HCV Activates Somatic L1 Retrotransposition—A Potential Hepatocarcinogenesis Pathway

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.

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

“…The combination reveals a novel role for L1 ORF1p in HCC in the regulation of key oncogenic pathways promoting hepatocarcinogenesis-including TGFβ signalling and inflammatory response pathways independently of active retrotransposition. We have recently demonstrated activation of L1 in chronic hepatitis C (CHC) infected patients and that activated L1 can influence hepatocarcinogenesis beyond viral clearance [37]. The current study highlights the potential contribution of L1 expression in CHC patients towards hepatocarcinogenesis by alteration of key oncogenic pathways.…”

“…Human HCC RNAseq data was downloaded from the TCGA-LIHC project and mapped to the human L1-Ta sequence (5'UTR-promoter, Genbank: L19092) by BLAT alignment using an in-house algorithm to obtain L1 counts [37]. The counts were normalised by the total number of reads in each library and expressed here as counts per million.…”

LINE1-mediated reverse transcription and genomic integration of SARS-CoV-2 mRNA detected in virus-infected but not in viral mRNA-transfected cells

“…It has been established that cellular stress, for example, aging or viral infection can induce LINE1 expression (2)(3)(4)(7)(8)(9)(10)(11). Upon SARS-CoV-2 infection, double-stranded RNA intermediates are generated during viral replication/transcription (24,25) and reactive oxygen species (ROS) can be produced in patient tissues (54)(55)(56), which could potentially induce endogenous LINE1 expression based on our in vitro experiments.…”

An update on post‐transcriptional regulation of retrotransposons

“…On top of that, L1-ORF1p is incorporated into HIV-1 VLPs but with no apparent effect on HIV-1 infectivity [174]. A couple of other studies reported modulation of LINE-1 retrotransposition upon viral infections: restriction following infection with enteroviruses [260] and HCV [175], or activation following infection with HCV [261]. The discrepancy in the results of the latter two studies likely requires further elucidation.…”