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

✍ Scribed by Shujie Zhao; Yubao Wang; Lin Cao; Michel M. Ouellette; James W. Freeman

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: French
• Weight: 863 KB
• Volume: 127
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.25412

✦ Synopsis

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‐β 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.