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Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus
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Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus
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Journal Article
Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus
2017
Overview
Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 dependence receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (
n
=550) as well as in
in vitro
. In patients,
UNC5A
mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples.
UNC5A
mRNA is downregulated in F2 (3-fold;
P
=0.009), in F3 (10-fold,
P
=0.0004) and more dramatically so in F4/cirrhosis (44-fold;
P
<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(−) tissues.
UNC5A
transcript was found strongly downregulated in HCC samples (33-fold;
P
<0.0001) as compared with non-HCC samples.
In vivo
, association of
UNC5A
transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained
in vitro
showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the
UNC5
promoter and translation in a
UNC5A
5′UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A dependence receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Publishing Group [1987-....]
Subject
