微小 RNA155 的异常表达可能通过靶向性地作用于肝癌中的性别决定区 Y 框 6 而促进细胞增殖。

Aberrant expression of microRNA 155 may accelerate cell proliferation by targeting sex-determining region Y box 6 in hepatocellular carcinoma.

机构信息

Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China.

出版信息

Cancer. 2012 May 1;118(9):2431-42. doi: 10.1002/cncr.26566. Epub 2011 Oct 11.

DOI:10.1002/cncr.26566

PMID:21989846

Abstract

BACKGROUND

Recent research has suggested that the oncomir microRNA 155 (miR-155) is up-regulated in hepatocellular carcinoma (HCC). In this study, the authors investigated the tumorigenic mechanism of this oncomir in the development of HCC.

METHODS

Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was conducted to analyze the expressions of miR-155 and its potential target genes in paired tumor tissues and adjacent tumor-free tissues and in disease-free liver tissue samples. The in silico predicted target genes of miR-155 were assessed by dual-luciferase reporting assay, real-time RT-PCR, and Western blot analyses. U6 promoters that drive miR-155 precursor overexpression and miR-155 tough decoy knock-down constructs were used to study its affects on cell proliferation in vitro and on tumor formation in nude mice.

RESULTS

Quantitative RT-PCR demonstrated a gradual ascension of miR-155 expression in cirrhotic liver tissues and in HCC tumor tissues compared with low expression levels in normal liver tissues. Ectopic expression of miR-155 in HepG2 cells enhanced its tumorigenesis, whereas depletion of the endogenous miR-155 reversed these tumorigenic properties. Ectopic expression of sex-determining region Y box 6 (SOX6) was able to reverse the growth-promoting property of miR-155. Concordantly, the results demonstrated for the first time that SOX6 is a direct target of miR-155. Further analysis revealed that SOX6 reduced cell growth by up-regulating p21waf1/cip1 expression in a p53-dependent manner. In addition, a decline in p21waf1/cip1 expression caused by miR-155 could be reversed by SOX6 expression.

CONCLUSIONS

The current data indicated that SOX6 is a novel target of miR-155 and that miR-155 enhances liver cell tumorigenesis at least in part through the novel miR-155/SOX6/p21waf1/cip1 axis. These findings suggest that miR-155 may be a potential target for HCC treatment.

摘要

背景

最近的研究表明，癌基因 microRNA 155（miR-155）在肝细胞癌（HCC）中上调。在这项研究中，作者研究了这种致癌 miRNA 在 HCC 发展中的肿瘤发生机制。

方法

采用定量逆转录聚合酶链反应（RT-PCR）分析配对肿瘤组织和相邻无肿瘤组织以及无病肝组织样本中 miR-155 及其潜在靶基因的表达。采用双荧光素酶报告基因检测、实时 RT-PCR 和 Western blot 分析评估 miR-155 的预测靶基因。使用 U6 启动子驱动 miR-155 前体过表达和 miR-155 强阻断敲低构建体，研究其对体外细胞增殖和裸鼠肿瘤形成的影响。

结果

定量 RT-PCR 显示，与正常肝组织相比，肝硬化组织和 HCC 肿瘤组织中 miR-155 的表达逐渐升高。HepG2 细胞中 miR-155 的异位表达增强了其致瘤性，而内源性 miR-155 的耗竭则逆转了这些致瘤特性。性别决定区 Y 盒 6（SOX6）的异位表达能够逆转 miR-155 的促生长作用。一致地，首次证明 SOX6 是 miR-155 的直接靶标。进一步分析表明，SOX6 通过依赖于 p53 的方式上调 p21waf1/cip1 的表达来抑制细胞生长。此外，miR-155 引起的 p21waf1/cip1 表达下降可以通过 SOX6 表达来逆转。