Modulation of Hepatitis B Virus Replication and Hepatocyte Differentiation by MicroRNA-1
Modulation of Hepatitis B Virus Replication and Hepatocyte Differentiation by MicroRNA-1
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DOI：
10.1002/hep.24195
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发表时间：
2011-05-01
期刊：
影响因子：
13.5
通讯作者：
Lu, Mengji
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoyong;Zhang, Ejuan;Lu, Mengji
MicroRNAs(MiRNAs)是一种高度保守的非编码小RNA，参与调节多种细胞过程。病毒已被证明利用细胞内的miRNAs来增加它们在宿主细胞中的复制。到目前为止，miRNAs在乙肝病毒复制中的作用在很大程度上还不清楚。在本研究中，一些miRNA模拟物被导入到具有复制的肝癌细胞系中。研究发现，microRNA-1(miR-1)基因转染后，细胞内的HBVDNA复制显著增加，同时其转录、抗原表达和子代分泌也明显上调。然而，生物信息学和荧光素酶报告分析表明，miR-1可能不是直接针对乙肝病毒基因组，而是调节宿主基因的表达，以促进乙肝病毒的复制。进一步的研究表明，miR-1能够通过增强法尼醇X受体a的表达来增强乙肝病毒核心启动子的转录活性。此外，miR-1通过靶向组蛋白脱乙酰基酶4和E2F转录因子5使细胞周期停滞在G(1)期，并抑制细胞增殖。细胞基因表达谱分析表明，miR-1转基因肝癌细胞形成了分化的肝细胞表型。结论：MIR-1可调节多种宿主基因的表达，促进乙肝病毒复制，逆转癌细胞表型，明显有利于病毒复制。我们的发现为研究miRNAs在乙肝病毒感染中宿主-病毒相互作用中的作用提供了一个新的视角。(《肝病》2011；53：1476-1485)
MicroRNAs (miRNAs) are highly conserved small noncoding RNAs participating in regulation of various cellular processes. Viruses have been shown to utilize cellular miRNAs to increase their replication in host cells. Until now, the role of miRNAs in hepatitis B virus (HBV) replication has remained largely unknown. In this study, a number of miRNA mimics were transfected into hepatoma cell lines with HBV replication. It was noted that microRNA-1 (miR-1) transfection resulted in a marked increase of HBV replication, accompanied with up-regulated HBV transcription, antigen expression, and progeny secretion. However, bioinformatics and luciferase reporter analysis suggested that miR-1 may not target the HBV genome directly but regulate the expression of host genes to enhance HBV replication. Further studies showed that miR-1 was able to enhance the HBV core promoter transcription activity by augmenting farnesoid X receptor a expression. In addition, miR-1 arrested the cell cycle at the G(1) phase and inhibited cell proliferation by targeting histone deacetylase 4 and E2F transcription factor 5. Analysis of the cellular gene expression profile indicated that miR-1 transfected hepatoma cells developed a differentiated phenotype of hepatocytes. Conclusion: MiR-1 regulates the expression of several host genes to enhance HBV replication and reverse cancer cell phenotype, which is apparently beneficial for HBV replication. Our findings provide a novel perspective on the role of miRNAs in host-virus interactions in HBV infection. (HEPATOLOGY 2011;53:1476-1485)