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Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus

Abstract

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.

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Acknowledgements

This study was supported by the European Union (Marie Curie International Reintegration Grant #248364), The LYric Grant (INCa-DGOS-4664), The French National Agency for AIDS and Viral Hepatitis Research (ANRS, Grant #2011-379), The French Ligue Contre Le Cancer and The DevWeCan French Laboratories of Excellence Network (Labex, Grant #ANR-10-LABX-61). We thank T. Wakita (National Institute of Infectious Diseases, Japan), CM Rice (The Rockefeller University, NY, USA) and F Helle (Inserm, France) for Huh7.5 cells and HCV strains.

Author contributions

MLP, TL, MR, MM, CRL, RP: experimental design, acquisition of data, analysis and interpretation of data. MR, PM: technical and material support, critical revision of the manuscript. KS, PM, DD, ML, FZ: obtained funding, clinical samples, interpretation of data, critical revision of the manuscript. RP: obtained funding, study concept and design, study supervision, manuscript writing.

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Correspondence to R Parent.

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Plissonnier, ML., Lahlali, T., Raab, M. et al. Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus. Oncogene 36, 6712–6724 (2017). https://doi.org/10.1038/onc.2017.271

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