Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function.
Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-beta (TGF-beta)-induced growth arrest. As TGF-beta 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-beta-induced transcriptional activity, which is associated with increased TGF-beta-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-beta-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.
Wang
Peng
P
Department of Hepatobiliary and Pancreatic Oncology, Cancer Hospital, Fudan University, Shanghai 200032, People's Republic of China.
Chen
Zhen
Z
Meng
Zhi-Qiang
ZQ
Fan
Jie
J
Luo
Jian-Min
JM
Liang
Wang
W
Lin
Jun-Hua
JH
Zhou
Zhen-Hua
ZH
Chen
Hao
H
Wang
Kun
K
Shen
Ye-Hua
YH
Xu
Zu-De
ZD
Liu
Lu-Ming
LM
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000473:pathology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C060614:SKI protein, human