title: MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma.
abstract: Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Dong-Qin
authors.initials: DQ
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Haizhu
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Yitian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, First Hospital Affiliated to The Chinese PLA General Hospital, Beijing, China.
authors.forename: Ziman
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Liver Disease Center of PLA, The 81th Hospital of PLA, Nanjing, Jiangsu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Long-Bang
authors.initials: LB
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc
keywords: c-Myc; epithelial-mesenchymal transition; hepatocellular carcinoma; invasion; miR-451