Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin

// Qiongzhu Dong 1, 2, 3, * , Xuchao Zhu 1, 2, 3, * , Chun Dai 3, * , Xiaofei Zhang 1, 2 , Xiaomei Gao 3 , Jinwang Wei 3 , Yuanyuan Sheng 3 , Yan Zheng 3 , Jian Yu 4 , Lu Xie 4 , Yi Qin 3 , Peng Qiao 3 , Chuang Zhou 2 , Xinxin Yu 3 , Huliang Jia 1, 2 , Ning Ren 2 , Haijun Zhou 2 , Qinghai Ye 2 , Lunxiu Qin 1, 2, 3 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China 2 Liver Cancer Institute, Fudan University, Shanghai, China 3 Institute of Biomedical Sciences, Fudan University, Shanghai, China 4 Shanghai Center for Bioinformation Technology, Shanghai, China * These authors contributed equally to the work Correspondence to: Lunxiu Qin, e-mail: qin_lx@yahoo.com Keywords: osteopontin, epithelial-mesenchymal transition, hepatocellular carcinoma, vimentin, stability Received: June 16, 2015 Accepted: January 04, 2016 Published: January 25, 2016 ABSTRACT 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.