Expression of oncogenic K-ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells

Shujie Zhao, Yubao Wang, Lin Cao, Michel M Ouellette, James W. Freeman

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Activating mutation of K-ras and inactivation of DPC4 are two common genetic alterations that occur in the development and progression of pancreatic ductal adenocarcinomas (PDAC). A separate common event in PDAC progression is increased expression of phosphotyrosine kinase receptors (PTKRs). In our study, we examined whether activating mutations of K-ras and loss of Smad4 play a role in causing the aberrant expression of PTKRs. Immortalized human pancreas ductal cells (HPNE) were genetically modified by expressing oncogenic K-ras and/or by shRNA knockdown of Smad4. EGFR and erbB2 protein levels but not Ron or IGF-1R were substantially upregulated in HPNE cells that express K-ras (GD12). The increased expression of EGFR in HPNE cells that expressed K-ras(GD12) was mediated by both stabilizing EGFR protein and by increasing EGFR transcription. TGF- signaling partially suppressed K-ras (GD12) induced EGFR transcription in Smad4 intact HPNE cells; whereas knockdown of Smad4 in cells expressing K-ras(GD12) further enhanced expression of EGFR and erbB2. The upregulation of EGFR and erbB2 was associated with an increase of invasion, which was blocked by a kinase inhibitor of EGFR. Our study indicates for the first time, that oncogenic ras and loss of Smad signaling cooperate to upregulate EGFR and erbB2, which plays a role in promoting invasion.

Original languageEnglish (US)
Pages (from-to)2076-2087
Number of pages12
JournalInternational Journal of Cancer
Volume127
Issue number9
DOIs
Publication statusPublished - Nov 1 2010

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Keywords

  • EGFR
  • K-ras
  • Smad4
  • TGF-
  • cell signaling
  • pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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