The antiviral effects of human microRNA miR‐302c‐3p against hepatitis B virus infection

• Published in: Alimentary pharmacology & therapeutics Vol. 49; no. 8; pp. 1060 - 1070
• Main Authors: Hamada‐Tsutsumi, Susumu, Naito, Yutaka, Sato, Seiichi, Takaoka, Akinori, Kawashima, Keigo, Isogawa, Masanori, Ochiya, Takahiro, Tanaka, Yasuhito
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2019
• Subjects: Animals; Bone morphogenetic protein receptor type II; Chronic infection; Core protein; DNA-directed RNA polymerase; Down-Regulation; Gene Knockdown Techniques; Hepatitis; Hepatitis B; Hepatitis B surface antigen; Hepatitis B Surface Antigens - blood; Hepatitis B virus - genetics; Hepatitis B, Chronic - blood; Hepatitis B, Chronic - genetics; Hepatitis B, Chronic - therapy; Hepatocyte nuclear factor 4; Humans; Immunoprecipitation; Male; Mice; Mice, Transgenic; MicroRNAs; MicroRNAs - administration & dosage; miRNA; mRNA; Replication; RNA, Messenger; siRNA; Transgenic animals; Transgenic mice
• ISSN: 0269-2813; 1365-2036; 1365-2036
• DOI: 10.1111/apt.15197

Summary Background Conventional treatments of chronic hepatitis B virus (HBV) infection rarely achieve a decline of serum hepatitis B surface antigen (HBsAg) levels and eradication of the virus. Aim To elucidate the antiviral mechanisms of a human microRNA, miR‐302c‐3p, against HBV replication. Methods The antiviral effect of miR‐302c‐3p was evaluated in vitro and in vivo by transfecting the miR‐302c‐3p mimic into HBV‐infected HepG2‐hNTCP‐C4 cells and HBV transgenic mice respectively. Results miR‐302c‐3p decreased not only HBV replication but also production of HBsAg. Pregenomic RNA and HBsAg mRNA concentrations decreased in the cells treated with miR‐302c‐3p. Interestingly, the amount of cccDNA was significantly reduced in the miR‐302c‐3p‐treated cells, in association with disappearance of the HBV core protein. An RNA immunoprecipitation assay showed that miR‐302c‐3p decreased the binding of the HBV polymerase to the pregenomic RNA by hybridising with the ε‐loop region. A number of host genes were downregulated in miR‐302c‐3p‐treated cells, including BMPR2 and HNF4A. Knockdown of these two genes by corresponding siRNAs also suppressed HBV replication and HBsAg secretion. The antiviral effect of miR‐302c‐3p was also observed in HBV transgenic mice. Conclusion miR‐302c‐3p had anti‐HBV activity, in vitro and in vivo, via several mechanisms.