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) |
|---|---|
| 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 |
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Keywords
- EGFR
- K-ras
- Smad4
- TGF-
- cell signaling
- pancreatic cancer
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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. / Zhao, Shujie; Wang, Yubao; Cao, Lin; Ouellette, Michel M; Freeman, James W.
In: International Journal of Cancer, Vol. 127, No. 9, 01.11.2010, p. 2076-2087.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Zhao, Shujie
AU - Wang, Yubao
AU - Cao, Lin
AU - Ouellette, Michel M
AU - Freeman, James W.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - 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.
AB - 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.
KW - EGFR
KW - K-ras
KW - Smad4
KW - TGF-
KW - cell signaling
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=77956642350&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956642350&partnerID=8YFLogxK
U2 - 10.1002/ijc.25412
DO - 10.1002/ijc.25412
M3 - Article
C2 - 20473902
AN - SCOPUS:77956642350
VL - 127
SP - 2076
EP - 2087
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 9
ER -