Activated K‐Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype

Journal of Cellular Physiology - Tập 228 Số 3 - Trang 556-562 - 2013
Zhiwei Wang1,2, Shadan Ali3, Sanjeev Banerjee2, Bin Bao2, Yiwei Li2, Asfar S. Azmi2, Murray Korc4, Fazlul H. Sarkar2
1Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui, P.R. China
2Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan
3Department of Oncology, Karmanos Cancer Institute/Wayne State University School of Medicine, Detroit, Michigan
4Department of Medicine, Indiana University, Indianapolis, Indiana

Tóm tắt

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most frequently diagnosed cancers and the fourth leading cause of cancer‐related death in the United States, suggesting that there is an urgent need to design novel strategies for achieving better treatment outcome of patients diagnosed with PDAC. Our previous study has shown that activation of Notch and NF‐κB play a critical role in the development of PDAC in the compound K‐RasG12D and Ink4a/Arf deficient transgenic mice. However, the exact molecular mechanism by which mutated K‐Ras and Ink4a/Arf deficiency contribute to progression of PDAC remains largely elusive. In the present study, we used multiple methods, such as real‐time RT‐PCR, Western blotting assay, and immunohistochemistry to gain further mechanistic insight. We found that the deletion of Ink4a/Arf in K‐RasG12D expressing mice led to high expression of PDGF‐D signaling pathway in the tumor and tumor‐derived cell line (RInk‐1 cells). Furthermore, PDGF‐D knock‐down in RInk‐1 cells resulted in the inhibition of pancreatosphere formation and down‐regulation of EZH2, CD44, EpCAM, and vimentin. Moreover, we demonstrated that epithelial–mesenchymal transition (EMT) was induced in the compound mice, which is linked with aggressiveness of PDAC. In addition, we demonstrated that tumors from compound transgenic mice have higher expression of cancer stem cell (CSC) markers. These results suggest that the acquisition of EMT phenotype and induction of CSC characteristics could be linked with the aggressiveness of PDAC mediated in part through the activation of PDGF‐D, signaling. J. Cell. Physiol. 228: 556–562, 2013. © 2012 Wiley Periodicals, Inc.

Từ khóa


Tài liệu tham khảo

10.1101/gad.1158703

10.1007/s10549-010-0883-2

10.1002/jcp.24036

10.1371/journal.pone.0017850

10.1002/jcb.23150

10.1016/j.canlet.2011.03.012

Brembeck FH, 2003, The mutant K‐ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice, Cancer Res, 63, 2005

10.1100/tsw.2010.183

10.1016/j.bbcan.2005.08.003

10.1002/ijc.26493

10.1016/j.ccr.2009.09.027

10.1158/1940-6207.CAPR-10-0258

10.1158/0008-5472.CAN-09-4645

10.1158/1078-0432.CCR-06-2926

10.1245/s10434-007-9539-9

10.1053/j.gastro.2009.05.052

10.1038/35074129

10.1158/0008-5472.CAN-07-3241

10.1634/stemcells.2007-1076

10.1002/stem.101

10.3390/cancers30100716

10.1016/j.cell.2008.03.027

10.1038/nrc2620

10.1093/jnci/djp535

10.1016/j.cell.2011.04.029

10.1158/0008-5472.CAN-08-1290

10.1593/tlo.10244

10.3322/caac.20138

10.1016/j.cell.2009.11.007

10.1128/MCB.25.14.6279-6288.2005

10.1158/0008-5472.CAN-10-0511

10.1158/0008-5472.CAN-05-4281

10.1158/0008-5472.CAN-07-2803

10.2174/138945009787122914

10.1016/j.bbcan.2010.04.003

10.1371/journal.pone.0020537

10.1038/nrgastro.2010.188

Thông tin
Thông tin xuất bản

Journal of Cellular Physiology

Tập 228 Số 3

556-562

Thông tin tác giả