Sudhindar, Praveen D., Wainwright, Daniel, Saha, Santu, Howarth, Rachel, McCain, Misti, Bury, Yvonne, Saha, Sweta S., McPherson, Stuart, Reeves, Helen, Patel, Arvind H., Faulkner, Geoffrey J., Lunec, John and Shukla, Ruchi (2021) HCV Activates Somatic L1 Retrotransposition—A Potential Hepatocarcinogenesis Pathway. Cancers, 13 (20). p. 5079. ISSN 2072-6694
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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: | Article |
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| Additional Information: | Funding Information: Funding: P.D.S.’s PhD was supported by the Newcastle University Overseas Research Scholarship scheme and the JGW Patterson Foundation Special grant (Grant ref: RES/0190/7948). D.W. was supported by the JGW Patterson Foundation (Grant ref: RES/0260/0217). R.S. was funded by Newcastle University’s Research Fellowship funds. H.L.R. and M.M. were supported by a grant from Cancer Research UK (CRUK) (C18342/A23390); H.L.R. was also supported by a CRUK Accelerator award (HUNTER: Hepatocellular Carcinoma Expediter Network C9380/A26813). S.S. was supported by Newton International Fellowship of Academy of Medical Sciences (Newton fund, Grant ref: RES/0280/0076). S.S.S. was funded by the Newcastle upon Tyne Hospitals NHS Charity (Grant ref: RES/0280/0080). G.J.F. was supported by a CSL Centenary Fellowship and an NHMRC Investigator Grant (GNT1173711). A.H.P. was supported by Medical Research Council (Grant ref: MC_UU12014/2). |
| Uncontrolled Keywords: | DNA damage, HCV, Hepatocellular carcinoma, L1, Retrotransposition |
| Subjects: | A300 Clinical Medicine B800 Medical Technology |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Depositing User: | Rachel Branson |
| Date Deposited: | 25 Jan 2023 15:36 |
| Last Modified: | 25 Jan 2023 15:45 |
| URI: | https://nrl.northumbria.ac.uk/id/eprint/51244 |
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