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. 2021 Jun 15;13(6):509–535. doi: 10.4251/wjgo.v13.i6.509

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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/

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Woodchuck hepatitis virus-induced hepatocarcinogenesis in woodchucks. After infection of normal hepatocytes, woodchuck hepatitis virus (WHV) replicates via cccDNA and produces high loads of intracellular and circulating viral proteins (WHsAg, WHeAg and WPreC) that interfere with the antiviral immunity. The deficient immune response is unable to clear WHV from infected liver cells but causes inflammation. WHsAg accumulates in hepatocytes and gives rise to ground glass hepatocytes. WHV also integrates into the chromosomal DNA of hepatocytes via double-stranded linear (dsl) DNA leading to oxidative stress, oxidation-dependent cellular DNA breakages, insertional mutagenesis, chromosomal alterations, and protooncogene activation. WHsAg and WHV X antigen (WHxAg) are produced from viral DNA integrants. Integrant- and replication-derived viral proteins activate cellular proteins, such as transcription factors, that support the oncogenic process. The continued liver inflammation leads to cell degeneration and regeneration and facilities accumulation of genetic and epigenetic defects in hepatocytes. Individual hepatocytes with critical mutations and low WHV replication and/or antigen presentation escape immune surveillance and their clonal outgrowth results in FAHs that further develop into liver tumors and HCC. CccDNA: Covalently-closed circular DNA; Dsl DNA: Double-stranded linear DNA; FAH: Focus of altered hepatocytes; HCC: Hepatocellular carcinoma; WHV: Woodchuck hepatitis virus.