HCV activates somatic L1 retrotransposition—a potential hepatocarcinogenesis pathway

Praveen D. Sudhindar, Daniel Wainwright, Santu Saha, Rachel Howarth, Misti McCain, Yvonne Bury, Sweta S. Saha, Stuart McPherson, Helen Reeves, Arvind H. Patel, Geoffrey J. Faulkner, John Lunec, Ruchi Shukla*

*Corresponding author for this work

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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.

Original languageEnglish
Article number5079
Number of pages17
JournalCancers
Volume13
Issue number20
DOIs
Publication statusPublished - 11 Oct 2021
Externally publishedYes

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