title: MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis.
abstract: MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Sandy Leung-Kuen
authors.initials: SL
authors.lastname: Au
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Dorothy Ngo-Yin
authors.initials: DN
authors.lastname: Fan
authors.affiliation: Department of Physics and Department of Biology, Centre for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Felice Ho-Ching
authors.initials: FH
authors.lastname: Tsang
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Cheuk-Ting
authors.initials: CT
authors.lastname: Law
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Joyce Man-Fong
authors.initials: JM
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xianghuo
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Physics and Department of Biology, Centre for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C533896:MIRN200 microRNA, human; C546363:MIRN429 microRNA, human; D035683:MicroRNAs; C066737:RHOA protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Rho/ROCK signaling pathway; cancer metastasis; cytoskeletal reorganization; hepatocellular carcinoma; miR-200 family