Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

Daoyan Wei, Xiangdong Le, Leizhen Zheng, Liwei Wang, Jennifer A. Frey, Allen C Gao, Zhihai Peng, Suyun Huang, Henry Q. Xiong, James L. Abbruzzese, Keping Xie

Research output: Contribution to journalArticle

415 Scopus citations

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. Immunohisto-chemical 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 Star3 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.

Original languageEnglish (US)
Pages (from-to)319-329
Number of pages11
JournalOncogene
Volume22
Issue number3
DOIs
StatePublished - Jan 23 2003
Externally publishedYes

Keywords

  • Angiogenesis
  • Metastasis
  • Pancreas
  • Stat3
  • Tumor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Wei, D., Le, X., Zheng, L., Wang, L., Frey, J. A., Gao, A. C., Peng, Z., Huang, S., Xiong, H. Q., Abbruzzese, J. L., & Xie, K. (2003). Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 22(3), 319-329. https://doi.org/10.1038/sj.onc.1206122