HCV Activates Somatic L1 Retrotransposition-A Potential Hepatocarcinogenesis Pathway
| Autor: | Rachel Howarth, John Lunec, Ruchi Shukla, Helen L. Reeves, Santu Kumar Saha, Yvonne Bury, Sweta Sharma Saha, Stuart McPherson, Geoffrey J. Faulkner, Praveen D. Sudhindar, Misti Vanette McCain, Daniel Wainwright, Arvind H. Patel |
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| Rok vydání: | 2021 |
| Předmět: |
Genome instability
Cancer Research Sofosbuvir DNA damage Somatic cell Hepatitis C virus Retrotransposon Biology medicine.disease_cause Article retrotransposition medicine L1 HCV hepatocellular carcinoma RC254-282 Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease digestive system diseases Oncology Hepatocellular carcinoma Cancer research Homologous recombination medicine.drug |
| Zdroj: | Cancers Cancers, Vol 13, Iss 5079, p 5079 (2021) Cancers; Volume 13; Issue 20; Pages: 5079 |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Chronic hepatitis C virus (HCV) infection is a common cause of liver cancer in the developed world. Although anti-viral treatment can cure HCV infection, the risk of cancer development remains in individuals with consequent advanced fibrosis or cirrhosis. In this study, we show that HCV can influence transposable DNA elements called L1 retrotransposons. These are mobile genetic elements that can negatively alter the host genome, potentially promoting cancer development. L1 elements are known to be activated in several cancer types, including liver cancer. Hence, we suggest a novel pathway involved in liver cancer development in patients with chronic HCV, including those with active infection as well as after viral clearance. 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. |
| Databáze: | OpenAIRE |
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