Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Guilian Niu, Kenneth L. Wright, Mei Huang, Lanxi Song, Eric Haura, James Turkson, Shumin Zhang, Tianhong Wang, Dominic Sinibaldi, Domenico Coppola, Richard Heller, Lee M. Ellis, James Karras, Jacqueline Bromberg, Drew Pardoll, Richard Jove, Hua Yu

Research output: Contribution to journalArticlepeer-review

Abstract

Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (Stat3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with Stat3 activity in diverse human cancer cell lines. An activated Stat3 mutant (Stat3C) up-regulates VEGF expression and stimulates tumor angiogenesis. Stat3C-induced VEGF up-regulation is abrogated when a Stat3-binding site in the VEGF promoter is mutated. Furthermore, interrupting Stat3 signaling with dominant-negative Stat3 protein or Stat3 antisense oligonucleotide in tumor cells down-regulates VEGF expression. Consistent with an important role of Stat3 in VEGF up-regulation induced by various oncogenic tyrosine kinases, v-Src-mediated VEGF expression is inhibited when Stat3 signaling is blocked. Moreover, chromatin immunoprecipitation assays indicate that Stat3 protein binds to the VEGF promoter in vivo and mutation of a Stat3-binding site in the VEGF promoter abrogates v-Src-induced VEGF promoter activity. These studies provide evidence that the VEGF gene is regulated directly by Stat3 protein, and indicate that Stat3 represents a common molecular target for blocking angiogenesis induced by multiple signaling pathways in human cancers.

Original languageEnglish (US)
Pages (from-to)2000-2008
Number of pages9
JournalOncogene
Volume21
Issue number13
DOIs
StatePublished - 2002

Keywords

  • Stat3 activation
  • Tumor angiogenesis
  • VEGF

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis'. Together they form a unique fingerprint.

Cite this