Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity

TLDR

Hepatitis B virus infects roughly 350 million people worldwide, causing chronic disease. The study aimed to determine how the liver‑specific microRNA miR‑122 regulates HBV replication and its underlying mechanism. Mechanistically, miR‑122 targets cyclin G1, whose interaction with p53 blocks p53 binding to HBV enhancer elements and removes p53‑mediated transcriptional repression of HBV. The authors found that miR‑122 is markedly reduced in HBV‑infected livers, its depletion boosts viral replication while overexpression suppresses it, and this effect is mediated through cyclin G1’s inhibition of p53‑dependent antiviral activity, suggesting that miR‑122 loss facilitates HBV persistence and may promote carcinogenesis.

Abstract

Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G(1) as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G(1) regulated viral replication in HBV transfected cells. We also observed that cyclin G(1) expression was up-regulated in HBV-infected patients, and cyclin G(1) levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G(1) specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53-mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells.miR-122 down-regulates its target cyclin G(1) , and thus interrupts the interaction between cyclin G(1) and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis.