MicroRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases.

Guoyu Zhang,Cuiling Yang,Zhengwen Liu,Zhihua Zhou,Zhu Li,Qunying Han,Na Li,Yi Lv,Qianqian Zhu,Fang Li

doi:10.18632/oncotarget.3662

Guoyu Zhang, Cuiling Yang + Show 8 more

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https://doi.org/10.18632/oncotarget.3662

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Journal: Oncotarget	Publication Date: Mar 26, 2015
Citations: 111	License type: cc-by

Affiliation: Xi'an Jiaotong University

Abstract

Programmed cell death-1 (PD-1) is involved in hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma (HCC) worldwide. Single-nucleotide polymorphism, rs10204525, located in the PD1 3' untranslated regions (UTR), is associated with chronic HBV infection. MicroRNAs (miRNAs) regulate gene expression via specific binding to the target 3'UTR of mRNA. In this study, three miRNAs were predicted to putatively interact with PD1 rs10204525 polymorphic site of allele G. One of them, miRNA-4717, was demonstrated to allele-specifically affect luciferase activity in a dose-dependent manner in cells transfected with vectors containing different rs10204525 alleles. In lymphocytes from chronic HBV patients withrs10204525 genotype GG, miR-4717 mimics significantly decreased PD-1 expression and increased (TNF)-α and interferon (IFN)-γ production. miR-4717 inhibitor significantly increased PD-1 expression and decreased TNF-α and IFN-γ production although not significantly. In lymphocytes from chronic HBV patients with rs10204525 genotype AA, no similar effects were observed. miR-4717 levels in peripheral lymphocytes from patients with HBV-related chronic hepatitis, cirrhosis and HCC were significantly decreased. In conclusion, miR-4717 may allele-specifically regulate PD-1 expression through interaction with the 3' UTR of PD1 mRNA, leading to the alteration of immune regulation and affecting the susceptibility and disease course of chronic HBV infection.

Highlights

Infection with hepatitis B virus (HBV) remains a major public health problem
It is estimated that more than 350 million people are HBV carriers worldwide and about one million annual deaths are resulted from HBVrelated liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) [1]
We further investigated the effect of the identified miRNA on Programmed cell death-1 (PD-1) expression and tumor necrosis factor (TNF)-α and IFN-γ production in lymphocytes from chronic HBV patients with different rs10204525 genotypes

Summary

Introduction

Infection with hepatitis B virus (HBV) remains a major public health problem. The liver damage and disease progression of HBV infection is primarily associated with immunoinflammatory responses of the host to the virus [2,3,4,5]. Programmed cell death-1 (PD-1) is a prominent regulator of T cell function and a major factor of apoptosis sensitivity [6, 7]. Engagement of PD-1 by its ligands PD-L1 or PD-L2 could inhibit T-cell receptor-mediated proliferation and cytokine production in activated T lymphocytes [8]. Viral infection and interferon (IFN)-α and IFN-γ could induce PD-L1 in hepatocytes which could mediate T cell apoptosis [9].

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