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      Hepatocellular Carcinoma Recurrence in HCV Patients Treated with Direct Antiviral Agents

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          Abstract

          The risk of hepatocellular carcinoma recurrence is universal regardless of the treatment modality applied, and secondary prevention is still an unmet issue even though the elimination of hepatitis C (HCV) with direct antiviral agents (DAAs) was expected to be one of the new options. Unfortunately, the impact of DAAs on hepatocellular carcinoma (HCC) development (de novo and recurrence) is still controversial. Since the first publication on the subject in 2016, almost all groups worldwide have carried out research in this field with hundreds of publications now available. This revision is focused on the impact of DAAs on HCC recurrence and aims to discuss the potential underlying mechanisms and host factors pointing out the time association phenomenon between DAA treatment and HCC recurrence. Moreover, we comment on the methodological issues that could affect the different interpretations of the published results. In conclusion, this is an area of research with potential in the understanding of the impact of factors not previously considered, and may also help change hepatocarcinogenesis tenets, such as the belief that the elimination of HCV should be used as a second prevention treatment.

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          Most cited references 58

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          Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.

          miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
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            Hepatitis C virus RNA functionally sequesters miR-122.

            Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV. Copyright © 2015 Elsevier Inc. All rights reserved.
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              Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts.

              (2016)
              Sustained virological response following interferon-based antiviral treatment of chronic hepatitis C is associated with decreased long-term risk of hepatocellular carcinoma (HCC) in advanced liver fibrosis. An unexpected high rate of HCC recurrence following antiviral treatment using direct-acting antiviral (DAA) has recently been reported.
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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                01 May 2019
                May 2019
                : 11
                : 5
                Affiliations
                [1 ]Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; MSANDUZZI@ 123456clinic.cat (M.S.-Z.); LBOIX@ 123456clinic.cat (L.B.); GUEDES@ 123456clinic.cat (C.L.)
                [2 ]Centro de Investigación Médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
                Author notes
                [* ]Correspondence: mreig1@ 123456clinic.ub.es ; Tel.: +34-932279803; Fax: +34-932275792
                Article
                viruses-11-00406
                10.3390/v11050406
                6563506
                31052463
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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