Review
Mechanisms of HBV-induced hepatocellular carcinoma

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Summary

Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation.

Introduction

Hepatocellular carcinoma (HCC) represents, with an estimated 500,000–600,000 deaths/year [1], [2], the second cause of cancer death worldwide [3]. HCC development is driven by the interaction of genetic predisposition, environmental factors (metabolic syndrome, alcohol, aflatoxin B1, aristocholic acid) and viruses (hepatitis B virus (HBV), hepatitis C virus (HCV)). Despite the establishment of HBV vaccine programs since the early 90s, the decreased incidence of HBV new infections in many countries and the availability of potent antiviral treatments that lead to long-term inhibition of HBV replication, 240 million people are chronically infected with HBV and remain at risk of developing liver cirrhosis and HCC [2], [3].

Driving forces in hepatocyte transformation, HCC development and progression are chronic inflammation, DNA damage, epigenetic modifications, senescence and telomerase reactivation, chromosomal instability and early neo-angiogenesis. Although most HCCs develop in the context of liver cirrhosis, which is recognized as a pro-carcinogenic field, HCC can also develop in non-cirrhotic livers. All “etiologic” factors seem to act through similar mechanisms (i.e. point mutations, chromosomal aberrations, epigenetic changes) that converge to affect common pathways. Notably, mutations and chromosomal aberrations have been predominantly found in benign and malignant tumor tissues whereas the dysregulation of signaling pathways and epigenetic changes are also detected earlier in the natural history of HCC development, at the stage of cirrhosis. In the last 10 years, genome-wide technologies and next generation sequencing (NGS) have enabled the identification of molecular signatures to classify subgroups of HCCs and stratify patients according to prognosis, and have highlighted the role of pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. The molecular pathogenesis and classification of HCCs and their impact on the design of new therapeutic approaches has been the object of several recent and comprehensive reviews [4], [5], [6], [7], [8]. Here, we focus on the molecular characterization of HBV-related carcinomas, the contribution of HBV genetic variability, HBV integration into the host genome and wild-type and mutated/truncated viral proteins to HCC development.

Section snippets

Epidemiology and co-factors

Recent estimates attribute over 50% of HCC cases worldwide to HBV [1], [2], making it the most common carcinogen after tobacco. The role of HBV in HCC may be greater than that depicted by sero-epidemiologic studies, as suggested by the increased risk of developing HCC in patients with occult HBV infection (defined as persistence of free and/or integrated forms of HBV DNA in the liver in the absence of the viral marker HBsAg in the serum [9]) and after hepatitis B surface antigen (HBsAg)

HBV life cycle, viral heterogeneity and HCC

HBV is responsible for over 50% of HCCs; the second cause of cancer death worldwide.

HBV genomic variability is attributed to lack of proof-reading by the HBV polymerase and the high copy number of the virus. This leads to the selection of HBV quasi-species containing several mutations; some providing a replicative advantage to the virus while others are detrimental. Circulating infectious HBV particles contain a circular partially double-stranded DNA of about 3200 nucleotides [20]. Soon after

The genetic/epigenetic landscape of HBV-related HCC

HBV contributes to HCC development through direct and indirect mechanisms.

Extensive evidence indicates that HCC is an extremely heterogeneous tumor at the genetic and molecular level, with a complex mutational landscape and multiple transcription and signaling pathways involved [8] (Fig. 1).

Direct oncogenic roles of HBV

HBV can promote carcinogenesis by three different mechanisms: a) a classic retrovirus-like insertional mutagenesis with the integration of viral DNA into host cancer genes like TERT, CCNE1, and MLL4; b) the promotion of genomic instability as the result of both the integration of viral DNA into the host genome and the activity of viral proteins; c) the ability of wild-type and mutated/truncated viral proteins (HBx, HBc and preS) to affect cell functions, activate oncogenic pathways and

Conclusions

HBV is a major risk factor worldwide for developing HCC and contributes to HCC development through direct and indirect mechanisms. Productive HBV infections trigger inflammation and continuous necrosis mediated by the immune response against infected hepatocytes. Compensatory proliferation of adult hepatocytes as well as of the bipotential hepatobilliary progenitors acting as facultative stem cells and residing in bile canaliculi (hepatic progenitor cells (HPCs) in humans, oval cells in

Financial support

JZR has grants from the Ligue contre le Cancer – France, INCa (Institut National du Cancer) ICGC Project – France; ANRS (Agence National de Recherche sur le SIDA et les Hepatities Virales) – France; ANR (Agence National de la Recherche) – France; PALSE (Package d’Accueil Lyon Saint Etienne) – France; EC Horizon 2020 (HepCar Project n. 667273).

Conflict of interest

These authors disclose the following: JZR is consultant for IntraGen. ML received consulting honoraria from Gilead, BMS, Assembly, Arbutus, Janssen, Medimmune, Galapagos.

Author contributions

ML and JZR participated in all stages of manuscript production, design, figures, tables, writing, and review of final version.

References (206)

  • C.T. Bock et al.

    Structural organization of the hepatitis B virus minichromosome

    J Mol Biol

    (2001)
  • M. Levrero et al.

    Control of cccDNA function in hepatitis B virus infection

    J Hepatol

    (2009)
  • T. Pollicino et al.

    Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones

    Gastroenterology

    (2006)
  • G.V. Papatheodoridis et al.

    Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review

    J Hepatol

    (2010)
  • T. Pollicino et al.

    Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications

    J Hepatol

    (2014)
  • C.H. Chen et al.

    Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients

    Gastroenterology

    (2007)
  • V. Bruss

    Revisiting the cytopathic effect of hepatitis B virus infection

    Hepatology

    (2002)
  • F.V. Chisari et al.

    Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice

    Cell

    (1989)
  • J.H. Hung et al.

    Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase

    J Biol Chem

    (2004)
  • A.M. Mathai et al.

    Type II ground-glass hepatocytes as a marker of hepatocellular carcinoma in chronic hepatitis B

    Hum Pathol

    (2013)
  • S.A. Lee et al.

    Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases

    J Hepatol

    (2012)
  • X. Gu et al.

    149G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population

    Hum Immunol

    (2010)
  • K. Migita et al.

    Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection–association between TGF-beta1 polymorphisms and hepatocellular carcinoma

    J Hepatol

    (2005)
  • X.D. Long et al.

    The polymorphism of XRCC3 codon 241 and AFB1-related hepatocellular carcinoma in Guangxi population, China

    Ann Epidemiol

    (2008)
  • B. Wang et al.

    Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis

    J Hepatol

    (2010)
  • E.T. Sawey et al.

    Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening

    Cancer Cell

    (2011)
  • V. Tovar et al.

    IGF activation in a molecular subclass of hepatocellular carcinoma and preclinical efficacy of IGF-1R blockage

    J Hepatol

    (2010)
  • P. Newell et al.

    Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo

    J Hepatol

    (2009)
  • S. Cairo et al.

    Hepatic stemlike phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer

    Cancer Cell

    (2008)
  • A.P. Venook et al.

    The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective

    Oncologist

    (2010)
  • Cancer IARC. Globocan. Estimated cancer incidence, mortality and prevalence worldwide in 2012. World Health...
  • D.R. McGivern et al.

    Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer

    Oncogene

    (2011)
  • F. Guerrieri et al.

    Molecular mechanisms of HBV-associated hepatocarcinogenesis

    Semin Liver Dis

    (2013)
  • J. Zucman-Rossi et al.

    Genetic landscape and biomarkers of hepatocellular carcinoma

    Gastroenterology

    (2015)
  • C.J. Chen et al.

    REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level

    JAMA

    (2006)
  • M. Sherman

    Risk of hepatocellular carcinoma in hepatitis B and prevention through treatment

    Cleve Clin J Med

    (2009)
  • S.H. Wang et al.

    Estrogen receptor a represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4a

    Gastroenterology

    (2012)
  • W.E. Naugler et al.

    Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production

    Science

    (2007)
  • F. Donato et al.

    Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women

    Am J Epidemiol

    (2002)
  • L. Belloni et al.

    Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

    Proc Natl Acad Sci U S A

    (2009)
  • S. Benhenda et al.

    Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription

    J Virol

    (2013)
  • D. Cougot et al.

    Inhibition of PP1 phosphatase activity by HBx: a mechanism for the activation of hepatitis B virus transcription

    Sci Signal

    (2012)
  • EASL clinical practice guidelines: management of CHB

    J Hepatol

    (2009)
  • T. Tu et al.

    Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection

    J Viral Hepat

    (2015)
  • A.M. Di Bisceglie

    Hepatitis B and hepatocellular carcinoma

    Hepatology

    (2009)
  • H.L. Chan et al.

    Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

    Gut

    (2004)
  • F. Zoulim et al.

    Hepatitis B virus resistance to nucleos(t)ide analogues

    Gastroenterology

    (2009)
  • S.Y. Kuang et al.

    Specific mutations of hepatitis B virus in plasma predict liver cancer development

    Proc Natl Acad Sci U S A

    (2004)
  • S. Liu et al.

    Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis

    J Natl Cancer Inst

    (2009)
  • F.V. Chisari et al.

    Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice

    J Virol

    (1986)
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