Modulation of HBV replication by microRNA-15b through targeting hepatocyte nuclear factor 1α

Xiaopeng Dai,Guangyu Zhao,Shibo Jiang,Junfeng Li,Yan Guo,Lanying Du,Hong Yu,Jianying Zhang,Shihui Sun,Hongfei Zhang,Zhihua Kou,Wei Zhang,Yusen Zhou

doi:10.1093/nar/gku260

Abstract

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.

Highlights

MicroRNAs are a family of endogenous conserved noncoding RNAs, about 21–25 nucleotides in length, which can regulate gene expression at posttranslational level by incomplete or complete complementary to 3’-untranslated region (3’-UTR) of the target transcripts [1]
This finding was confirmed by real-time PCR (Figure 1A) and indicated that miR-15b may be associated with Hepatitis B virus (HBV) replication
The results indicated that ectopic miR-15b expression increased the HBV replicative intermediate DNA in HBV replication cells

Summary

Introduction

MicroRNAs (miRNAs) are a family of endogenous conserved noncoding RNAs, about 21–25 nucleotides (nts) in length, which can regulate gene expression at posttranslational level by incomplete or complete complementary to 3’-untranslated region (3’-UTR) of the target transcripts [1]. The miRNAs play pivotal roles in diverse biological processes including cell development, differentiation, apoptosis, metabolism, stress response and virus infection. It has been well demonstrated that viruses can either activate or repress the expression of specific cellular miRNAs [2]. The disruption of this process can perturb the ability of viruses to replicate normally. It is currently evident that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses [3]. In order to eliminate viral infections in host cells, cellular miRNA can be directly involved in the process of antiviral immune response by inhibiting or promoting viral replication. The continuous study on the role of miRNA in host–virus interaction is of great significance for understanding the pathogenesis and biology of viruses

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Conclusion