Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function
Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function
复制标题
Ski 在胰腺癌细胞中的双重作用：促进肿瘤与抑制转移的功能
DOI：
10.1093/carcin/bgp154
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发表时间：
2009-09-01
期刊：
影响因子：
4.7
通讯作者：
Liu, Lu-Ming
中科院分区：
文献类型：
--
作者：
Wang, Peng;Chen, Zhen;Liu, Lu-Ming
SKI过去被定义为有助于肿瘤细胞抵抗转化生长因子-β(TGF-β)诱导的生长停滞的癌基因。由于转化生长因子-β对肿瘤生长具有双重作用，抑制肿瘤和促进肿瘤的活性取决于肿瘤发生的阶段和细胞类型，因此Ski在肿瘤发生中的确切作用尚不清楚。在这项研究中，我们发现通过慢病毒介导的RNA干扰下调Ski在体外和体内都降低了肿瘤的生长，但在体外促进了细胞的侵袭性，并在体内促进了胰腺癌细胞株SW1990和Smad4缺失的BxPC3细胞系的肺转移。我们还表明，Ski的下调增加了转化生长因子-β诱导的转录活性，这与转化生长因子-β依赖的Smad2/3磷酸化增加有关，并导致参与转移、血管生成、细胞增殖和上皮-间充质转化的转化生长因子-β诱导基因的表达谱改变。71例胰腺癌标本的免疫组织化学分析显示，Ski的过度表达与患者的生存时间显著相关(P=0.0024)。我们的结果提示，在人胰腺癌中，Ski可能是一种肿瘤增殖促进因子或转移抑制因子。
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.