Methylation-regulated miR-124-1 suppresses tumorigenesis in hepatocellular carcinoma by targeting CASC3.

Kan Chen,Tong Liu,Jie Lu,Sainan Li,Weiqi Dai,Yujing Xia,Lei He,Ling Xu,Chuanyong Guo,Yingqun Zhou,Yugang Wang,Fan Wang,JingJing Li

doi:10.18632/oncotarget.8266

Abstract

This study was to investigate the roles and mechanisms of miR-124-1 in hepatocellular carcinoma (HCC). We analyzed the expression of miR-124-1 in human HCC tissues and cell lines. Luciferase reporter assays were used to analyze the target of miR-124-1. Human HCC cell lines were transduced with lentiviruses expressing miR-124-1, and proliferation and colony formation were analyzed. The growth of human HCC cells overexpressing miR-124-1 was assessed in nude mice. The expression of p38-MAPK, JNK, ERK and related signaling molecules was detected by western blotting and immunohistochemistry. Our results showed that miR-124-1 levels were reduced in HCC tissues and cell lines compared with those in adjacent non-cancer tissues and normal liver cell lines respectively. Downregulation of miR-124-1 in HCC cell lines were attributed to hypermethylation of its promoter region. Overexpression of miR-124-1 inhibited HCC cell proliferation in vitro, whereas miR-124-1 was correlated with clinicopathological parameters of HCC patients. HCC cell-mediated overexpression of miR-124-1 in nude mice suppressed tumor growth. Cancer susceptibility candidate 3 (CASC3) was identified as a direct target of miR-124-1 by computational analysis and experimental assays. MiR-124-1-mediated downregulation of CASC3 resulted in the inactivation of p38-MAPK, JNK and ERK. Our findings provide potential new targets for the prevention or treatment of HCC.

Highlights

A large number of studies have shown that alterations in chromosome number and the structure of tumor cells play an important role in carcinogenesis
We identified Cancer susceptibility candidate 3 (CASC3) as a direct target of miR-124-1 and found that miR-124-1 modulates the activity of the p38-ERK-JNK pathway by regulating CASC3 expression, which may play a role in hepatocellular carcinoma (HCC) tumorigenesis
The results showed that the expression levels of miR-124-1and miR320a were downregulated in HCC cell lines with genomic deletion

Summary

Introduction

A large number of studies have shown that alterations in chromosome number and the structure of tumor cells play an important role in carcinogenesis. These changes have led to the identification of crucial oncogenes and tumor suppressors, which is essential for a better understanding of the pathogenesis of cancer and for clinical applications [1]. Chromosomal alterations including homozygous deletion and loss of heterozygosity are the most common form of genetic variation. The development and progression of HCC is significantly correlated with the absence of more than 10 chromosomes, including loss of heterozygosity (LOH), and a high rate of genetic variation. If the chromosome region containing a tumor suppressor is lost, consistent with the loss of tumor suppressor genes contributing to tumorigenesis

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Results

Conclusion