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.
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.
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DOI：
10.1002/ijc.25412
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发表时间：
2010-11-01
影响因子：
6.4
通讯作者：
Freeman, James W.
中科院分区：
文献类型：
--
作者：
Zhao, Shujie;Wang, Yubao;Cao, Lin;Ouellette, Michel M.;Freeman, James W.
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 this 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 knock down of Smad4. EGFR and erbB2 protein levels but not Ron or IGF-1R were substantially up regulated 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 up regulation of EGFR and erbB2 was associated with an increase of invasion, which was blocked by a kinase inhibitor of EGFR. This study indicates for the first time, that oncogenic ras and loss of Smad signaling cooperate to up regulate EGFR and erbB2, which plays a role in promoting invasion.
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DOI：
10.1073/pnas.0605333103
发表时间：
2006-08-22
影响因子：
11.1
作者：
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2003-02-21
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影响因子：
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