Modulation of HBV replication by microRNA-15b through targeting hepatocyte nuclear factor 1α.
Modulation of HBV replication by microRNA-15b through targeting hepatocyte nuclear factor 1α.
复制标题
DOI：
10.1093/nar/gku260
复制
发表时间：
2014-06
影响因子：
14.9
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Dai X;Zhang W;Zhang H;Sun S;Yu H;Guo Y;Kou Z;Zhao G;Du L;Jiang S;Zhang J;Li J;Zhou Y
B型肝炎病毒（HBV）感染仍然是世界范围内的主要健康问题。microRNA（miRNAs）在HBV复制和发病机制中的作用正日益被人们所认识。在这项研究中，我们发现miR-15 b是HBV感染和肝细胞癌发展过程中的重要miRNA，它直接结合HBV增强子I的负调控因子肝细胞核因子1α（HNF 1 α）mRNA，从而减弱HNF 1 α的表达，导致HBV增强子I的反式激活，进而引起HBV复制和HBV抗原（包括HBx蛋白）表达的增强，最终导致细胞系和小鼠中miR-15 b的表达下调，这是一个长级联事件。我们的研究表明，miR-15 b通过直接靶向HNF 1 α增强HBV增强子I的活性来促进HBV复制，而HBV复制和抗原表达，特别是HBx蛋白，则抑制miR-15 b的表达。miR-15 b与HBV之间的相互调节控制了HBV的复制水平，可能在HBV持续感染中发挥作用。这项工作增加了关于HBV和宿主miRNA之间复杂相互作用的知识体系。
Hepatitis B virus (HBV) infection remains a major health problem worldwide. The role played by microRNAs (miRNAs) in HBV replication and pathogenesis is being increasingly recognized. In this study, we found that miR-15b, an important miRNA during HBV infection and hepatocellular carcinoma development, directly binds hepatocyte nuclear factor 1α (HNF1α) mRNA, a negative regulator of HBV Enhancer I, to attenuate HNF1α expression, resulting in transactivation of HBV Enhancer I, in turn causing the enhancement of HBV replication and expression of HBV antigens, including HBx protein, finally leading to the down-regulated expression of miR-15b in both cell lines and mice in a long cascade of events. Our research showed that miR-15b promotes HBV replication by augmenting HBV Enhancer I activity via direct targeting HNF1α, while HBV replication and antigens expression, particularly the HBx protein, then repress the expression of miR-15b. The reciprocal regulation between miR-15b and HBV controls the level of HBV replication and might play a role in persistent HBV infection. This work adds to the body of knowledge concerning the complex interactions between HBV and host miRNAs.