Abstract
Hepatitis C virus (HCV) is a major cause of death and morbidity globally and is a leading cause of hepatocellular carcinoma (HCC). Incidence of HCV infections, as well as HCV-related liver diseases, are increasing. Although now, with new direct acting antivirals (DAAs) therapy available, HCV is a curable cancer-associated infectious agent, HCC prevalence is expected to continue to rise because HCC risk still persists after HCV cure. Understanding the factors that lead from HCV infection to HCC pre- and post-cure may open-up opportunities to novel strategies for HCC prevention. Herein, we provide an overview of the reported evidence for the induction of alterations in the transcriptome of host cells via epigenetic dysregulation by HCV infection and describe recent reports linking the residual risk for HCC post-cure with a persistent HCV-induced epigenetic signature. Specifically, we discuss the contribution of the epigenetic changes identified following HCV infection to HCC risk pre- and post-cure, the molecular pathways that are epigenetically altered, the downstream effects on expression of cancer-related genes, the identification of targets to prevent or revert this cancer-inducing epigenetic signature, and the potential contribution of these studies to early prognosis and prevention of HCC as an approach for reducing HCC-related mortality.
Highlights
Molecular Virology Laboratory, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel; Abstract: Hepatitis C virus (HCV) is a major cause of death and morbidity globally and is a leading cause of hepatocellular carcinoma (HCC)
The epigenetic alternations discussed here include only those studied in HCV-infected samples in vivo and in vitro and do not include studies only performed on human HCC samples, in order to dissect the effect of the infection itself, from alterations that accumulate during carcinogenesis that may no longer represent viral-associated influence
In cell culture models, we demonstrated that HCV massively alters the epigenetic state of the host cell, through various acetylation and methylation modifications of histones
Summary
Viruses rely on host machineries for transcription and translation and disrupt cell functions to create a favorable environment for their propagation. Recent studies suggest that the long-term remaining of an HCV-induced epigenetic signature, even after cure of infection, is a potential mechanism for the persistence of HCC risk following SVR, and substantial evidence is provided to support this paradigm [7,8,9]. In light of this intriguing new concept, in this review, we provide a comprehensive overview of the evidence for HCV-induced dysregulation of cancer related genes and pathways via epigenetic interference. Other recently suggested mechanisms that contribute to HCC progression following SVR by DAAs, such as the potential involvement of host immunity (Reviewed in [28]), are not discussed in this review
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