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Carcinogenesis Advance Access published online on June 22, 2009
Carcinogenesis, doi:10.1093/carcin/bgp154
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dual role of Ski in pancreatic cancer cells: Tumor-promoting versus metastasis-suppressive function

Peng Wang1, Zhen Chen1, Zhiqiang Meng1, Jie Fan3, Jianmin Luo2, Wang Liang4, Junhua Lin1, Zhenhua Zhou1, Hao Chen1, Kun Wang1, Yehua Shen1, Zude Xu3 and Luming Liu1,*

1 Department of Hepatobiliary and Pancreatic Oncology, and Department of Oncology, Shanghai Medical College
2 Central Laboratory, Cancer Hospital/Cancer institute, Fudan University, 270 Dong An Road, Shanghai 200032, People's Republic of China
3 Department of Pathology, Huashan Hospital, Fudan University, 12 Wulumuqi Road Central, Shanghai 200032, People's Republic of China
4 Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical College, Fudan University, 130 Dong An Road, Shanghai 200032, China

* To whom correspondence should be addressed: Tel: +86 21 64175590-1308; Fax: +86 21 64049440; E-mail: llm1010{at}yahoo.com.cn

Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-β (TGF-β)-induced growth arrest. As TGF-β has a dual effect on tumor growth with both tumor suppressing and promoting activity depending on the stage of carcinogenesis and the cell type, the precise role of Ski in carcinogenesis remains unclear. In this study, we show that downregulation of Ski through lentivirus-mediated RNA interference decreases tumor growth both in vitro and in vivo, yet promotes cell invasiveness in vitro, and lung metastasis in vivo in the pancreatic cancer cell line SW1990, which contain wild-type Smad4 expression, and the BxPC3 line, which is Smad4 deficient. We also show that the downregulation of Ski increases TGF-β-induced transcriptional activity, which is associated with increased TGF-β-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-β-inducible genes involved in metastasis, angiogenesis and cell proliferation and epithelial-mesenchymal transition. Immunohistochemical analysis of specimens from 71 patients with pancreatic adenocarcinoma showed a significant association between overexpression of Ski and decreased patient survival time (P = 0.0024). Our results suggest that Ski may act as a tumor proliferation promoting factor or as a metastatic suppressor in human pancreatic cancer.

Key Words: Ski • TGF-β • RNA interference • pancreatic cancer • prognosis

Received March 31, 2009; revised June 11, 2009; accepted June 16, 2009.


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