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 language | English (US) |
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Pages (from-to) | 2076-2087 |
Number of pages | 12 |
Journal | International Journal of Cancer |
Volume | 127 |
Issue number | 9 |
DOIs | |
State | Published - Nov 1 2010 |
Keywords
- EGFR
- K-ras
- Smad4
- TGF-
- cell signaling
- pancreatic cancer
ASJC Scopus subject areas
- Oncology
- Cancer Research