title: KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells.
abstract: Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to hepatocellular carcinoma (HCC) tumorigenesis and development. Here, we found that miR-615-5p was obviously downregulated in HCC. Furthermore, the deficiency of demethylase KDM4B stimulated the CpG methylation of miR-615-5p promoter and then decreased the miR-615-5p expression. The Ras-related protein RAB24 was found to be downregulated by miR-615-5p. The low level of miR-615-5p increased the expression of RAB24 and facilitated HCC growth and metastasis in vitro and in vivo. Moreover, miR-615-5p suppresses HCC cell growth by influencing cell cycle progression and apoptosis. Downregulation of miR-615-5p and upregulation of RAB24 promotes the epithelial-mesenchymal transition (EMT), adhesion and vasculogenic mimicry (VM) of HCC cells, all of which contribute to cell motility and metastasis. Thus, miR-615-5p, who is downregulated by KDM4B-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting RAB24 expression in HCC. In conclusion, our findings characterize miR-615-5p as an important epigenetically silenced miRNA involved in the Rab-Ras pathway in hepatocellular carcinoma and expand our understanding of the molecular mechanism underlying hepatocarcinogenesis and metastasis.
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Wang
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Department of Laboratory Medicine, the First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Liu
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Yi
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Shuang
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Li
authors.affiliation: Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis*
chemical_list: C534344:MIRN615 microRNA, human; D035683:MicroRNAs; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C514248:RAB24 protein, human; D020691:rab GTP-Binding Proteins
keywords: DNA methylation; HCC; gene regulation; metastasis; miRNAs