HCV activates somatic L1 retrotransposition—a potential hepatocarcinogenesis pathway

Sudhindar, P. D. et al. (2021) HCV activates somatic L1 retrotransposition—a potential hepatocarcinogenesis pathway. Cancers, 13(20), 5079. (doi: 10.3390/cancers13205079) (PMID:34680227) (PMCID:PMC8533982)

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Abstract

Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance.

Item Type:Articles
Keywords:L1, HCV, retrotransposition, DNA damage, hepatocellular carcinoma.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Patel, Professor Arvind
Authors: Sudhindar, P. D., Wainwright, D., Saha, S., Howarth, R., McCain, M., Bury, Y., Saha, S. S., McPherson, S., Reeves, H., Patel, A. H., Faulkner, G. J., Lunec, J., and Shukla, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Journal Name:Cancers
Publisher:MDPI
ISSN:2072-6694
ISSN (Online):2072-6694
Published Online:11 October 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cancers 13(20): 5079
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH