RNA interference‐mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells

Abstract

Signal transducers and activators of transcription-3 (STAT3), a central cytoplasmic transcription factor, is frequently overexpressed and constitutively activated by tyrosine during malignant transformation. The overexpression and phosphorylation of STAT3 in pancreatic cancer has been described only recently, but the roles and mechanism still remain unclear. In this study, we elucidate the significance of the STAT3 signaling pathway in metastatic potentials of pancreatic cancer. We stably silence the expression of the STAT3 and p-STAT3 by using RNA interference (RNAi) in the pancreatic cancer cell line SW1990, and then reduce its invasion capacity in vitro and metastasis capacity in vivo compared to parental cells or cells tansfected with a control vector. Furthermore, silencing SW1990 cells with the STAT3 gene by RNAi also led to a decrease of matrix metalloproteinases-2 (MMP-2) and vascular endothelial growth factor (VEGF) at the mRNA and protein level. Collectively, these studies suggest that activation of the STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and that silence of the STAT3 gene with RNAi may be a useful anti-invasive therapeutic option in pancreatic cancer. (Cancer Sci 2007; 98: 1099-1106) P ancreatic cancer remains a widespread and difficult disease to treat with an overall 5-year survival of less than 5%. Thus, it represents one of the leading causes of cancer deaths in industrialized countries despite advances in medical therapy and surgical techniques.(1,2) Because of the insidious and aggressive natural history of the disease, most patients have local or metastatic spread at the time of presentation that precludes a resection. Therefore, less than 10% of cases constitute candidates for surgical resection at the time of diagnosis. Even among patients undergoing a potentially curative resection, the longterm outcome remains unsatisfactory due to early recurrence and metastatic disease.(3) Effective systemic therapy capable of reversing the aggressive biology of this disease is currently not available. Thus, understanding the molecular mechanisms underlying the aggressive biology of pancreatic cancer is one of the most important issues for this disease.STAT3, a member of the signal transduction and activation of transcription (STAT) family, is a central cytoplasmic transcription factor that is activated by phosphorylation of a conserved tyrosine residue in response to extracellular signals and oncogenes. Once tyrosine is phosphorylated, two STAT3 monomers form dimers through reciprocal phosphotyrosine-SH2 interactions. The dimers are phosphorylated STAT3 (p-STAT3), which translocate to the nucleus and bind to cognate DNA sequences, regulate the transcription of target genes and modulate fundamental cellular processes, such as proliferation and differentiation.(4,5) Lines of evidence demonstrate that elevated activity of STAT3 has been found frequently in a wide variety of human tumors including pancreatic cancer (6)(7)(8)(9) and STAT3 regulates a number...

Inhibition of STAT3 by RNA interference suppresses angiogenesis in colorectal carcinoma

“…In breast cancer, gastric cancer and hepatocellular carcinoma, STAT3 signaling controls VEGFA expression (4,5,14). In pancreatic cancer, STAT3 signaling regulates the expression of MMP2 (15), and in human melanoma brain metastases, activated Stat3 regulates the expression of FGF2 (3). These results demonstrate that constitutive STAT3 signaling contributes to tumor angiogenesis through multiple mechanisms.…”

“…Several studies have reported that STAT3 directly regulates vascular endothelial growth factor A (VEGFA) expression to induce tumor angiogenesis in breast cancer, gastric cancer and hepatocellular carcinoma (4,5,14). In pancreatic cancer, STAT3-targeting RNA interference (RNAi) inhibits angiogenesis by suppressing the expression of matrix metalloproteinase-2 (MMP2) (15). In human melanoma brain metastases, activated STAT3 contributes to tumor angiogenesis by regulating the expression of basic fibroblast growth factor (FGF2) (3).…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…STAT signaling is critical for normal cellular processes such as embryonic development, organogenesis and organ function, innate and adaptive immune function, regulation of cell differentiation, growth, and apoptosis [122][123][124][125][126][127]. In normal cells, STAT3 protein activation is strictly controlled to prevent unscheduled gene regulation, while constitutive activation of STAT3 has been detected in a wide number of human cancer cell lines and primary tumors, such as 50% of HCC, leukemias, lymphomas, multiple myelomas, prostate, gastric, breast, lung, and head and neck cancer [128][129][130][131][132][133][134].…”

Lipogenesis in cancer progression (Review)

“…Correlative associations between FAS expression and poor prognosis for patients were also observed in non-hormonedependent cancers (69)(70)(71) as well as with metastasis (72).…”