Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro.
Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro.
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乙型肝炎病毒X蛋白在体外下调恶性肝细胞中miR-16家族的表达
DOI：
10.1038/bjc.2011.190
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发表时间：
2011-06-28
影响因子：
8.8
通讯作者：
Song, E.
中科院分区：
文献类型：
--
作者：
Wu, G.;Yu, F.;Xiao, Z.;Xu, K.;Xu, J.;Tang, W.;Wang, J.;Song, E.
乙肝病毒X蛋白（HBx）通过调控宿主蛋白质编码基因参与肝细胞癌（HCC）的发生和发展。在本研究中，我们发现HBx改变微小RNA（miRNAs）的表达，从而在体外促进恶性肝细胞的增殖和转化。
采用miRNA微阵列和定量逆转录聚合酶链反应（qRT - PCR）来鉴定在肝癌细胞中受HBx差异调控的miRNAs。进行蛋白质、mRNA和miRNA表达分析、细胞周期和凋亡分析、功能缺失/获得分析以及荧光素酶报告基因检测，以阐明miR - 16家族在HepG2细胞中受抑制的结果。
乙肝病毒X蛋白诱导HepG2细胞中miRNAs广泛的失调，并且miR - 16家族的下调在HepG2、SK - HEP - 1和Huh7细胞中可重复出现。CCND1是miR - 16家族的一个靶标，在HepG2细胞中被HBx去抑制。c - Myc介导HBx诱导的HepG2细胞中miR - 15a/16的抑制。异位表达的miR - 15a/16通过将表达HBx的HepG2细胞阻滞在G1期并诱导凋亡，从而抑制其增殖、克隆形成能力和非贴壁生长，而miR - 16表达降低则加速HepG2细胞的生长和细胞周期进程。
乙肝病毒X蛋白改变宿主恶性肝细胞中miRNAs的体外表达，特别是下调miR - 16家族。miR - 15a/16的抑制由c - Myc介导，并且是HBx在体外诱导HepG2细胞转化所必需的。因此，miR - 16家族可作为乙肝病毒（HBV）相关肝细胞癌的一个治疗靶点。
Background:Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of microRNAs (miRNAs) to promote proliferation and transformation in malignant hepatocytes in vitro.Methods:miRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify miRNAs that were differentially regulated by HBx in HCC cells. Protein, mRNA, and miRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of-function analysis; and luciferase reporter assays were performed to delineate the consequences of miR-16 family repression in HepG2 cells.Results:Hepatitis B virus X protein induced widespread deregulation of miRNAs in HepG2 cells, and the downregulation of the miR-16 family was reproducible in HepG2, SK-HEP-1, and Huh7 cells. CCND1, a target of the miR-16 family, was derepressed by HBx in HepG2 cells. c-Myc mediated the HBx-induced repression of miR-15a/16 in HepG2 cells. Ectopically expressed miR-15a/16 suppressed the proliferation, clonogenicity, and anchorage-independent growth of HBx-expressing HepG2 cells by arresting them in the G1 phase and inducing apoptosis, whereas reduced expression of miR-16 accelerated the growth and cell-cycle progression of HepG2 cells.Conclusions:Hepatitis B virus X protein altered the in vitro expression of miRNAs in host malignant hepatocytes, particularly downregulating the miR-16 family. Repression of miR-15a/16 is c-Myc mediated and is required for the HBx-induced transformation of HepG2 cells in vitro. Therefore, miR-16 family may serve as a therapeutic target for hepatitis B virus (HBV)-associated HCC.
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