Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin.
Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin.
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骨桥蛋白通过调节波形蛋白促进肝细胞癌上皮间质转化
DOI：
10.18632/oncotarget.7016
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发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Qin L
中科院分区：
文献类型：
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作者：
Dong Q;Zhu X;Dai C;Zhang X;Gao X;Wei J;Sheng Y;Zheng Y;Yu J;Xie L;Qin Y;Qiao P;Zhou C;Yu X;Jia H;Ren N;Zhou H;Ye Q;Qin L
我们之前的研究发现骨桥蛋白（OPN）是肝细胞癌（HCC）进展的促进剂。然而，OPN 增强 HCC 转移的分子机制仍不清楚。癌细胞的上皮间质转化（EMT）在促进转移过程中发挥着关键作用。在这项研究中，我们证明 OPN 通过在体外和体内诱导类似 EMT 的更具侵袭性的细胞表型来促进 HCC 转移。此外，通过 OPN 和波形蛋白相互免疫沉淀以及联合免疫荧光检查，确定 OPN 与波形蛋白相互作用。通过使用缺失突变体，我们发现波形蛋白中 246 至 406 之间的残基是与 OPN 结合所必需的。重要的是，OPN 通过抑制其蛋白质降解显着提高了波形蛋白的稳定性。波形蛋白的敲低可中和 OPN 在体外和体内诱导的 EMT。此外，在临床 HCC 标本中发现 OPN 和波形蛋白水平之间存在显着相关性，它们的组合预后较差，总生存期 (OS) 和复发时间 (TTR) 较短。多变量分析表明，OPN 及其组合是 HCC 患者 OS 和 TTR 的独立预后指标。总的来说，这项研究表明OPN可以通过增加波形蛋白稳定性来诱导HCC细胞的EMT，这为OPN促进HCC转移的分子机制提供了更深入的了解，并为HCC的治疗开辟了诱人的可能性。
Our previous studies have found that osteopontin (OPN) is a promoter for hepatocellular carcinoma (HCC) progression. However, the molecular mechanism by which OPN enhances HCC metastasis remains elusive. Epithelial-mesenchymal transition (EMT) of cancer cells plays a pivotal role in promoting metastatic process. In this study, we demonstrated that OPN promotes HCC metastasis by inducing an EMT-like, more aggressive cellular phenotype in vitro and in vivo. Furthermore, OPN was identified to interact with vimentin by reciprocal OPN and vimentin immunoprecipitation as well as co-immunofluorescence examination. By using deletion mutants, we found that the residues between 246 and 406 in vimentin are required for binding to OPN. Importantly, OPN significantly increased vimentin stability through inhibition of its protein degradation. Knockdown of vimentin neutralized the EMT induced by OPN both in vitro and in vivo. Moreover, a significant correlation between OPN and vimentin levels was found in clinical HCC specimens and their combination had a worse prognosis with shorter overall survival (OS) and time to recurrence (TTR). In multivariate analysis, OPN and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Collectively, this study indicates that OPN can induce EMT of HCC cells through increasing vimentin stability, which provides more in-depth understanding about the molecular mechanisms of OPN in promoting HCC metastasis and opens tantalizing therapeutic possibilities in HCC.