Negative Correlation Between Hepatitis C Virus (HCV) and Let-7 MicroRNA Family in Transplanted Livers: The Role of rs868 Single-Nucleotide Polymorphism

Abstract

BackgroundGenetic alterations of TGF-β pathway members, including its transmembrane receptor, TGFBR1, may influence the course of HCV infection. Rs868 is a single-nucleotide polymorphism of the 3′UTR region of TGFBR1, located in a binding site for the conserved let-7/miR98 microRNA family. Previously, we demonstrated a favorable course of hepatitis C recurrence after liver transplantation in rs868 AG genotype of the transplanted liver when compared to rs868 AA. The aim of the present study was to confirm the biological effect of rs868.Material/MethodsHepG2 cell line was transfected with luciferase vectors cloned with 3′UTR of TGFBR1 gene encompassing different rs868 alleles. Post-transplant liver biopsies from 61 patients with HCV-related end-stage liver disease were evaluated histopathologically and analyzed for the expression of TGFBR1 mRNA, let-7/miR98 microRNAs, HCV RNA load, and rs868 genotype.ResultsLuciferase expression was significantly lower in the A allele-containing vector. TGFBR1 mRNA and HCV RNA load were correlated negatively with let-7/miR98 microRNAs and this correlation was significantly stronger for rs868 AG compared to AA genotype. A strong positive correlation was demonstrated between TGFBR1 and HCV in both genotypes. In AG heterozygotes, let-7/miR98 microRNAs showed a strong negative correlation with periportal or periseptal interface hepatitis (Ishak A score).ConclusionsThere is a negative correlation between let-7/miR98 microRNAs and HCV viral load and TGFBR1 mRNA after liver transplantation. In the rs868 AG heterozygotes, this correlation was stronger and there was a negative correlation between let-7/miR98 and Ishak A score, which is in concordance with the previously demonstrated protective role of this genotype in post-transplant hepatitis C recurrence.

Downregulation of hepatitis C virus replication by miR‐196a using lentiviral vectors

“…Establishment of this cell culture system can support future studies on new antiviral agents against HCV. 3,32 We observed overexpression of miR-196a downregulating HCV genome replication in human hepatocytes. It is suggested that there is a significant inverse relationship between miRNA-196a and HCV infection.…”

“…Our results of real‐time PCR showed a high titer of the virus. Establishment of this cell culture system can support future studies on new antiviral agents against HCV 3,32 …”

“…According to the World Health Organization (WHO) reports, about 3% of the world population is infected, of which 15%-30% will develop liver cirrhosis and hepatocellular carcinoma. 2,3 Hepatocellular carcinoma is the third leading cause of cancer deaths worldwide and the fifth and ninth most common cancer in men and women, respectively. [4][5][6] In 1989, HCV was identified as an important non-A/non-B chronic hepatitis.…”

“…Hepatitis C virus (HCV) infection is a global health problem, 1 associated with the later stages of liver disease. According to the World Health Organization (WHO) reports, about 3% of the world population is infected, of which 15%–30% will develop liver cirrhosis and hepatocellular carcinoma 2,3 . Hepatocellular carcinoma is the third leading cause of cancer deaths worldwide and the fifth and ninth most common cancer in men and women, respectively 4‐6 .…”

MicroRNA-Related Polymorphisms in Infectious Diseases—Tiny Changes With a Huge Impact on Viral Infections and Potential Clinical Applications

“…Finally, there is some evidence showing that TGFBR1 A/G SNP (rs868) (located at miR-let-7 and miR-98-binding sites) could have an impact on clinical parameters of HCV infection, especially on HCV RNA loads and hepatic inflammation ( 98 ). However, in the current scenario, the interaction between this TGFBR1 SNP (rs868) and HCV infection is poorly understood.…”