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Huang C.,Shanghai Key Laboratory of Pancreas Disease | Huang C.,Shanghai JiaoTong University | Yang G.,Taian Central Hospital | Jiang T.,Shanghai Key Laboratory of Pancreas Disease | And 4 more authors.
World Journal of Gastroenterology | Year: 2011

AIM: To evaluate the effect of RNA interference (RNAi) mediated silence of signal transduction and activation of transcription (STAT)3 on the growth of human pancreatic cancer cells both in vitro and in vivo.METHODS: STAT3 specific shRNA was used to silence the expression of STAT3 in pancreatic cancer cell line SW1990. The anti-growth effects of RNAi against STAT3 were studied in vitro and in experimental cancer xenografts in nude mice. The potential pathways involved in STAT3 signaling were detected using reverse transcription polymerase chain reaction and western blotting. RESULTS: The expression of the STAT3 was inhibited using RNAi in SW1990 cells. RNAi against STAT3 inhibited cell proliferation, induced cell apoptosis and significantly reduced the levels of CyclinD1 and Bcl-xL when compared with parental and control vector-transfected cells. In vivo experiments showed that RNAi against STAT3 inhibited the tumorigenicity of SW1990 cells and significantly suppressed tumor growth when it was directly injected into tumors. CONCLUSION: STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and silence of STAT3 gene using RNAi technique may be a novel therapeutic option for treatment of pancreatic cancer. © 2011 Baishideng. All rights reserved. Source


Huang C.,Shanghai JiaoTong University | Huang C.,Shanghai Key Laboratory of Pancreas Disease | Huang R.,Fudan University | Chang W.,Soochow University of China | And 6 more authors.
Neoplasma | Year: 2012

Signal transducers and activators of transcription 3 (STAT3) is a central cytoplasmic transcription factor and regulates a number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis.This study aims to investigate the expression of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma and their relations to the clinicopathological features, tumor angiogenesis and prognosis. In the present study, the expression of pSTAT3, VEGF and VEGF-C and microvascular density (MVD) were examined via immunohistochemistry. The clinicopathological information was collected and patients were regularly followed up. The relationship between the parameters and the clinicopathological features were analyzed, and the univariate and multivariate prognostic factors were also analyzed. The expression of pSTAT3 in tumor tissues was significantly higher in contrast to that in normal tissues, and pSTAT3 was related to VEGF and VEGF-C expression, MVD, tumor size, lymphogenous status and TNM staging (P<0.05). Survival analysis suggested that tumor size, TNM staging, pSTAT3 and VEGF expression were risk factors of prognosis, but no independent factors were found. We concluded that pSTAT3, which was a risk factor of prognosis, was abnormally expressed in pancreatic adenocarcinoma and related to tumor size, TNM staging and lymphatic metastasis. pSTAT3 may promote tumor angiogenesis via up-regulating VEGF on protein and even gene levels, and enhance the early lymphatic metastasis through VEGF-C. Better understanding of STAT3 signaling pathways in angiogenesis may contribute to the development of novel therapeutic strategies in angiogenesis and metastasis of pancreatic cancer. Source


Huang C.,Shanghai JiaoTong University | Huang C.,Shanghai Key Laboratory of Pancreas Disease | Yang G.,Taian Central Hospital | Jiang T.,Shanghai JiaoTong University | And 6 more authors.
Neoplasma | Year: 2011

Aberrant Signal transducers and activators of transcription-3 (STAT3) signaling pathway is a major cause of tumor invasion and metastasis; the underlying mechanisms, however, are not well understood. Epithelial-mesenchymal transition (EMT) is an early event that occurs during invasion of cancers of an epithelial origin. It remains elusive whether STAT3signaling pathway is involved in EMT. The objective of this study was to evaluate the effect of blockage of STAT3 signaling pathway on IL-6 inducing EMT in human pancreatic cancer cells. We used SW1990 cells and induced them to undergo EMT by exposing these cells to soluble factor interleukin-6 (IL-6). The expression of Snail, E-cadherin, and Twist was detected by reverse transcription-PCR, real-time PCR, and Western blotting. Cell morphology was observed under invert phase-contrast microscope.The invasion ability was determined by cell invasion assay in vitro. Our results demonstrated that STAT3 signaling pathway was involved in pancreatic cancer cell invasion and EMT, and that EMT induced by IL-6 was associated with the activation of STAT3 signaling pathway. Inhibition of STAT3 signaling pathway by silencing of the STAT3 gene with RNAi blocked STAT3 signaling pathway activation and suppressed EMT in pancreatic cancer cells. Collectively, the STAT3 signaling pathway plays an important role in the process of EMT of pancreatic cancer by regulating Snail gene expression. Better understanding of STAT3 signaling pathways in EMT may contribute to development of novel therapeutic strategies in invasion and metastasis of pancreatic cancer. Source


Huang C.,Shanghai JiaoTong University | Huang C.,Shanghai Key Laboratory of Pancreas Disease | Jiang T.,Shanghai JiaoTong University | Zhu L.,Shanghai JiaoTong University | And 6 more authors.
International Journal of Oncology | Year: 2011

Signal transducers and activators of transcription 3 (STAT3) is a central cytoplasmic transcription factor that is activated by phosphorylation in response to extracellular signals and oncogenes. STAT3 regulates a number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis, and tumor cell evasion of the immune system. Our studies demonstrated that constitutively activated STAT3 plays an important role in the angiogenesis of pancreatic cancer. The objective of this study was to evaluate the potential use of RNA interference (RNAi) to knock down the STAT3 gene and the effect on angiogenesis of human pancreatic cancer cells in vitro and in vivo. We stably inhibited the expression of STAT3 and phosphorylated STAT3 (p-STAT3) using RNAi in the SW1990 pancreatic cancer cell line. Furthermore, RNAi for STAT3 inhibited STAT3-induced HUVEC cell migration and cell proliferation, and significantly suppressed the levels of secreted vascular endothelial growth factor (VEGF) and matrix metalloproteinases-2 (MMP-2) of SW1990 cells. In vivo experiments showed that RNAi for STAT3 significantly suppressed tumor growth and angiogenesis of SW1990 cells. Furthermore, silencing the STAT3 gene in SW1990 cells by RNAi also led to a decrease of VEGF and MMP-2 at the mRNA and protein levels. Collectively, these results demonstrate that the STAT3 signaling pathway plays an important role in the angiogenesis of pancreatic cancer and that knockdown of the STAT3 gene using the RNAi technique may be a novel therapeutic option for the treatment of pancreatic cancer. Source


Li H.d.,Shanghai JiaoTong University | Li H.d.,Shanghai Key Laboratory of Pancreas Disease | Huang C.,Shanghai JiaoTong University | Huang C.,Shanghai Key Laboratory of Pancreas Disease | And 7 more authors.
PLoS ONE | Year: 2011

Aims: Transducer and activator of transcription-3 (STAT3) plays an important role in tumor cell invasion and metastasis. The aim of the present study was to investigate the effects of STAT3 knockdown in nude mouse xenografts of pancreatic cancer cells and underlying gene expression. Methods: A STAT3 shRNA lentiviral vector was constructed and infected into SW1990 cells. qRT-PCR and western immunoblot were performed to detect gene expression. Nude mouse xenograft assays were used to assess changes in phenotypes of these stable cells in vivo. HE staining was utilized to evaluate tumor cell invasion and immunohistochemistry was performed to analyze gene expression. Results: STAT3 shRNA successfully silenced expression of STAT3 mRNA and protein in SW1990 cells compared to control cells. Growth rate of the STAT3-silenced tumor cells in nude mice was significantly reduced compared to in the control vector tumors and parental cells-generated tumors. Tumor invasion into the vessel and muscle were also suppressed in the STAT3-silenced tumors compared to controls. Collagen IV expression was complete and continuous surrounding the tumors of STAT3-silenced SW1990 cells, whereas collagen IV expression was incomplete and discontinuous surrounding the control tumors. Moreover, microvessel density was significantly lower in STAT3-silenced tumors than parental or control tumors of SW1990 cells. In addition, MMP-7 expression was reduced in STAT3-silenced tumors compared to parental SW1990 xenografts and controls. In contrast, expression of IL-1β and IgT7α was not altered. Conclusion: These data clearly demonstrate that STAT3 plays an important role in regulation of tumor growth, invasion, and angiogenesis, which could be act by reducing MMP-7 expression in pancreatic cancer cells. © 2011 Li et al. Source

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