title: Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin.
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.
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.|Liver Cancer Institute, Fudan University, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Qiongzhu
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.|Liver Cancer Institute, Fudan University, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xuchao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.|Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jinwang
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Shanghai Center for Bioinformation Technology, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Shanghai Center for Bioinformation Technology, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xie
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Qiao
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.|Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Huliang
authors.initials: H
authors.lastname: Jia
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.|Liver Cancer Institute, Fudan University, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Lunxiu
authors.initials: L
authors.lastname: Qin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D053495:Osteopontin / Q000378:metabolism*; D011379:Prognosis; D055550:Protein Stability; D014746:Vimentin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C506895:SPP1 protein, human; D014746:Vimentin; D053495:Osteopontin
keywords: epithelial-mesenchymal transition; hepatocellular carcinoma; osteopontin; stability; vimentin
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