title: MicroRNA-122 triggers mesenchymal-epithelial transition and suppresses hepatocellular carcinoma cell motility and invasion by targeting RhoA.
abstract: The loss of microRNA-122 (miR-122) expression is strongly associated with increased invasion and metastasis, and poor prognosis of hepatocellular carcinoma (HCC), however, the underlying mechanisms remain poorly understood. In the present study, we observed that miR-122 over-expression in HCC cell lines Sk-hep-1 and Bel-7402 triggered the mesenchymal-epithelial transition (MET), as demonstrated by epithelial-like morphological changes, up-regulated epithelial proteins (E-cadherin, ZO-1, α-catenin, occludin, BVES, and MST4), and down-regulated mesenchymal proteins (vimentin and fibronectin). The over-expression of miRNA-122 also caused cytoskeleton disruption, RhoA/Rock pathway inactivation, enhanced cell adhesion, and suppression of migration and invasion of Sk-hep-1 and Bel-7402 cells, whereas, these effects could be reversed through miR-122 inhibition. Additional studies demonstrated that the inhibition of wild-type RhoA function induced MET and inhibited cell migration and invasion, while RhoA over-expression reversed miR-122-induced MET and inhibition of migration and invasion of HCC cells, suggesting that miR-122 induced MET and suppressed the migration and invasion of HCC cells by targeting RhoA. Moreover, our results demonstrated that HNF4α up-regulated its target gene miR-122 that subsequently induced MET and inhibited cell migration and invasion, whereas miR-122 inhibition reversed these HNF4α-induced phenotypes. These results revealed functional and mechanistic links among the tumor suppressors HNF4α, miR-122, and RhoA in EMT and invasive and metastatic phenotypes of HCC. Taken together, our study provides the first evidence that the HNF4α/miR-122/RhoA axis negatively regulates EMT and the migration and invasion of HCC cells.
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Sheng-Chun
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Lin
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Jun-Wen
authors.initials: JW
authors.lastname: Shi
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Zhao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Rao-Ying
authors.initials: RY
authors.lastname: Xie
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Qin
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China.
authors.forename: Kai-Tai
authors.initials: KT
authors.lastname: Yao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, China; Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D051178:alpha Catenin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D015820:Cadherins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D014746:Vimentin; D051178:alpha Catenin; D020742:rhoA GTP-Binding Protein