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Hepatitis C virus infection, endogenous retrotransposons activation and cancer risk

Lookup NU author(s): Dr Ruchi ShuklaORCiD, Professor Helen ReevesORCiD, Dr Stuart McPhersonORCiD, Misti McCainORCiD, Dr Praveen Dhondurao Sudhindar, Dr Yvonne BuryORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Background and Aims: Mortality from hepatocellular carcinoma (HCC) continues to rise, due to a combination of late detection and lack of curative treatments. Chronic Hepatitis C (CHC) virus infection is a major risk factor for HCC and the use of direct acting antivirals (DAAs), potentially curing HCV infection, heralded a major break- through. However, the risk of HCC persists even after HCV clearance. The key drivers of HCC in chronic liver disease remain elusive, as do the mechanisms post-DAAs. Recently, we demonstrated the activa- tion and mutagenic consequences of long-interspersed repeat elements (L1 s) in human HCC, when the epigenetic silencing of these elements is compromised. Since HCV infection contributes to global epigenetic changes, we hypothesise that L1 s become activated during the process, mediating genomic instability, with chimeric transcripts and consequent upregulation of TGFβ signaling leading to cancer development post viral clearance. We aimed to evaluate activation of L1 s in chronic hepatitis C patients, in association with viral hepatitis-associated HCC development and prognosis. Method: L1 transcript expression was evaluated in RNAseq datasets of CHC (GSE84346) and The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) with an in-house pipeline. Immunohistochemical (IHC) examination of L1orf1 protein (L1orf1p) in the biopsy and/or resection tissue of CHC and CHC-HCC patients was using an automated Ventana system. An in vitro engineered-L1 retro- transposition assay in Huh7 cells in the presence or absence of an HCV replicon evaluated the influence of HCV on retrotransposition rate. Results: Liver L1 transcripts were upregulated in GSE84346 CHC patients compared to controls ( p = 0.001), as well as in TCGA-LIHC non-tumour tissue in patients with a history of viral hepatitis or alcohol abuse ( p < 0.05). In our own IHC pilot study, the L1 status of HCC expression in diagnostic biopsies matched that of L1orf1p expression in the non-tumour biopsy tissues predating HCC development by a number of years. In vitro, there was a 4-fold increase in retrotransposition rate in Huh7-HCV compared to control Huh7 cells, confirming an influence of HCV on retrotransposons activation. Conclusion: L1 can be activated before oncogenic transformation in patients with chronic HCV infection, with HCV promoting retro- transposition and potentially its mutagenic consequences. Persistence of L1 activation may contribute to HCC development even beyond viral clearance.


Publication metadata

Author(s): Shukla R, Reeves HL, McPherson S, McCain M, Sudhindar P, Bury Y, Faulkner G, Lunec G

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2020

Volume: 73

Pages: S401–S652

Online publication date: 16/09/2020

Acceptance date: 23/04/2020

Date deposited: 02/12/2020

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier

URL: https://doi.org/10.1016/S0168-8278(20)31712-8

DOI: 10.1016/S0168-8278(20)31712-8


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