KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells
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Zheng Chen1,*, Xiangling Wang1,*, Ruiyan Liu1,2,*, Lin Chen1, Jianying Yi1, Bing Qi1, Zeyu Shuang3, Min Liu1, Xin Li1, Shengping Li3, Hua Tang1
1Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
2Department of Laboratory Medicine, the First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China
3State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
*These authors have contributed equally to this work
Hua Tang, email: email@example.com
Keywords: DNA methylation, miRNAs, metastasis, HCC, gene regulation
Received: October 20, 2015 Accepted: June 17, 2016 Published: July 25, 2016
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.
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