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
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Guoyu Zhang1, Na Li1, Zhu Li1, Qianqian Zhu1, Fang Li1, Cuiling Yang1, Qunying Han1, Yi Lv2,3, Zhihua Zhou1, Zhengwen Liu1,3
1 Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
2 Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China
3 Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
Zhengwen Liu, email:
Keywords: programmed cell death-1, 3’-untranslated region, single nucleotide polymorphism, microRNA, hepatitis B virus infection
Received: January 26, 2015 Accepted: February 26, 2015 Published: March 26, 2015
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.
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