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.
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-beta 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.
Zhao
Shujie
S
Department of Medicine, Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX, USA.
Wang
Yubao
Y
Cao
Lin
L
Ouellette
Michel M
MM
Freeman
James W
JW
D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D010183:Pancreatic Ducts / Q000378:metabolism* / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics*; D015854:Up-Regulation
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D051901:Smad4 Protein; C508053:ERBB2 protein, human
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