MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis

// Chun-Ming Wong 1 , Lai Wei 1 , Sandy Leung-Kuen Au 1 , Dorothy Ngo-Yin Fan 1 , Yuan Zhou 2 , Felice Ho-Ching Tsang 1 , Cheuk-Ting Law 1 , Joyce Man-Fong Lee 1 , Xianghuo He 3 , Jue Shi 2 , Carmen Chak-Lui Wong 1  and Irene Oi-Lin Ng 1 1 Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China 2 Department of Physics and Department of Biology, Centre for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Chun-Ming Wong, email: // Irene Oi-Lin Ng, email: // Keywords : hepatocellular carcinoma, miR-200 family, cytoskeletal reorganization, Rho/ROCK signaling pathway, cancer metastasis Received : January 16, 2015 Accepted : March 02, 2015 Published : March 30, 2015 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.