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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
Author(s) -
Zhao Shujie,
Wang Yubao,
Cao Lin,
Ouellette Michel M.,
Freeman James W.
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25412
Subject(s) - downregulation and upregulation , cancer research , gene knockdown , biology , epidermal growth factor receptor , carcinogenesis , transcription factor , signal transduction , small hairpin rna , cell culture , microbiology and biotechnology , receptor , cancer , gene , genetics
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.