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 journalArticlepeer-review

25 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
StatePublished - Nov 1 2010

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this