Oncotarget

Research Papers:

KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells

Zheng Chen, Xiangling Wang, Ruiyan Liu, Lin Chen, Jianying Yi, Bing Qi, Zeyu Shuang, Min Liu, Xin Li, Shengping Li and Hua Tang _

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Oncotarget. 2017; 8:17712-17725. https://doi.org/10.18632/oncotarget.10832

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Abstract

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

Correspondence to:

Hua Tang, email: htang2002@yahoo.com

Keywords: DNA methylation, miRNAs, metastasis, HCC, gene regulation

Received: October 20, 2015    Accepted: June 17, 2016    Published: July 25, 2016

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.


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