STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression

Oncogene. 2016 Feb 25;35(8):1049-57. doi: 10.1038/onc.2015.161. Epub 2015 May 11.


The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor β (TGF-β) in certain kinds of cancer cells through the induction of Snail, a key regulator of EMT. We have previously found that TGF-β remarkably induces Snail expression in cooperation with Ras signals; however, the underlying mechanism of this synergism has not yet been determined. Here, we demonstrate that signal transducer and activator of transcription 3 (STAT3) acts as a mediator that synergizes TGF-β and Ras signals. The overexpression of STAT3 enhanced Snail induction, whereas siRNA-mediated knockdown of STAT3 inhibited it. The STAT3-YF mutant, which has Tyr 705 substituted with Phe, did not enhance Snail induction. Several STAT3 mutants lacking transcriptional activity also failed to enhance it; however, the putative STAT3-binding elements in the Snail promoter regions were not required for STAT3-mediated Snail induction. Protein inhibitor of activated STAT3 (PIAS3) inhibited the enhanced Snail promoter activity induced by TGF-β and Ras. The interaction between PIAS3 and STAT3 was reduced by TGF-β in cells harboring oncogenic Ras, whereas TGF-β promoted the binding of PIAS3 to Smad3, a crucial mediator of TGF-β signaling. Therefore, these findings suggest that STAT3 enhances Snail induction when it is dissociated from PIAS3 by TGF-β in cooperation with Ras signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • HeLa Cells
  • Humans
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • ras Proteins / metabolism*


  • STAT3 Transcription Factor
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • ras Proteins