Abstract
Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.
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Acknowledgements
This work was supported in part by the Topfer Foundation for Pancreatic Cancer Research, the Research Project Grant #RPG-00-054-01-CMS from the American Cancer Society, the WM Keck Foundation for Cancer Gene Therapy, the Physician Referral Service Award, and Cancer Center Support Core Grant CA 16672-23 from the National Cancer Institute, National Institutes of Health. We thank Judy King for expert help in the preparation of this manuscript and Don Norwood for editorial comments.
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Wei, D., Le, X., Zheng, L. et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319–329 (2003). https://doi.org/10.1038/sj.onc.1206122
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DOI: https://doi.org/10.1038/sj.onc.1206122
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