Abstract
Signal transducer and activator of transcription 3 (STAT3) is a central cytoplasmic transcription factor. Abnormal activation of STAT3 plays a critical role in oncogenesis and has been found frequently in a wide variety of human tumors including pancreatic cancer. In this study, we elucidated the significance of the STAT3 signaling pathway on metastatic potentials of pancreatic cancer. We found that phosphorylated STAT3 (p-STAT3) protein levels were significantly higher in highly metastatic SW1990 cells compared to the poorly metastatic CaPan-2 cells, which expressed weak levels of this protein. Furthermore, a Janus kinase (JAK) specific inhibitor, AG490, significantly inhibited the expression of p-STAT3, and subsequently reduced invasion and adhesion potential of SW1990 cells compared to the cells treated with vehicle only. Finally, inhibition of the STAT3 signaling pathway by AG490 also led to a decrease in matrix metalloproteinase-2 and vascular endothelial growth factor expression at the protein and mRNA levels. These results demonstrate that activation of the STAT3 signaling pathway plays an important role in the progression of pancreatic cancer and that inhibition of this pathway may be useful for an anti-invasive therapeutic option in pancreatic cancer.
MeSH terms
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Blotting, Western
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Cell Adhesion / drug effects
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Electrophoretic Mobility Shift Assay
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Neoplastic*
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Humans
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Neoplasm Invasiveness / prevention & control*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / pathology
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Phosphorylation / drug effects
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Protein-Tyrosine Kinases / antagonists & inhibitors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Signal Transduction
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Trans-Activators
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Transcription, Genetic
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Tumor Cells, Cultured
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Tyrphostins / pharmacology*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Enzyme Inhibitors
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RNA, Messenger
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RNA, Neoplasm
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Tyrphostins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Protein-Tyrosine Kinases
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Matrix Metalloproteinase 2