Abstract
BackgroundSignal transducer and activator of transcription 3 (Stat3) is a member of the Janus-activated kinase(Jak)/Stat signaling pathway. Abnormal activation of Stat3 plays a critical role in metastasis and invasion in varieties of human tumors including pancreatic cancer. This study aimed to investigate the mechanisms of activation and blocking of the Stat3 signaling pathway and its effects on invasion and metastasis of human pancreatic cancer cells.MethodsThe Jak inhibitor AG490 and interleukin-6 (IL-6) were added to the culture media of human pancreatic cancer cells SW1990 and Capan-2, respectively. Cell growth was measured by MTT assays. Western blotting and immunocytochemistry were performed to detect phosphorylated Stat3 (p-Stat3) protein, while VEGF and MMP-2 mRNA and protein expression were examined with fluorescence quantitative polymerase chain reaction and Western blotting, respectively. The invasion ability of SW1990 and Capan-2 cells was determined by cell invasion assay.ResultsStat3 was activated by IL-6 in Capan-2 cells; protein expression of p-Stat3 was increased significantly in Capan-2 cells. IL-6 remarkably promoted the growth of Capan-2 cells (P < 0.05), and VEGF and MMP-2 mRNA and protein expression were increased significantly. Also, IL-6 increased the invasion ability of Capan-2 cells. AG490 inhibited Stat3 activation in SW1990 cells. Western blotting and immunocytochemistry analysis showed that p-Stat3 protein expression was decreased significantly with AG490 treatment in SW1990 cells. AG490 remarkably inhibited the growth of Capan-2 cells (P < 0.05), and VEGF and MMP-2 mRNA and protein expression was decreased significantly. And AG490 decreased the invasion ability of SW1990 cells.ConclusionsAbnormal activation of Stat3 plays an important role in the invasion and metastasis of pancreatic cancer. Activation and blocking of the Stat3 signaling pathway can affect invasion ability and expression of the VEGF and MMP-2 genes in pancreatic cancer cells. The Stat3 signaling pathway may provide a novel therapeutic target for treatment of pancreatic cancer.
Highlights
Pancreatic cancer is one of the most virulent malignances, with an overall 5-year survival rate of only 3-5% and a median survival time after diagnosis of less than 6 months[1]
We used AG490 to deplete Signal transducer and activator of transcription 3 (Stat3) protein in the human pancreatic cancer cell line SW1990 and IL-6 to activate Stat3 protein in the human pancreatic cancer cell line Capan-2; we investigated the changes in cell proliferation and invasion
Effects of AG490 and IL-6 on growth in pancreatic cancer cells Because Stat3 activation was positively associated with proliferation potential in cancer cells, we measured the absorbance of the SW1990 cell line in the presence of AG490
Summary
Pancreatic cancer is one of the most virulent malignances, with an overall 5-year survival rate of only 3-5% and a median survival time after diagnosis of less than 6 months[1]. This highly lethal disease is usually diagnosed in an advanced stage, when there are few or no effective therapies[2]. Signal transducer and activator of transcription (Stat) proteins were initially described in the context of regulating physiological cell signaling. This study aimed to investigate the mechanisms of activation and blocking of the Stat signaling pathway and its effects on invasion and metastasis of human pancreatic cancer cells
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