flow cytometry. The cell's invasion ability was performed on Matrigel transwell assay. We also detect MMP2 (metalloproteinase-2) proteins by ELISA. The results showed that the level of MACC1 mRNA and protein was significantly reduced after RNAi. MTT assay showed that the proliferation of T24 cell was decreased due to RNA interference. Apoptosis studies also showed that MACC1 gene interference in T24 loses its anti-apoptotic effects. The expression of apoptosis proteins (Caspase-3, Caspase-8 and Bax) increased significantly due to the MACC1 RNAi. The level of Met protein was down-regulated obviously due to RNAi. Transwell assay showed that invasion abilities of T24 cells were reduced obviously due to MACC1 RNAi. Further studies showed that the secretion of MMP-2 was reduced by RNAi. It can conclude that the ability of proliferation and invasion in T24 cells can be inhibited by RNAi-targeting MACC1. As a result, MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma.

  4. Sonic hedgehog pathway contributes to gastric cancer cell growth and proliferation.

    Science.gov (United States)

    Wan, Jianhua; Zhou, Ji; Zhao, Hailong; Wang, Mei; Wei, Zhuanqin; Gao, Hongyan; Wang, Yongzhong; Cui, Hongjuan

    2014-04-01

    The Sonic Hedgehog (Shh) signaling pathway is commonly activated in gastrointestinal cancer. However, our understanding of the Shh pathway in gastric cancer remains limited. Here we examined the effects of cyclopamine, a specific inhibitor of the Shh signaling pathway, on cell growth and proliferation in gastric primary cancer cells GAM-016 and the MKN-45 cell line. The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells. Furthermore, we observed that cyclopamine inhibited gastric cancer cell proliferation through cell cycle arrest and apoptosis. An in vivo study using NOD/SCID mouse xenografts demonstrated that cyclopamine significantly prevented tumor growth and development. Our study indicated that Shh signaling pathway could promote gastric cancer cell proliferation and tumor development, and blocking this pathway may be a potential strategy in gastric cancer treatment.

  5. Homeobox A7 stimulates breast cancer cell proliferation by up-regulating estrogen receptor-alpha

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yu [Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006 (China); Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4 (Canada); Cheng, Jung-Chien [Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4 (Canada); Huang, He-Feng, E-mail: huanghefg@hotmail.com [Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006 (China); Leung, Peter C.K., E-mail: peter.leung@ubc.ca [Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006 (China); Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4 (Canada)

    2013-11-01

    Highlights: •HOXA7 regulates MCF7 cell proliferation. •HOXA7 up-regulates ERα expression. •HOXA7 mediates estrogen-induced MCF7 cell proliferation. -- Abstract: Breast cancer is the most common hormone-dependent malignancy in women. Homeobox (HOX) transcription factors regulate many cellular functions, including cell migration, proliferation and differentiation. The aberrant expression of HOX genes has been reported to be associated with human reproductive cancers. Estradiol (E2) and its nuclear receptors, estrogen receptor (ER)-alpha and ER-beta, are known to play critical roles in the regulation of breast cancer cell growth. However, an understanding of the potential relationship between HOXA7 and ER in breast cancer cells is limited. In this study, our results demonstrate that knockdown of HOXA7 in MCF7 cells significantly decreased cell proliferation and ERα expression. In addition, HOXA7 knockdown attenuated E2-induced cell proliferation as well as progesterone receptor (PR) expression. The stimulatory effects of E2 on cell proliferation and PR expression were abolished by co-treatment with ICI 182780, a selective ERα antagonist. In contrast, overexpression of HOXA7 significantly stimulated cell proliferation and ERα expression. Moreover, E2-induced cell proliferation, as well as PR expression, was enhanced by the overexpression of HOXA7. Neither knockdown nor overexpression of HOXA7 affected the ER-beta levels. Our results demonstrate a novel mechanistic role for HOXA7 in modulating breast cancer cell proliferation via regulation of ERα expression. This finding contributes to our understanding of the role HOXA7 plays in regulating the proliferation of ER-positive cancer cells.

  6. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Directory of Open Access Journals (Sweden)

    Brábek Jan

    2010-09-01

    Full Text Available Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.

  7. Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion.

    Science.gov (United States)

    Ye, Tinghong; Zhu, Shirui; Zhu, Yongxia; Feng, Qiang; He, Bing; Xiong, Yiong; Zhao, Lifeng; Zhang, Yiwen; Yu, Luoting; Yang, Li

    2016-08-01

    Melanoma is the most serious type of skin cancer because it is highly frequency of drug resistance and can spread earlier and more quickly than other skin cancers. The objective of this research was to investigate the anticancer effects of cryptotanshinone on human melanoma cells in vitro, and explored its mechanisms of action. Our results have shown that cryptotanshinone could inhibit cell proliferation in human melanoma cell lines A2058, A375, and A875 in a dose- and time-dependent manner. In addition, flow cytometry assay showed that cryptotanshinone inhibited the proliferation of human melanoma cell line A375 by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. Moreover, western blot analysis indicated that the occurrence of its apoptosis was associated with upregulation of cleaved caspases-3 and pro-apoptotic protein Bax while downregulation of anti-apoptotic protein Bcl-2. Meanwhile, cryptotanshinone could decrease the levels of reactive oxygen species (ROS). Furthermore, cryptotanshinone also blocked A375 cell migration and invasion in vitro which was associated with the downregulation with MMP-9. Taken together, these results suggested that cryptotanshinone might be a potential drug in human melanoma treatment by inhibiting proliferation, inducing apoptosis via ROS-mitochondrial apoptotic pathway and blocking cell migration and invasion.

  8. Argentatin B Inhibits Proliferation of Prostate and Colon Cancer Cells by Inducing Cell Senescence

    OpenAIRE

    Ela Alcántara-Flores; Alicia Enriqueta Brechú-Franco; Patricia García-López; Leticia Rocha-Zavaleta; Rebeca López-Marure; Mariano Martínez-Vázquez

    2015-01-01

    Argentatin B has been shown to inhibit the growth of colon HCT-15, and prostate PC-3 cancer cells. However, the mechanism by which argentatin B inhibits cell proliferation is still unknown. We aimed to investigate the mechanism by which argentatin B inhibits cell proliferation. The cell cycle was studied by flow cytometry. Apoptosis was evaluated by Annexin-V-Fluos, and Hoechst 33342 dye staining. Cell senescence was evaluated by proliferation tests, and staining for SA-β-galactosidase. Senes...

  9. Identification of glucocorticoid-induced leucine zipper as a key regulator of tumor cell proliferation in epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Fernandez Hervé

    2009-10-01

    Full Text Available Abstract Background Little is known about the molecules that contribute to tumor progression of epithelial ovarian cancer (EOC, currently a leading cause of mortality from gynecological malignancies. Glucocorticoid-Induced Leucine Zipper (GILZ, an intracellular protein widely expressed in immune tissues, has been reported in epithelial tissues and controls some of key signaling pathways involved in tumorigenesis. However, there has been no report on GILZ in EOC up to now. The objectives of the current study were to examine the expression of GILZ in EOC and its effect on tumor cell proliferation. Results GILZ expression was measured by immunohistochemical staining in tissue sections from 3 normal ovaries, 7 benign EOC and 50 invasive EOC. GILZ was not detected on the surface epithelium of normal ovaries and benign tumors. In contrast, it was expressed in the cytoplasm of tumor cells in 80% EOC specimens. GILZ immunostaining scores correlated positively to the proliferation marker Ki-67 (Spearman test in univariate analysis, P P Conclusion The present study is the first to identify GILZ as a molecule produced by ovarian cancer cells that promotes cell cycle progression and proliferation. Our findings clearly indicate that GILZ activates AKT, a crucial signaling molecule in tumorigenesis. GILZ thus appears as a potential key molecule in EOC.

  10. Focal adhesion kinase and Src phosphorylations in HGF-induced proliferation and invasion of human cholangiocarcinoma cell line, HuCCA-1

    Institute of Scientific and Technical Information of China (English)

    Urai Pongchairerk; Jun-Lin Guan; Vijittra Leardkamolkarn

    2005-01-01

    AIM: To study the role of focal adhesion kinase (FAK) and its association with Src in hepatocyte growth factor (HGF)-induced cell signaling in cholangiocarcinoma progression.METHODS: Previously isolated HuCCA-1 cells were re-characterized by immunofluorescent staining and reverse transcriptase-polymerase chain reaction assay for the expression of cytokeratin 19, HGF and c-Met mRNA. Cultured HuCCA-1 cells were treated with HGF and determined for cell proliferation and invasion effects by MTT and invasion assays. Western blotting, immunoprecipitation, and co-immunoprecipitation were also performed to study the phosphorylation and interaction of FAK and Src. A novel Src inhibitor (AZM555130) was applied in cultures to investigate the effects on FAK phosphorylation inhibition and on cell proliferation and invasion.RESULTS: HGF enhanced HuCCA-1 cell proliferation and invasion by mediating FAK and Src phosphorylations.FAK-Src interaction occurred in a time-dependent manner that Src was proved to be an upstream signaling molecule to FAK. The inhibitor to Src decreased FAK phosphorylation level in correlation with the reduction of cell proliferation and invasion.CONCLUSION: FAK plays a significant role in signaling pathway of HGF-responsive cell line derived from cholangiocarcinoma. Autophosphorylated Src, induced by HGF, mediates Src kinase activation, which subsequently phosphorylates its substrate, FAK, and signals to cell proliferation and invasion.

  11. Suppression of growth and invasive behavior of human prostate cancer cells by ProstaCaid™: mechanism of activity.

    Science.gov (United States)

    Jiang, Jiahua; Eliaz, Isaac; Sliva, Daniel

    2011-06-01

    Since the use of dietary supplements as alternative treatments or adjuvant therapies in cancer treatment is growing, a scientific verification of their biological activity and the detailed mechanisms of their action are necessary for the acceptance of dietary supplements in conventional cancer treatments. In the present study we have evaluated the anti-cancer effects of dietary supplement ProstaCaid™ (PC) which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3-gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95®), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Job's tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, β sitosterolzinc, lycopene, α lipoic acid, boron, berberine and 3.3'-diinodolymethane (DIM). We show that PC treatment resulted in the inhibition of cell proliferation of the highly invasive human hormone refractory (independent) PC-3 prostate cancer cells in a dose- and time-dependent manner with IC50 56.0, 45.6 and 39.0 µg/ml for 24, 48 and 72 h, respectively. DNA-microarray analysis demonstrated that PC inhibits proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. In addition, PC also suppresses metastatic behavior of PC-3 by the inhibition of cell adhesion, cell migration and cell invasion, which was associated with the down-regulation of expression of CAV1, IGF2, NR2F1, and PLAU genes and suppressed secretion of the urokinase plasminogen activator (uPA) from PC-3 cells. In conclusion, the dietary supplement PC is a promising natural complex with the potency to inhibit invasive human prostate cancer.

  12. Notch1 is overexpressed in human intrahepatic cholangiocarcinoma and is associated with its proliferation, invasiveness and sensitivity to 5-fluorouracil in vitro.

    Science.gov (United States)

    Wu, Wen-Rui; Zhang, Rui; Shi, Xiang-De; Zhu, Man-Sheng; Xu, Lei-Bo; Zeng, Hong; Liu, Chao

    2014-06-01

    The Notch signaling pathway has been reported to play crucial roles in inhibiting hepatocyte differentiation and allowing formation of intrahepatic bile ducts. However, little is known about its significance in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to investigate the effects of Notch1 expression in ICC tissues and cells. The expression of Notch1 was examined in paraffin-embedded sections of ICC (n=44) by immunohistochemistry. Notch1 was knocked down by RNA interference (RNAi) in cultured ICC cells (RBE and HCCC-9810). The proliferation, invasiveness and sensitivity to 5-fluorouracil (5-FU) were detected by Cell Counting Kit-8 (CCK-8), colony formation assays, Transwell assays and flow cytometry, respectively. The expression levels of several multidrug resistance (MDR)-related genes, MDR1-P-glycoprotein (ABCB‑1), breast cancer resistance protein (ABCG‑2) and the multidrug resistance protein isoform 1 (MRP‑1), were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Notch1 was overexpressed in cell membranes and cytoplasm of ICC compared with the adjacent liver tissue (35/44, 79.5%) and this was more common in cases with tumor size≥5 cm (p=0.021) and HBs-Ag positive (p=0.018). By silencing Notch1, the proliferation and invasiveness of ICC cells were inhibited and the inhibition rate of 5-FU was markedly increased. In addition, IC50 values of 5-FU in RBE cells were decreased from 148.74±0.72 to 5.37±0.28 µg/ml and the corresponding values for HCCC-9810 cells were 326.92±0.87 to 42.60±0.35 µg/ml, respectively. Furthermore, Notch1 silencing clearly increased the percentage of apoptotic cells treated by 5-FU compared with the control. Notch1 knockdown led to diminished expression levels of ABCB‑1 and MRP‑1. Therefore, Notch may play important roles in the development of ICC. Silencing Notch1 can inhibit the proliferation and invasiveness of ICC cells and increase their

  13. Matrine Suppresses Proliferation and Invasion of SGC7901 Cells through Inactivation of PI3K/Akt/uPA Pathway.

    Science.gov (United States)

    Peng, Xiaochun; Zhou, Dawei; Wang, Xianwang; Hu, Zhifan; Yan, Yan; Huang, Jiangrong

    2016-09-01

    This study was to examine the inhibitory effect of matrine on the proliferation and metastasis of gastric cancer cells, and to explore the possible mechanisms involved in these processes. MTT was used to evaluate the proliferation ability of SGC7901 cells. A two and three-dimensional cell migration assay were performed to determine the effect of matrine on the migration of SGC7901 cells. Then, the changes of the uPA protein and other possible signal molecules were detected by western blot. We found that the proliferation ability of SGC 7901 cells was suppressed by matrine (pmatrine when compared to the control in a two-dimensional cell migration assay. In addition, SGC7901cells treated with matrine (50μg/ml) migrated less than the control cells in a three-dimensional cell migration assay. At the meantime, the decreased uPA protein expression in SGC7901 cells treated with matrine was observed, and the PI3K/Akt pathway was inhibited. These results suggested that matrine can inhibit the proliferation and metastasis of gastric cancer cells through the PI3K/Akt/uPA pathway, indicating that matrine might be a potential molecular target for treatment of gastric carcinoma.

  14. MAGI1 inhibits migration and invasion via blocking MAPK/ERK signaling pathway in gastric cancer

    Science.gov (United States)

    Jia, Shuqin; Lu, Jiajia; Qu, Tingting; Feng, Yi; Wang, Xiaohong; Liu, Caixia; Ji, Jiafu

    2017-01-01

    Objective To explore the association of membrane-associated guanylate kinase inverted 1 (MAGI1) with gastric cancer (GC) and the related molecular mechanisms. Methods The reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were utilized to measure the MAGI1 expression level in GC tissues. Quantitative real-time PCR and Western blotting were used to ensure the MAGI1 expression in GC cell lines. Small hairpin RNA (shRNA) was applied for knockdown of endogenous MAGI1 in GC cells. MTT assay and colony formation assay, scratch wounding migration assay and transwell chamber migration assay, as well as transwell chamber invasion assay were employed respectively to investigate the GC cell proliferation, migration and invasion in MAGI1-knockdown and control GC cells. The potential molecular mechanism mediated by MAGI1 was studied using Western blotting and RT- PCR. Results RT-PCR and IHC verified MAGI1 was frequently expressed in matched adjacent noncancerous mucosa compared with GC tissues and the expression of MAGI1 was related to clinical pathological parameters. Functional assays indicated that MAGI1 knockdown significantly promoted GC cell migration and invasion. Further mechanism investigation demonstrated that one pathway of MAGI1 inhibiting migration and invasion was mainly by altering the expression of matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT)-related molecules via inhibiting MAPK/ERK signaling pathway. Conclusions MAGI1 was associated with GC clinical pathological parameters and acted as a tumor suppressor via inhibiting of MAPK/ERK signaling pathway in GC. PMID:28373751

  15. Effects of miR-200c on the migration and invasion abilities of human prostate cancer Du145 cells and the corresponding mechanism.

    Science.gov (United States)

    Shi, Runlin; Xiao, Haibing; Yang, Tao; Chang, Lei; Tian, Yuanfeng; Wu, Bolin; Xu, Hua

    2014-12-01

    microRNAs (miRNAs) have played a key role in human tumorigenesis, tumor progression, and metastasis. On the one hand, miRNAs are aberrantly expressed in many types of human cancer; on the other hand, miRNAs can function as tumor suppressors or oncogenes that target many cancer-related genes. This study aimed to investigate the effects of miRNA-200c (miR-200c) on the biological behavior and mechanism of proliferation, migration, and invasion in the prostate cancer cell line Du145. In this study, Du145 cells were transfected with miR-200c mimics or negative control miR-NC by using an X-tremeGENE siRNA transfection reagent. The relative expression of miR-200c was measured by RT-PCR. The proliferation, migration, and invasion abilities of Du145 cells were detected by CCK8 assays, migration assays and invasion assays, respectively. The expressions of ZEB1, E-cadherin, and vimentin were observed by western blot. Results showed that DU145 cells exhibited a high expression of miR-200c compared with immortalized normal prostate epithelial cell RWPE-1. Du145 cells were then transfected with miR-200c mimics and displayed lower abilities of proliferation, migration, and invasion than those transfected with the negative control. The protein levels of ZEB1 and vimentin were expressed at a low extent in Du145 cells, which were transfected with miR-200c mimics; by contrast, E-cadherin was highly expressed. Hence, miR-200c could significantly inhibit the proliferation of the prostate cancer cell line Du145; likewise, miR-200c could inhibit migration and invasion by epithelial-mesenchymal transition.

  16. Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.

    Science.gov (United States)

    Arjonen, Antti; Kaukonen, Riina; Mattila, Elina; Rouhi, Pegah; Högnäs, Gunilla; Sihto, Harri; Miller, Bryan W; Morton, Jennifer P; Bucher, Elmar; Taimen, Pekka; Virtakoivu, Reetta; Cao, Yihai; Sansom, Owen J; Joensuu, Heikki; Ivaska, Johanna

    2014-03-01

    Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

  17. [Neoadjuvant chemotherapy of invasive cancer of the urinary bladder].

    Science.gov (United States)

    Selivanov, S P; Isaeva, S N; Kovalik, T A; Chén', M N; Aleksandrovich, I N; Kaliev, E A

    2007-01-01

    We studied efficacy of a combination of intraosseous and systemic administration of drugs in patients with invasive cancer of the urinary bladder (UB). A total of 20 patients aged 54-79 years with verified had recurrence, 2 had tumors with continuous growth. T2N0M0 UB carcinoma was diagnosed in 7 patients, T3N0M0--in 12, T6N0M0--in 1 patient. All the patients received systemic chemotherapy with gemzar in a single daily dose 800-1000 mg/m2 on day 1, 7 and 14. On day 2 a single intraosseous 100 mg eloxatin was given. A total of three courses of combined chemotherapy with 4-week interval was used. Intravenous gemzar administration was accompanied with mild leukopenia in 4 patients, moderate leukopenia--in 1, allergic reaction--in 2 patients. This required gemzar discontinuation. No side effects were seen in response to intraosseous administration of eloxatin. The combined chemotherapy produced complete regression of UB cancer in 3 of 18 patients, partial regression--in 12, stabilization--in 3 patients. Neither local nor long-term tumor progression was found. Short-term therapeutic efficacy of combined therapy was 70%. Fifteen patients with partial regression or stabilization have undergone transurethral resection. Duration of a recurrence-free period reached 5 to 72 months (mean 17 months). The neoadjuvant chemotherapy proposed by us allows achievement of a high percentage of regression in patients with invasive UB cancer located in UB cervix and provides concervative surgery including patients over 70 years of age.

  18. Novel non invasive diagnostic strategies in bladder cancer.

    Science.gov (United States)

    Truta, Anamaria; Popon, Tudor Adrian Hodor; Saraci, George; Ghervan, Liviu; Pop, Ioan Victor

    2016-01-01

    Bladder cancer is one of the most commonly diagnosed malignancies worldwide, derived from the urothelium of the urinary bladder and defined by long asymptomatic and atypical clinical picture. Its complex etiopathogenesis is dependent on numerous risk factors that can be divided into three distinct categories: genetic and molecular abnormalities, chemical or environmental exposure and previous genitourinary disorders and family history of different malignancies. Various genetic polymorphisms and microRNA might represent useful diagnostic or prognostic biomarkers. Genetic and molecular abnormalities - risk factors are represented by miRNA or genetic polymorphisms proved to be part of bladder carcinogenesis such as: genetic mutations of oncogenes TP53, Ras, Rb1 or p21 oncoproteins, cyclin D or genetic polymorhisms of XPD,ERCC1, CYP1B1, NQO1C609T, MDM2SNP309, CHEK2, ERCC6, NRF2, NQO1Pro187Ser polymorphism and microRNA (miR-143, -145, -222, -210, -10b, 576-3p). The aim of our article is to highlight the most recent acquisitions via molecular biomarkers (miRNAs and genetic polymorphisms) involved in bladder cancer in order to provide early diagnosis, precise therapy according to the molecular profile of bladder tumors, as well as to improve clinical outcome, survival rates and life quality of oncological patients. These molecular biomarkers play a key role in bladder carcinogenesis, clinical evolution, prognosis and therapeutic response and explain the molecular mechanisms involved in bladder carcinogenesis; they can also be selected as therapeutic targets in developing novel therapeutic strategies in bladder malignancies. Moreover, the purpose in defining these molecular non invasive biomarkers is also to develop non invasive screening programs in bladder malignancies with the result of decreasing bladder cancer incidence in risk population.

  19. MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Nianxi [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Shen, Liangfang [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Wang, Jun; He, Dan [Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Duan, Chaojun, E-mail: duancjxy@163.com [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China)

    2015-01-02

    Highlights: • Decreased miR-153 and up-regulated ADAM19 are correlated with NSCLC pathology. • MiR-153 inhibits the proliferation and migration and invasion of NSCLC cells in vitro. • ADAM19 is a direct target of miR-153. • ADAM19 is involved in miR-153-suppressed migration and invasion of NSCLC cells. - Abstract: MiR-153 was reported to be dysregulated in some human cancers. However, the function and mechanism of miR-153 in lung cancer cells remains unknown. In this study, we investigated the role of miR-153 in human non-small-cell lung cancer (NSCLC). Using qRT-PCR, we demonstrated that miR-153 was significantly decreased in clinical NSCLC tissues and cell lines, and downregulation of miR-153 was significantly correlated with lymph node status. We further found that ectopic expression of miR-153 significantly inhibited the proliferation and migration and invasion of NSCLC cells in vitro, suggesting that miR-153 may be a novel tumor suppressor in NSCLC. Further integrated analysis revealed that ADAM19 is as a direct and functional target of miR-153. Luciferase reporter assay demonstrated that miR-153 directly targeted 3′UTR of ADAM19, and correlation analysis revealed an inverse correlation between miR-153 and ADAM19 mRNA levels in clinical NSCLC tissues. Knockdown of ADAM19 inhibited migration and invasion of NSCLC cells which was similar with effects of overexpression of miR-153, while overexpression of ADAM19 attenuated the function of miR-153 in NSCLC cells. Taken together, our results highlight the significance of miR-153 and ADAM19 in the development and progression of NSCLC.

  20. The effect of CCL19/CCR7 on the proliferation and migration of cell in prostate cancer.

    Science.gov (United States)

    Peng, Cheng; Zhou, Keliang; An, Sensheng; Yang, Jie

    2015-01-01

    Multiple studies have shown that CC motif chemokine ligand 19 (CCL19) promotes cell proliferation in several human cancers. In this study, we investigated the clinical significance of CCL19 and its specific receptor CCR7 and its function in our large collection of prostate samples. Between August 2000 and December 2013, 108 patients with histologically confirmed prostate cancer (PCa) and 80 with benign prostate hyperplasia (BPH) were recruited into the study. Quantitative RT-PCR immunohistochemistry analyses were used to quantify CCL19 and CCR7 expression in PCa cell lines and clinical samples. The functional role of CCL19 in PCa cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and invasion. The positive rate of CCL19 staining was 87.04 % (94/108) in 108 cases of prostatic carcinoma and 16.25 % (13/80) in 80 cases of BPH, and high expression of CCR7 was observed in 83.33 % (90/108) of the PCa tissues versus (17.50 %; 14/80) of the BPH tissues, the difference of CCL19 and CCR7 expression between two groups was statistically significant, respectively. The results were confirmed by quantitative real-time PCR. CCL19 and CCR7 were significantly elevated in all five PCa cell lines when compared to the RWPE-1 cells. Silencing of CCL19 inhibited the proliferation of DU-145 cells which have a relatively high level of CCL19 in a time- and concentration-dependent manner, and the invasion and migration of DU-145 cells were distinctly suppressed. Our data suggest that the pathogenesis of human PCa maybe mediated by the CCL19/CCR7 axis, and CCL19 inhibition treatment may provide a promising strategy for the anti-tumor therapy of PCa.

  1. Calcitriol inhibits Ether-a go-go potassium channel expression and cell proliferation in human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Becerra, Rocio [Department of Reproductive Biology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico); Diaz, Lorenza, E-mail: lorenzadiaz@gmail.com [Department of Reproductive Biology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico); Camacho, Javier [Department of Pharmacology, Centro de Investigacion y de Estudios Avanzados, Instituto Politecnico Nacional, Av. Instituto Politecnico Nacional 2508, San Pedro Zacatenco 07360, Mexico, D.F. (Mexico); Barrera, David; Ordaz-Rosado, David; Morales, Angelica [Department of Reproductive Biology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico); Ortiz, Cindy Sharon [Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico); Avila, Euclides [Department of Reproductive Biology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico); Bargallo, Enrique [Department of Breast Tumors, Instituto Nacional de Cancerologia, Av. San Fernando No. 22, Tlalpan 14080, Mexico, D.F. (Mexico); Arrecillas, Myrna [Department of Pathology, Instituto Nacional de Cancerologia, Av. San Fernando No. 22, Tlalpan 14080, Mexico, D.F. (Mexico); Halhali, Ali; Larrea, Fernando [Department of Reproductive Biology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, Tlalpan 14000 Mexico, D.F. (Mexico)

    2010-02-01

    Antiproliferative actions of calcitriol have been shown to occur in many cell types; however, little is known regarding the molecular basis of this process in breast carcinoma. Ether-a-go-go (Eag1) potassium channels promote oncogenesis and are implicated in breast cancer cell proliferation. Since calcitriol displays antineoplastic effects while Eag1 promotes tumorigenesis, and both factors antagonically regulate cell cycle progression, we investigated a possible regulatory effect of calcitriol upon Eag1 as a mean to uncover new molecular events involved in the antiproliferative activity of this hormone in human breast tumor-derived cells. RT real-time PCR and immunocytochemistry showed that calcitriol suppressed Eag1 expression by a vitamin D receptor (VDR)-dependent mechanism. This effect was accompanied by inhibition of cell proliferation, which was potentiated by astemizole, a nonspecific Eag1 inhibitor. Immunohistochemistry and Western blot demonstrated that Eag1 and VDR abundance was higher in invasive-ductal carcinoma than in fibroadenoma, and immunoreactivity of both proteins was located in ductal epithelial cells. Our results provide evidence of a novel mechanism involved in the antiproliferative effects of calcitriol and highlight VDR as a cancer therapeutic target for breast cancer treatment and prevention.

  2. Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer.

    Science.gov (United States)

    Anjomshoaa, A; Lin, Y-H; Black, M A; McCall, J L; Humar, B; Song, S; Fukuzawa, R; Yoon, H-S; Holzmann, B; Friederichs, J; van Rij, A; Thompson-Fawcett, M; Reeve, A E

    2008-09-16

    The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options.

  3. Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.

    Science.gov (United States)

    Zhao, Chunyan; Qiao, Yichun; Jonsson, Philip; Wang, Jian; Xu, Li; Rouhi, Pegah; Sinha, Indranil; Cao, Yihai; Williams, Cecilia; Dahlman-Wright, Karin

    2014-07-15

    Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

  4. Effects of eicosapentaenoic acid and docosahexaenoic acid on prostate cancer cell migration and invasion induced by tumor-associated macrophages.

    Directory of Open Access Journals (Sweden)

    Cheng-Chung Li

    Full Text Available Eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA are the major n-3 polyunsaturated fatty acids (PUFAs in fish oil that decrease the risk of prostate cancer. Tumor-associated macrophages (TAMs are the main leukocytes of intratumoral infiltration, and increased TAMs correlates with poor prostate cancer prognosis. However, the mechanism of n-3 PUFAs on prostate cancer cell progression induced by TAMs is not well understood. In this study, we investigated the effects of EPA and DHA on modulating of migration and invasion of prostate cancer cells induced by TAMs-like M2-type macrophages. PC-3 prostate cancer cells were pretreated with EPA, DHA, or the peroxisome proliferator-activated receptor (PPAR-γ antagonist, GW9662, before exposure to conditioned medium (CM. CM was derived from M2-polarized THP-1 macrophages. The migratory and invasive abilities of PC-3 cells were evaluated using a coculture system of M2-type macrophages and PC-3 cells. EPA/DHA administration decreased migration and invasion of PC-3 cells. The PPAR-γ DNA-binding activity and cytosolic inhibitory factor κBα (IκBα protein expression increased while the nuclear factor (NF-κB p65 transcriptional activity and nuclear NF-κB p65 protein level decreased in PC-3 cells incubated with CM in the presence of EPA/DHA. Further, EPA/DHA downregulated mRNA expressions of matrix metalloproteinase-9, cyclooxygenase-2, vascular endothelial growth factor, and macrophage colony-stimulating factor. Pretreatment with GW9662 abolished the favorable effects of EPA/DHA on PC-3 cells. These results indicate that EPA/DHA administration reduced migration, invasion and macrophage chemotaxis of PC-3 cells induced by TAM-like M2-type macrophages, which may partly be explained by activation of PPAR-γ and decreased NF-κB p65 transcriptional activity.

  5. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    Science.gov (United States)

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent.

  6. Knockdown of STAT3 by iRNA Inhibiting Migration and Invasion of Epithelial Ovarian Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    LI Qin-hua; ZHU Ji-hong; LIU Lei; YUE Ying

    2012-01-01

    Signal transducer and activator of transcription 3(STAT3) is a dual functional transcription factor with the functions of signal transduction and transcription regulation.It is reported that the expression of STAT3 in ovarian cancer is significantly higher and STAT3 can facilitate ovarian cancer growth and metastasis.To clarify the definite effect and molecular mechanism of STAT3 involved in ovarian cancer growth and metastasis,STAT3 expression was significantly downregulated by transfeeting ovarian cancer model SK-OV-3 cells with the plasmid vector which express specific RNAi that targets human STAT3.The downregulated STAT3 not only decreased the invasion and migration but also inhibited the proliferation of SK-OV-3 cells.Western blot assay shows that the expression of vascular endothelial growth factor(VEGF) and that of Survivin were reduced in the cells with the plasma vector expressing specific RNAi that targets human STATY These results demonstrate that STAT3 involved in the invasion and migration of SK-OV-3 regulates the expression of VEGF and Survivin.In addition,VEGF and Survivin could play an important role in ovarian cancer growth and metastasis.

  7. Loss of GM130 in breast cancer cells and its effects on cell migration, invasion and polarity.

    Science.gov (United States)

    Baschieri, Francesco; Uetz-von Allmen, Edith; Legler, Daniel F; Farhan, Hesso

    2015-01-01

    Spatially distinct pools of the small GTPase Cdc42 were observed, but the major focus of research so far has been to investigate its signaling at the plasma membrane. We recently showed that the Golgi pool of Cdc42 is relevant for cell polarity and that it is regulated by GM130, a Golgi matrix protein. Loss of GM130 abrogated cell polarity and consistent with the notion that polarity is frequently impaired in cancer, we found that GM130 is downregulated in colorectal cancer. Whether the loss of GM130 solely affects polarity, or whether it affects other processes relevant for tumorigenesis remains unclear. In a panel of breast cancer cells lines, we investigated the consequences of GM130 depletion on traits of relevance for tumor progression, such as survival, proliferation, adhesion, migration and invasion. We show that cellular assays that depend on polarity, such as chemotaxis and wound scratch assays, are only of limited use to investigate the role of polarity modulators in cancer. Depletion of GM130 increases cellular velocity and increases the invasiveness of breast cancer cells, therefore supporting the view that alterations of polarity contribute to tumor progression.

  8. NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer.

    Directory of Open Access Journals (Sweden)

    Chenfei Kong

    Full Text Available Epithelial to mesenchymal transition (EMT plays an important role in many biological processes. The latest studies revealed that aggressive breast cancer, especially the triple-negative breast cancer (TNBC subtype was frequently associated with apparent EMT, but the mechanisms are still unclear. NEDD9/HEF1/Cas-L is a member of the Cas protein family and was identified as a metastasis marker in multiple cancer types. In this study, we wished to discern the role of NEDD9 in breast cancer progression and to investigate the molecular mechanism by which NEDD9 regulates EMT and promotes invasion in triple-negative breast cancer. We showed that expression of NEDD9 was frequently upregulated in TNBC cell lines, and in aggressive breast tumors, especially in TNBC subtype. Knockdown of endogenous NEDD9 reduced the migration, invasion and proliferation of TNBC cells. Moreover, ectopic overexpression of NEDD9 in mammary epithelial cells led to a string of events including the trigger of EMT, activation of ERK signaling, increase of several EMT-inducing transcription factors and promotion of their interactions with the E-cadherin promoter. Data presented in this report contribute to the understanding of the mechanisms by which NEDD9 promotes EMT, and provide useful clues to the evaluation of the potential of NEDD9 as a responsive molecular target for TNBC chemotherapy.

  9. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.

    Science.gov (United States)

    Pradeep, C-R; Zeisel, A; Köstler, W J; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

    2012-08-01

    The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.

  10. Early effects of preoperative radiation therapy for invasive bladder cancer

    Energy Technology Data Exchange (ETDEWEB)

    Isaka, Shigeo; Igarashi, Tatsuo; Ito, Haruo

    1983-10-01

    22 patients with high grade invasive bladder cancer were treated with preoperative radiation therapy (910 rad by fast neutron or 3000 rad by X ray during 2 weeks) followed by radical cystectomy and urinary diversion. 62.5 % of patients showed reduction in tumor size more than 50% evaluated by cystogram. Stage down was observed in 38% of patients compared between clinical and pathological stage. Histopathological effect of GII or GIII, according to the criteria described by Ohboshi, was noticed in 79 % of the patients. Better effect seemed to be obtained in fast neutron treated group than in X ray group. 19 patients received curative surgery, and 18 patients were alive without recurrence after 10 months (mean observed term). One died from lung metastasis 4.5 months after surgery. 50% of the patients complained of side effects of irradiation although they were tolerable, and 32% of the patients had major complications of surgery.

  11. Novel Simulation Model of Non-Muscle Invasive Bladder Cancer

    DEFF Research Database (Denmark)

    Patel, Sanjay R; Dinh, Tuan; Noah-Vanhoucke, Joyce

    2015-01-01

    Introduction: There have been no randomized controlled trials (RCTs) evaluating the clinical or economic benefit of mitomycin C intravesical therapy vs. radical cystectomy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). We used the Archimedes computational model to simulate...... RCT comparing radical cystectomy versus intravesical mitomycin C (MMC) therapy to evaluate the clinical and economic outcomes for BCG-refractory NMIBC as well demonstrate the utility of computer based models to simulate a clinical trial. Methods: The Archimedes model was developed to generate...... and is more cost-effective when compared to those undergoing MMC. Simulation of clinical trials using computational models similar to the Archimedes model can overcome shortcomings of real-world clinical trials and may prove useful in the face of current medical cost-conscious era....

  12. Emerging intravesical therapies for management of nonmuscle invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    Jeffrey J Tomaszewski

    2010-05-01

    Full Text Available Jeffrey J Tomaszewski, Marc C SmaldoneDepartment of Urology, University of Pittsburgh School of Medicine, Pennsylvania, USAAbstract: Transitional cell carcinoma (TCC is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer (NMIBC. Intravesical bacillus Calmette-Guerin (BCG is the most effective agent for preventing disease recurrence, and the only therapy able to inhibit disease progression. However, recurrence rates as high as 30% and significant local and systemic toxicity have led to increased interest in alternative intravesical therapies. In patients refractory or intolerant to BCG, BCG-interferon α2b, gemcitabine, and anthracyclines (doxorubicin, epirubicin, valrubicin have demonstrated durable clinical responses. Phase I trials investigating alternative cytotoxic agents, such as apaziquone, taxanes (docetaxel, paclitaxel, and suramin are reporting promising data. Novel immunomodulating agents have demonstrated promise as efficacious alternatives in patients refractory to BCG. Optimization of existing chemotherapeutic regimens using hyperthermia, photodynamic therapy, magnetically-targeted carriers, and liposomes remains an area of active investigation. Despite enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and selected patients with naïve T1 tumors and aggressive features. This report provides a comprehensive review of contemporary intravesical therapy for NMIBC and refractory NMIBC, with an emphasis on emerging agents and novel treatment modalities.Keywords: transitional cell carcinoma, nonmuscle, invasive, intravesical therapy, BCG

  13. GENETIC RISK MARKERS FOR SUPERFICIAL AND INVASIVE BLADDER CANCER

    Directory of Open Access Journals (Sweden)

    V. N. Pavlov

    2011-01-01

    Full Text Available To reveal possible associations of the polymorphic variants of the cytochrome P450 and enzymes glutathione-S-transferase genes with the risk for bladder cancer (BC, the authors analyzed the frequency of genotypes and alleles at the polymorphic loci of the CYP1A1 (A2454G, GSTM1 (del, and GSTP1 (A313G genes in 208 patients diagnosed as having BC (104 patients with invasive BC and 104 with superficial BC and in 367 patients without identified oncopathology. The *1A*2C (OR = 3.42 and *2C*2С (OR = 6.98 genotypes, *2C (OR = 3.73 allele of the CYP1A1 gene and the GG (OR = 2.53 genotype of the GSTP1 gene were ascertained to be genetic markers for a risk for BC. The presence of the *2C (OR = 1.69 allele of the CYP1A1 gene, the G (OR = 2.40 allele and the AG genotype (OR = 2.40 of the GSTP1 gene was associated with the invasive forms of BC. There were no substantial differences in the distribution of the frequency of genotypes of the GSTM1 gene between the samples of patients and healthy individuals.

  14. Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Xiangyang [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330006 (China); State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047 (China); Wang, Yao [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Liu, Chengmei [State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047 (China); Lu, Quqin [Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006 (China); Liu, Tao [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Chen, Guoan [Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006 (China); Rao, Hai [Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Luo, Shiwen, E-mail: shiwenluo@ncu.edu.cn [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China)

    2014-08-01

    Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233–620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer. - Highlights: • HSP90β protects FAK from degradation by the ubiquitin-proteasome pathway. • Inhibition of HSP90β or FAK attenuates tumorigenesis of breast cancer cells. • Genetic repression of HSP90β or FAK inhibits tumor cell migration and proliferation. • Inhibition of HSP90β or FAK interferes cell invasion and cytoskeleton.

  15. Role of Wnt Co-receptor LRP6 in Triple Negative Breast Cancer Cell Migration and Invasion.

    Science.gov (United States)

    Ma, Jinlu; Lu, Wenyan; Chen, Dongquan; Xu, Bo; Li, Yonghe

    2017-03-01

    The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential Wnt co-receptor of the Wnt/β-catenin signaling pathway. Although studies have shown an increased expression of LRP6 in several types of cancer, its function in tumor development and progression remains to be elucidated. We herein demonstrated that LRP6 expression is up-regulated in human triple negative breast cancer (TNBC) patients and human TNBC cell lines, and that knockdown of LRP6 expression and treatment of recombinant Mesd protein (a specific inhibitor of LRP6) significantly decreased cell migration and invasion of TNBC MDA-MB-231 and BT549 cells. Interestingly, the effects of LRP6 knockdown and Mesd treatment on TNBC cell migration and invasion were more prominent than on TNBC cell proliferation/viability. Mechanistically, LRP6 knockdown and Mesd treatment inhibited Wnt/β-catenin signaling and decreased the expression of S100A4, a mediator of cancer metastasis and a specific target of Wnt/β-catenin signaling, in TNBC cells. Together, our data suggest that LRP6 promotes TNBC cell migration and invasion by regulating the expression and function of S100A4 via the Wnt/β-catenin signaling pathway. This article is protected by copyright. All rights reserved.

  16. Unexpected Discovery of Dichloroacetate Derived Adenosine Triphosphate Competitors Targeting Pyruvate Dehydrogenase Kinase To Inhibit Cancer Proliferation.

    Science.gov (United States)

    Zhang, Shao-Lin; Hu, Xiaohui; Zhang, Wen; Tam, Kin Yip

    2016-04-14

    Pyruvate dehydrogenase kinases (PDKs) have recently emerged as an attractive target for cancer therapy. Herein, we prepared a series of compounds derived from dichloroacetate (DCA) which inhibited cancer cells proliferation. For the first time, we have successfully developed DCA derived inhibitors that preferentially bind to the adenosine triphosphate (ATP) pocket of PDK isoform 1 (PDK1).

  17. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion

    Directory of Open Access Journals (Sweden)

    Liu Jinsong

    2005-02-01

    Full Text Available Abstract Background Insulin-like growth factor binding protein 2 (IGFBP2 is overexpressed in ovarian malignant tissues and in the serum and cystic fluid of ovarian cancer patients, suggesting an important role of IGFBP2 in the biology of ovarian cancer. The purpose of this study was to assess the role of increased IGFBP2 in ovarian cancer cells. Results Using western blotting and tissue microarray analyses, we showed that IGFBP2 was frequently overexpressed in ovarian carcinomas compared with normal ovarian tissues. Furthermore, IGFBP2 was significantly overexpressed in invasive serous ovarian carcinomas compared with borderline serous ovarian tumors. To test whether increased IGFBP2 contributes to the highly invasive nature of ovarian cancer cells, we generated IGFBP2-overexpressing cells from an SKOV3 ovarian cancer cell line, which has a very low level of endogenous IGFBP2. A Matrigel invasion assay showed that these IGFBP2-overexpressing cells were more invasive than the control cells. We then designed small interference RNA (siRNA molecules that attenuated IGFBP2 expression in PA-1 ovarian cancer cells, which have a high level of endogenous IGFBP2. The Matrigel invasion assay showed that the attenuation of IGFBP2 expression indeed decreased the invasiveness of PA-1 cells. Conclusions We therefore showed that IGFBP2 enhances the invasion capacity of ovarian cancer cells. Blockage of IGFBP2 may thus constitute a viable strategy for targeted cancer therapy.

  18. Human Papillomavirus Genotype Distribution in Invasive Cervical Cancer in Pakistan.

    Science.gov (United States)

    Loya, Asif; Serrano, Beatriz; Rasheed, Farah; Tous, Sara; Hassan, Mariam; Clavero, Omar; Raza, Muhammad; De Sanjosé, Silvia; Bosch, F Xavier; Alemany, Laia

    2016-07-30

    Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0-91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV-DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7-83.3), compared to Asia (71.6%; 69.9-73.4) and worldwide (70.8%; 69.9-71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9-15.7 vs. 19.8%; 18.3-21.3 and 18.5%; 17.7-19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases.

  19. p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation.

    Directory of Open Access Journals (Sweden)

    Michelle K Y Siu

    Full Text Available p21-activated kinases (Paks are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028 and cytoplasmic p-Pak2 (P = 0.048 expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05. Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001. On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05 while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05. Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026. Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα and progestogen receptor (PR expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic

  20. A Milk Protein, Casein, as a Proliferation Promoting Factor in Prostate Cancer Cells

    Science.gov (United States)

    Park, Sung-Woo; Kim, Joo-Young; Kim, You-Sun; Lee, Sang Jin; Chung, Moon Kee

    2014-01-01

    Purpose Despite most epidemiologic studies reporting that an increase in milk intake affects the growth of prostate cancer, the results of experimental studies are not consistent. In this study, we investigated the proliferation of prostate cancer cells treated with casein, the main protein in milk. Materials and Methods Prostate cancer cells (LNCaP and PC3), lung cancer cells (A459), stomach cancer cells (SNU484), breast cancer cells (MCF7), immortalized human embryonic kidney cells (HEK293), and immortalized normal prostate cells (RWPE1) were treated with either 0.1 or 1 mg/mL of α-casein and total casein extracted from bovine milk. Treatments were carried out in serum-free media for 72 hours. The proliferation of each cell line was evaluated by an 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Results α-Casein and total casein did not affect the proliferations of RWPE1, HEK293, A459, SNU484, MCF7, HEK293, or RWPE1 cells. However, PC3 cells treated with 1 mg/mL of α-casein and casein showed increased proliferation (228% and 166%, respectively), and the proliferation of LNCaP cells was also enhanced by 134% and 142%, respectively. The proliferation mechanism of α-casein in PC3 and LNCaP cells did not appear to be related to the induction of Insulin-like growth factor-1 (IGF-1), since the level of IGF-1 did not change upon the supplementation of casein. Conclusions The milk protein, casein, promotes the proliferation of prostate cancer cells such as PC3 and LNCaP. PMID:25237656

  1. Regulation of deleted in liver cancer-1 gene domains on the proliferation of human colon cancer HT29 cell

    Institute of Scientific and Technical Information of China (English)

    吴平平

    2013-01-01

    Objective To study the role of deleted in liver cancer-1(DLC-1) gene main domains on the regulation of hu-man colon cancer HT29 cell proliferation. Methods Subcloning recombinant plasmid vectors with Rho GTPase activating protein(RhoGAP),sterile alpha motif(SAM)

  2. The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein

    Energy Technology Data Exchange (ETDEWEB)

    Bruyere, Emilie; Jonckheere, Nicolas; Frenois, Frederic [Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 ' Mucins, Epithelial Differentiation and Carcinogenesis' , rue Polonovski, 59045 Lille Cedex (France); Universite Lille-Nord de France, 1 place de Verdun, 59045 Lille Cedex (France); Mariette, Christophe [Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 ' Mucins, Epithelial Differentiation and Carcinogenesis' , rue Polonovski, 59045 Lille Cedex (France); Universite Lille-Nord de France, 1 place de Verdun, 59045 Lille Cedex (France); Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, 1 place de Verdun, 59045 Lille Cedex (France); Van Seuningen, Isabelle, E-mail: isabelle.vanseuningen@inserm.fr [Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 ' Mucins, Epithelial Differentiation and Carcinogenesis' , rue Polonovski, 59045 Lille Cedex (France); Universite Lille-Nord de France, 1 place de Verdun, 59045 Lille Cedex (France)

    2011-09-23

    Highlights: {yields} Loss of MUC4 reduces proliferation of esophageal cancer cells. {yields} MUC4 inhibition impairs migration of esophageal cancer cells but not their invasion. {yields} Loss of MUC4 significantly reduces in vivo tumor growth. {yields} Decrease of S100A4 induced by MUC4 inhibition impairs proliferation and migration. -- Abstract: MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.

  3. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.

    Science.gov (United States)

    Ramer, Robert; Merkord, Jutta; Rohde, Helga; Hinz, Burkhard

    2010-04-01

    Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.

  4. Wls promotes the proliferation of breast cancer cells via Wnt signaling.

    Science.gov (United States)

    Lu, Dong; Li, Ying; Liu, Qing-Ru; Wu, Qi; Zhang, Hao; Xie, Peng; Wang, Qingling

    2015-05-01

    The Wnt secretion protein Wntless (Wls)/GPR177 has been reported to be involved in the development of several human cancers. However, the biological significance of Wls in breast cancer progression has not been clarified. In this study, we show for the first time that Wls is an important molecule related to breast cancer. We find that Wls expression is markedly increased in clinical breast tumors compared with adjacent noncancerous tissues. Downregulation of Wls by short-hairpin RNA severely suppressed the proliferation of breast cancer cells. Wls is a core Wnt signaling component, and we show that knockdown of Wls is sufficient to inhibit Wnt secretion and its downstream signaling. Taken together, these results indicate that Wls contributes to the proliferation of breast cancer cells by regulating Wnt signaling. Therefore, Wls could be a novel therapeutic target for inhibiting cell growth in breast cancer.

  5. PSF3 marks malignant colon cancer and has a role in cancer cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Nagahama, Yumi [Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ueno, Masaya [Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095 (United States); Haraguchi, Naotsugu; Mori, Masaki [Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871 (Japan); Takakura, Nobuyuki, E-mail: ntakaku@biken.osaka-u.ac.jp [Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2010-02-05

    PSF3 (partner of Sld five 3) is a member of the tetrameric complex termed GINS, composed of SLD5, PSF1, PSF2, and PSF3, and well-conserved evolutionarily. Previous studies suggested that some GINS complex members are upregulated in cancer, but PSF3 expression in colon carcinoma has not been investigated. Here, we established a mouse anti-PSF3 antibody, and examined PSF3 expression in human colon carcinoma cell lines and colon carcinoma specimens. We found that PSF3 is expressed in the crypt region in normal colonic mucosa and that many PSF3-positive cells co-expressed Ki-67. This suggests that PSF3-positivity of normal mucosa is associated with cell proliferation. Expression of the PSF3 protein was greater in carcinoma compared with the adjacent normal mucosa, and even stronger in high-grade malignancies, suggesting that it may be associated with colon cancer progression. PSF3 gene knock-down in human colon carcinoma cell lines resulted in growth inhibition characterized by delayed S-phase progression. These results suggest that PSF3 is a potential biomarker for diagnosis of progression in colon cancer and could be a new target for cancer therapy.

  6. Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Abir Mukherjee

    2015-09-01

    Full Text Available Lysophosphatidic acid (LPA, a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2 was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1 and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.

  7. Bladder cancer: utility of MRI in detection of occult muscle-invasive disease

    Energy Technology Data Exchange (ETDEWEB)

    Rosenkrantz, Andrew B. [Dept. of Radiology, NYU Langone Medical Center, New York (United States)], E-mail: Andrew.rosenkrantz@nyumc.org; Mussi, Thais C. [Dept. of Radiology, NYU Langone Medical Center, New York (United States); Hospital Israelita Albert Einstein, Sao Paulo (Brazil); Melamed, Jonathan [Dept. of Pathology, NYU Langone Medical Center, New York (United States); Taneja, Samir S.; Huang, William C. [Dept. of Urology, Div. of Urologic Oncology, NYU Langone Medical Center, New York (United States)

    2012-07-15

    Background. The presence of muscularis propria invasion by bladder cancer is a key factor in prognosis and treatment decisions, although may be missed by biopsy due to sampling error. MRI has shown potential for detection of muscle invasion but has not specifically been evaluated for this purpose in the setting of bladder cancer patients without evidence of muscle invasion on initial biopsy. Purpose. To evaluate the role of MRI in detection of muscularis propria invasion by bladder cancer following a pathologic diagnosis of non-invasive tumor. Material and Methods. This retrospective study included 23 patients who underwent pelvic MRI following a pathologic diagnosis of bladder cancer without muscularis propria invasion and in whom additional histologic evaluation was performed following MRI. Two radiologists in consensus reviewed T2-weighted images to identify those cases suspicious for muscle invasion on MRI. The radiologists identified whether cases suspicious for invasion demonstrated disruption of the T2-hypointense muscularis layer of the bladder wall, peri-vesical fat stranding, and peri-vesical soft tissue nodularity. Findings were compared with pathologic results obtained after MRI. Results. Suspicion was raised for muscle inva