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HCV Activates Somatic L1 Retrotransposition to Influence Hepatocarcinogenesis Beyond Viral Clearance

Lookup NU author(s): Dr Praveen Dhondurao Sudhindar, Daniel Wainwright, Dr Santu Saha, Rachel Howarth, Misti McCainORCiD, Dr Yvonne BuryORCiD, Dr Stuart McPhersonORCiD, Professor Helen Reeves, Professor John Lunec, Dr Ruchi ShuklaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Abstract: Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). 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 6 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. Increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance by sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Together 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 risk of transformation that persists post-viral clearance.


Publication metadata

Author(s): Sudhindar PD, Wainwright D, Saha S, Howarth R, McCain M, Bury Y, Saha SS, McPherson S, Reeves H, Patel AH, Faulkner GJ, Lunec J, Shukla R

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2021

Volume: 13

Issue: 20

Online publication date: 11/10/2021

Acceptance date: 07/10/2021

Date deposited: 19/07/2022

ISSN (electronic): 2072-6694

Publisher: MDPI AG

URL: https://doi.org/10.3390/cancers13205079

DOI: 10.3390/cancers13205079


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Funding

Funder referenceFunder name
C9380/A26813
C18342/A23390Cancer Research UK CRUK (open competition)
GNT1173711
MC_UU12014/2
Newcastle University’s Research Fellowship
RES/0190/7948
RES/0260/0217
RES/0280/0080
Newcastle University Overseas Research Scholarship scheme
RES/0280/0076

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