Carcinogenesis Advance Access originally published online on June 22, 2009
Carcinogenesis 2009 30(9):1497-1506; doi:10.1093/carcin/bgp154
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Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function
1 Department of Hepatobiliary and Pancreatic Oncology, Cancer Hospital, Fudan University, 270 Dong An Road, Shanghai 200032, People's Republic of China
2 Department of Oncology, Shanghai Medical College, 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 Central Laboratory, Cancer Hospital/Cancer institute, Fudan University, 270 Dong An Road, Shanghai 200032, People's Republic of China
5 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; Email: 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 cell 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.
Abbreviations: MMP, matrix metalloproteinase; PCR, polymerase chain reaction; PDAC, Pancreatic ductal adenocarcinoma; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor
Received March 31, 2009; revised June 11, 2009; accepted June 16, 2009.