1 3254 58 HEPATITIS B VIRUS X PROTEIN AND HEPATOCARCINOGENESIS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ONE OF THE MOST ASSOCIATED FACTORS IN HEPATOCARCINOGENESIS. HBV IS ABLE TO INTEGRATE INTO THE HOST GENOME AND ENCODE THE MULTI-FUNCTIONAL HEPATITIS B VIRUS X PROTEIN (HBX). ALTHOUGH THE MECHANISM BETWEEN HBX AND CARCINOGENESIS IS STILL ELUSIVE, RECENT STUDIES HAVE SHOWN THAT HBX WAS ABLE TO INFLUENCE VARIOUS SIGNALING PATHWAYS, AS WELL AS EPIGENETIC AND GENETIC PROCESSES. THIS REVIEW WILL EXAMINE AND SUMMARIZE RECENT LITERATURE ABOUT HBX'S ROLE IN THESE VARIOUS PROCESSES. 2016 2 3255 26 HEPATITIS B VIRUS X PROTEIN MEDIATED EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM. HEPATITIS B VIRUS X PROTEIN (HBX), A PLEIOTROPIC REGULATORY PROTEIN ENCODED BY HBV, IS NECESSARY FOR THE TRANSCRIPTION OF HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) MINICHROMOSOMES, AND AFFECTS THE EPIGENETIC REGULATION OF HOST CELLS. THE EPIGENETIC REPROGRAMMING OF HBX ON HOST CELL GENOME IS STRONGLY INVOLVED IN HBV-RELATED HCC CARCINOGENESIS. HERE, WE REVIEW THE LATEST FINDINGS OF THE EPIGENETIC REGULATION INDUCED BY HBX PROTEIN IN HEPATOCELLULAR CARCINOMA (HCC), INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNA EXPRESSION. THE INFLUENCE OF HBX ON THE EPIGENETIC REGULATION OF CCCDNA IS ALSO SUMMARIZED. IN ADDITION, PRELIMINARY STUDIES OF TARGETED DRUGS FOR EPIGENETIC CHANGES INDUCED BY HBX ARE ALSO DISCUSSED. THE EXPLORATION OF EPIGENETIC MARKERS AS POTENTIAL TARGETS WILL HELP TO DEVELOP NEW PREVENTION AND/OR TREATMENT METHODS FOR HBX-RELATED HCC. 2022 3 4449 32 MOLECULAR MECHANISM OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) INFECTION IS A GLOBAL PUBLIC HEALTH PROBLEM WITH APPROXIMATELY 2 BILLION PEOPLE THAT HAVE BEEN EXPOSED TO THE VIRUS. HBV IS A MEMBER OF A FAMILY OF SMALL, ENVELOPED DNA VIRUSES CALLED HEPADNAVIRUSES, AND HAS A PREFERENTIAL TROPISM FOR HEPATOCYTES OF MAMMALS AND BIRDS. EPIDEMIOLOGICAL STUDIES HAVE PROVED A STRONG CORRELATION BETWEEN CHRONIC HEPATITIS B VIRUS INFECTION AND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HCC IS THE FIFTH MOST COMMON MALIGNANCY WITH ABOUT 700000 NEW CASES EACH YEAR, AND MORE THAN 50% OF THEM ARISE IN HBV CARRIERS. A LARGE NUMBER OF STUDIES DESCRIBE THE WAY IN WHICH HBV CAN CONTRIBUTE TO HCC DEVELOPMENT. MULTIPLE MECHANISMS HAVE BEEN PROPOSED, INCLUDING THE ACCUMULATION OF GENETIC DAMAGE DUE TO IMMUNE-MEDIATED HEPATIC INFLAMMATION AND THE INDUCTION OF OXIDATIVE STRESS. THERE IS EVIDENCE OF THE DIRECT EFFECTS OF THE VIRAL PROTEINS HBX AND HBS ON THE CELL BIOLOGY. INTEGRATION OF HBV-DNA INTO THE HUMAN GENOME IS CONSIDERED AN EARLY EVENT IN THE CARCINOGENIC PROCESS AND CAN INDUCE, THROUGH INSERTIONAL MUTAGENESIS, THE ALTERATION OF GENE EXPRESSION AND CHROMOSOMAL INSTABILITY. HBV HAS ALSO EPIGENETIC EFFECTS THROUGH THE MODIFICATION OF THE GENOMIC METHYLATION STATUS. FURTHERMORE, THE VIRUS PLAYS AN IMPORTANT ROLE IN THE REGULATION OF MICRORNA EXPRESSION. THIS REVIEW WILL SUMMARIZE THE MANY MECHANISMS INVOLVED IN HBV-RELATED LIVER CARCINOGENESIS. 2014 4 3263 29 HEPATITIS VIRUS AND HEPATOCELLULAR CARCINOMA: RECENT ADVANCES. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL HEALTH CHALLENGE, CAUSING 600,000 DEATHS EACH YEAR. INFECTIOUS FACTORS, INCLUDING HEPATITIS B VIRUS (HBV), HEPATITIS C VIRUS (HCV) AND HEPATITIS D VIRUS (HDV), HAVE LONG BEEN CONSIDERED THE MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF HCC. THESE PATHOGENS INDUCE HEPATOCYTE TRANSFORMATION THROUGH A VARIETY OF MECHANISMS, INCLUDING INSERTIONAL MUTATIONS CAUSED BY VIRAL GENE INTEGRATION, EPIGENETIC CHANGES, AND THE INDUCTION OF LONG-TERM IMMUNE DYSFUNCTION. THE DISCOVERY OF THESE MECHANISMS, WHILE ADVANCING OUR UNDERSTANDING OF THE DISEASE, ALSO PROVIDES TARGETS FOR NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. IN ADDITION, THE DISCOVERY AND RESEARCH OF CHRONIC HEV INFECTION OVER THE PAST DECADE INDICATE THAT THIS COMMON HEPATITIS VIRUS ALSO SEEMS TO HAVE THE POTENTIAL TO INDUCE HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT STUDIES ON THE LINK BETWEEN HEPATITIS VIRUS AND HCC, AS WELL AS NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO HCC BASED ON THESE FINDINGS. FINALLY, WE ALSO DISCUSS THE POTENTIAL RELATIONSHIP BETWEEN HEV AND HCC. IN CONCLUSION, THESE ASSOCIATIONS WILL FURTHER OPTIMIZE THE DIAGNOSIS AND TREATMENT OF INFECTION-ASSOCIATED HCC AND CALL FOR BETTER MANAGEMENT POLICIES. 2023 5 2939 23 GENETIC AND EPIGENETIC ALTERATIONS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). ITS CHRONIC INFECTION CAN LEAD TO CHRONIC LIVER INFLAMMATION AND THE ACCUMULATION OF GENETIC ALTERATIONS TO RESULT IN THE ONCOGENIC TRANSFORMATION OF HEPATOCYTES. HBV CAN ALSO SENSITIZE HEPATOCYTES TO ONCOGENIC TRANSFORMATION BY CAUSING GENETIC AND EPIGENETIC CHANGES OF THE HOST CHROMOSOMES. HBV DNA CAN INSERT INTO HOST CHROMOSOMES AND RECENT LARGE-SCALE WHOLE-GENOME SEQUENCING STUDIES REVEALED RECURRENT HBV DNA INTEGRATIONS SITES THAT MAY PLAY IMPORTANT ROLES IN THE INITIATION OF HEPATOCELLULAR CARCINOGENESIS. HBV CAN ALSO CAUSE EPIGENETIC CHANGES BY ALTERING THE METHYLATION STATUS OF CELLULAR DNA, THE POST-TRANSLATIONAL MODIFICATION OF HISTONES, AND THE EXPRESSION OF MICRORNAS. THESE CHANGES CAN ALSO LEAD TO THE EVENTUAL HEPATOCELLULAR TRANSFORMATION. THESE RECENT FINDINGS ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THE HOST CHROMOSOMES INDUCED BY HBV OPENED A NEW AVENUE FOR THE DEVELOPMENT OF NOVEL DIAGNOSIS AND TREATMENTS FOR HBV-INDUCED HCC. 2015 6 2980 24 GENETIC BASIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA: LINKAGE BETWEEN INFECTION, INFLAMMATION, AND TUMORIGENESIS. HEPATITIS VIRUS INFECTION IS A LEADING CAUSE OF CHRONIC LIVER DISEASE, INCLUDING CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH ANTI-VIRAL THERAPIES AGAINST HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) HAVE DRAMATICALLY PROGRESSED DURING THE PAST DECADE, THE ESTIMATED NUMBER OF PEOPLE CHRONICALLY INFECTED WITH HBV AND/OR HCV IS ~370 MILLION, AND HEPATITIS VIRUS-ASSOCIATED HEPATOCARCINOGENESIS IS A SERIOUS HEALTH CONCERN WORLDWIDE. UNDERSTANDING THE MECHANISM OF VIRUS-ASSOCIATED CARCINOGENESIS IS CRUCIAL TOWARD BOTH TREATMENT AND PREVENTION, AND THE RECENTLY DEVELOPED WHOLE GENOME/EXOME SEQUENCING ANALYSIS USING NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS CONTRIBUTED TO UNVEILING THE LANDSCAPE OF GENETIC AND EPIGENETIC ABERRATIONS IN NOT ONLY TUMOR TISSUES BUT ALSO THE BACKGROUND LIVER TISSUES UNDERLYING CHRONIC LIVER DAMAGE CAUSED BY HEPATITIS VIRUS INFECTION. SEVERAL MAJOR MECHANISMS UNDERLIE THE GENETIC AND EPIGENETIC ABERRATIONS IN THE HEPATITIS VIRUS-INFECTED LIVER, SUCH AS THE GENERATION OF REACTIVE OXIDATIVE STRESS, ECTOPIC EXPRESSION OF DNA MUTATOR ENZYMES, AND DYSFUNCTION OF THE DNA REPAIR SYSTEM. IN ADDITION, DIRECT ONCOGENIC EFFECTS OF HEPATITIS VIRUS, REPRESENTED BY THE INTEGRATION OF HBV-DNA, ARE OBSERVED IN INFECTED HEPATOCYTES. ELUCIDATING THE WHOLE PICTURE OF GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS THE MECHANISMS OF TUMORIGENESIS, WILL FACILITATE THE DEVELOPMENT OF EFFICIENT TREATMENT AND PREVENTION STRATEGIES FOR HEPATITIS VIRUS-ASSOCIATED HCC. 2017 7 3401 27 HOW DID HEPATITIS B VIRUS EFFECT THE HOST GENOME IN THE LAST DECADE? THE PRINCIPAL REASON OF CHRONIC LIVER DISEASE, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS CHRONIC VIRAL HEPATITIS ALL OVER THE WORLD. HEPATITIS B VIRUS (HBV) HAS SOME MUTAGENIC EFFECTS ON THE HOST GENOME. HBV MAY BE EXHIBITING THESE MUTAGENIC EFFECTS THROUGH INTEGRATING INTO THE HOST GENOME, THROUGH ITS VIRAL PROTEINS OR THROUGH SOME EPIGENETIC MECHANISMS RELATED WITH HBV PROTEINS. THIS REVIEW AIMS TO SUMMARIZE THE MOLECULAR MECHANISMS USED BY HBV FOR EFFECTING HOST GENOME DETERMINED IN THE LAST DECADE. THE FOCUS WILL BE ON THE EFFECTS OF INTEGRATION, HBV PROTEINS, ESPECIALLY HBV X PROTEIN AND EPIGENETIC MECHANISMS ON THE HOST GENOME. THESE INTERACTIONS BETWEEN HBV AND THE HOST GENOME ALSO FORMS THE UNDERLYING MECHANISMS OF THE EVOLUTION OF HEPATOCELLULAR CARCINOMA. 2014 8 3187 28 HBV INDUCED HEPATOCELLULAR CARCINOMA AND RELATED POTENTIAL IMMUNOTHERAPY. CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) HAS LONG BEEN RECOGNIZED AS A MAJOR RISK FACTOR IN THE INITIATION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CONTRIBUTING TO OVER HALF THE CASES OF HCC WORLDWIDE. TRANSFORMATION OF THE LIVER WITH HBV INFECTION TO HCC MAINLY RESULTS FROM LONG-TERM INTERACTION BETWEEN HBV AND THE HOST HEPATOCYTES VIA A VARIETY OF MECHANISMS, INCLUDING HBV DNA INTEGRATION, PROLONGED EXPRESSION OF THE VIRAL HBX REGULATORY PROTEIN AND/OR ABERRANT PRES/S ENVELOPE PROTEINS, AND EPIGENETIC DYSREGULATION OF TUMOR SUPPRESSOR GENES. WHILE THERE HAVE BEEN SEVERAL FAILURES IN THE DEVELOPMENT OF DRUGS FOR HCC, THE IMMUNE-TOLERANT MICROENVIRONMENT OF THIS MALIGNANCY SUGGESTS THAT IMMUNOTHERAPEUTIC AGENTS COULD PROVIDE BENEFITS FOR THESE PATIENTS. THIS IS SUPPORTED BY RECENT DATA SHOWING THAT IMMUNOTHERAPY HAS PROMISING ACTIVITY IN PATIENTS WITH ADVANCED HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF HBV-INDUCED HCC AND RECENT IMMUNE BASED APPROACHES FOR THE TREATMENT OF HCC PATIENTS. 2020 9 3274 36 HEPATOCELLULAR CARCINOMA: THE VIRUS OR THE LIVER? HEPATOCELLULAR CARCINOMA (HCC) REPRESENTS A MAJOR PUBLIC HEALTH PROBLEM BEING ONE OF THE MOST COMMON CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. HEPATITIS B (HBV) AND C VIRUSES HAVE BEEN CLASSIFIED AS ONCOVIRUSES AND ARE RESPONSIBLE FOR THE MAJORITY OF HCC CASES, WHILE THE ROLE OF HEPATITIS D VIRUS (HDV) IN LIVER CARCINOGENESIS HAS NOT BEEN ELUCIDATED. HDV/HBV COINFECTION IS RELATED TO MORE SEVERE LIVER DAMAGE THAN HBV MONO-INFECTION AND RECENT STUDIES SUGGEST THAT HDV/HBV PATIENTS ARE AT INCREASED RISK OF DEVELOPING HCC COMPARED TO HBV MONO-INFECTED PATIENTS. HBV IS KNOWN TO PROMOTE HEPATOCARCINOGENESIS VIA DNA INTEGRATION INTO HOST DNA, DISRUPTION OF MOLECULAR PATHWAYS BY REGULATORY HBV X (HBX) PROTEIN AND EXCESSIVE OXIDATIVE STRESS. RECENTLY, SEVERAL MOLECULAR MECHANISMS HAVE BEEN PROPOSED TO CLARIFY THE PATHOGENESIS OF HDV-RELATED HCC INCLUDING ACTIVATION OF SIGNALLING PATHWAYS BY SPECIFIC HDV ANTIGENS, EPIGENETIC DYSREGULATION AND ALTERED GENE EXPRESSION. ALONGSIDE, ONGOING CHRONIC INFLAMMATION AND IMPAIRED IMMUNE RESPONSES HAVE ALSO BEEN SUGGESTED TO FACILITATE CARCINOGENESIS. FINALLY, CELLULAR SENESCENCE SEEMS TO PLAY AN IMPORTANT ROLE IN CHRONIC VIRAL INFECTION AND INFLAMMATION LEADING TO HEPATOCARCINOGENESIS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT LITERATURE ON THE IMPACT OF HDV IN HCC DEVELOPMENT AND DISCUSS THE POTENTIAL INTERPLAY BETWEEN HBV, HDV AND NEIGHBOURING LIVER TISSUE IN LIVER CARCINOGENESIS. 2023 10 4454 26 MOLECULAR MECHANISMS DRIVING PROGRESSION OF LIVER CIRRHOSIS TOWARDS HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B AND C INFECTIONS: A REVIEW. ALMOST ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC), A MAJOR TYPE OF PRIMARY LIVER CANCER, ALSO HAVE LIVER CIRRHOSIS, THE SEVERITY OF WHICH HAMPERS EFFECTIVE TREATMENT FOR HCC DESPITE RECENT PROGRESS IN THE EFFICACY OF ANTICANCER DRUGS FOR ADVANCED STAGES OF HCC. HERE, WE REVIEW RECENT KNOWLEDGE CONCERNING THE MOLECULAR MECHANISMS OF LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC FROM GENETIC AND EPIGENOMIC POINTS OF VIEW. BECAUSE ~70% OF PATIENTS WITH HCC HAVE HEPATITIS B VIRUS (HBV) AND/OR HEPATITIS C VIRUS (HCV) INFECTION, WE FOCUSED ON HBV- AND HCV-ASSOCIATED HCC. THE LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC FACTORS, SUCH AS MICRORNAS, PLAY A ROLE IN LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC, AND THAT HBV- AND HCV-ENCODED PROTEINS APPEAR TO BE INVOLVED IN HEPATOCARCINOGENESIS. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE MECHANISMS, INCLUDING IMMUNE CHECKPOINTS AND MOLECULAR TARGETS OF KINASE INHIBITORS, ASSOCIATED WITH LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC. 2019 11 6271 27 THE ONCOGENIC ROLE OF HEPATITIS B VIRUS. THE HEPATITIS B VIRUS (HBV) IS A SMALL ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A WORLD HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV HAS BEEN CLASSIFIED AMONG HUMAN TUMOR VIRUSES BY VIRTUE OF A ROBUST EPIDEMIOLOGIC ASSOCIATION BETWEEN CHRONIC HBV CARRIAGE AND HCC OCCURRENCE. IN THE ABSENCE OF CYTOPATHIC EFFECT IN INFECTED HEPATOCYTES, THE ONCOGENIC ROLE OF HBV MIGHT INVOLVE A COMBINATION OF DIRECT AND INDIRECT EFFECTS OF THE VIRUS DURING THE MULTISTEP PROCESS OF LIVER CARCINOGENESIS. LIVER INFLAMMATION AND HEPATOCYTE PROLIFERATION DRIVEN BY HOST IMMUNE RESPONSES ARE RECOGNIZED DRIVING FORCES OF LIVER CELL TRANSFORMATION. GENETIC AND EPIGENETIC ALTERATIONS CAN ALSO RESULT FROM VIRAL DNA INTEGRATION INTO HOST CHROMOSOMES AND FROM PROLONGED EXPRESSION OF VIRAL GENE PRODUCTS. NOTABLY, THE TRANSCRIPTIONAL REGULATORY PROTEIN HBX ENCODED BY THE X GENE IS ENDOWED WITH TUMOR PROMOTER ACTIVITY. HBX HAS PLEIOTROPIC ACTIVITIES AND PLAYS A MAJOR ROLE IN HBV PATHOGENESIS AND IN LIVER CARCINOGENESIS. BECAUSE HEPATIC TUMORS CARRY A DISMAL PROGNOSIS, THERE IS URGENT NEED TO DEVELOP EARLY DIAGNOSTIC MARKERS OF HCC AND EFFECTIVE THERAPIES AGAINST CHRONIC HEPATITIS B. DECIPHERING THE ONCOGENIC MECHANISMS THAT UNDERLIE HBV-RELATED TUMORIGENESIS MIGHT HELP DEVELOPING ADAPTED THERAPEUTIC STRATEGIES. 2014 12 3253 29 HEPATITIS B VIRUS X PROTEIN ACCELERATES THE DEVELOPMENT OF HEPATOMA. THE CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) IS CLOSELY RELATED TO THE OCCURRENCE AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). ACCUMULATED EVIDENCE HAS SHOWN THAT HBV X PROTEIN (HBX PROTEIN) IS A MULTIFUNCTIONAL REGULATOR WITH A CRUCIAL ROLE IN HEPATOCARCINOGENESIS. HOWEVER, INFORMATION ON THE MECHANISM BY WHICH HBV INDUCES HCC IS LACKING. THIS REVIEW FOCUSES ON THE PATHOLOGICAL FUNCTIONS OF HBX IN HBV-INDUCED HEPATOCARCINOGENESIS. AS A TRANSACTIVATOR, HBX CAN MODULATE NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) AND TRANSCRIPTION FACTOR AP-2. MOREOVER, HBX CAN AFFECT REGULATORY NON-CODING RNAS (NCRNAS) INCLUDING MICRORNAS AND LONG NCRNAS (LNCRNAS), SUCH AS MIRNA-205 AND HIGHLY UPREGULATED IN LIVER CANCER (HULC), RESPECTIVELY. HBX IS ALSO INVOLVED IN EPIGENETIC MODIFICATION, INCLUDING METHYLATION AND ACETYLATION. HBX INTERACTS WITH VARIOUS SIGNAL-TRANSDUCTION PATHWAYS, SUCH AS PROTEIN KINASE B/AKT, WNT/BETA-CATENIN, SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION, AND NF-KAPPAB PATHWAYS. MOREOVER, HBX AFFECTS CELLULAR FATE BY SHIFTING THE BALANCE TOWARD CELL SURVIVAL. HBX MAY LEAD TO THE LOSS OF APOPTOTIC FUNCTIONS OR DIRECTLY CONTRIBUTES TO ONCOGENESIS BY ACHIEVING TRANSFORMING FUNCTIONS, WHICH INDUCE HEPATOCARCINOGENESIS. ADDITIONALLY, HBX CAN MODULATE APOPTOSIS AND IMMUNE RESPONSE BY DIRECT OR INDIRECT INTERACTION WITH HOST FACTORS. WE CONCLUDE THAT HBX HASTENS THE DEVELOPMENT OF HEPATOMA. 2014 13 3394 24 HOST EPIGENETIC ALTERATIONS AND HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST FREQUENT PRIMARY MALIGNANCY OF THE LIVER AND A LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH MUCH PROGRESS HAS BEEN MADE IN HCC DRUG DEVELOPMENT IN RECENT YEARS, TREATMENT OPTIONS REMAIN LIMITED. THE MAJOR CAUSE OF HCC IS CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. DESPITE THE EXISTENCE OF A VACCINE, MORE THAN 250 MILLION INDIVIDUALS ARE CHRONICALLY INFECTED BY HBV. CURRENT ANTIVIRAL THERAPIES CAN REPRESS VIRAL REPLICATION BUT TO DATE THERE IS NO CURE FOR CHRONIC HEPATITIS B. OF NOTE, INHIBITION OF VIRAL REPLICATION REDUCES BUT DOES NOT ELIMINATE THE RISK OF HCC DEVELOPMENT. HBV CONTRIBUTES TO LIVER CARCINOGENESIS BY DIRECT AND INDIRECT EFFECTS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF HBV-INDUCED HOST EPIGENETIC ALTERATIONS AND THEIR ASSOCIATION WITH HCC, WITH AN EMPHASIS ON THE INTERACTIONS BETWEEN HBV PROTEINS AND THE HOST CELL EPIGENETIC MACHINERY LEADING TO MODULATION OF GENE EXPRESSION. 2021 14 6016 29 THE ASSOCIATION BETWEEN HEPATOCARCINOGENESIS AND INTRACELLULAR ALTERATIONS DUE TO HEPATITIS B VIRUS INFECTION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM LEADING TO SEVERE LIVER DYSFUNCTION, INCLUDING LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. ALTHOUGH CURRENT ANTIVIRAL THERAPIES FOR CHRONIC HBV INFECTION HAVE BEEN IMPROVED AND CAN LEAD TO A STRONG SUPPRESSION OF VIRAL REPLICATION, IT IS DIFFICULT TO COMPLETELY ELIMINATE THE VIRUS WITH THESE THERAPIES ONCE CHRONIC HBV INFECTION IS ESTABLISHED IN THE HOST. FURTHERMORE, CHRONIC HBV INFECTION ALTERS INTRACELLULAR METABOLISM AND SIGNALLING PATHWAYS, RESULTING IN THE ACTIVATION OF CARCINOGENESIS IN THE LIVER. HBV PRODUCES FOUR VIRAL PROTEINS: HEPATITIS B SURFACE-, HEPATITIS B CORE-, HEPATITIS B X PROTEIN, AND POLYMERASE; EACH PLAYS AN IMPORTANT ROLE IN HBV REPLICATION AND THE INTRACELLULAR SIGNALLING PATHWAYS ASSOCIATED WITH HEPATOCARCINOGENESIS. IN VITRO AND IN VIVO EXPERIMENTAL MODELS FOR ANALYZING HBV INFECTION AND REPLICATION HAVE BEEN ESTABLISHED, AND GENE EXPRESSION ANALYSES USING MICROARRAYS OR NEXT-GENERATION SEQUENCING HAVE ALSO BEEN DEVELOPED. THUS, IT IS POSSIBLE TO CLARIFY THE MOLECULAR MECHANISMS FOR INTRACELLULAR ALTERATIONS, SUCH AS ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, THE IMPACT OF HBV VIRAL PROTEINS AND INTRACELLULAR ALTERATIONS IN HBV-ASSOCIATED HEPATOCARCINOGENESIS ARE DISCUSSED. 2021 15 2165 30 EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION OF THE LIVER BY THE HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH INCREASED RISK FOR DEVELOPING HEPATOCELLULAR CARCINOMA (HCC). A MULTITUDE OF STUDIES HAVE INVESTIGATED THE MECHANISM OF LIVER CANCER PATHOGENESIS DUE TO CHRONIC HBV INFECTION. CHRONIC INFLAMMATION, EXPRESSION OF SPECIFIC VIRAL PROTEINS SUCH AS HBX, THE INTEGRATION SITE OF THE VIRAL GENOME INTO THE HOST GENOME, AND THE VIRAL GENOTYPE, ARE KEY PLAYERS CONTRIBUTING TO HCC PATHOGENESIS. IN ADDITION, THE GENETIC BACKGROUND OF THE HOST AND EXPOSURE TO ENVIRONMENTAL CARCINOGENS ARE ALSO PREDISPOSING PARAMETERS IN HEPATOCARCINOGENESIS. DESPITE THE PLETHORA OF STUDIES, THE MOLECULAR MECHANISM OF HCC PATHOGENESIS REMAINS INCOMPLETELY UNDERSTOOD. IN THIS REVIEW, THE FOCUS IS ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF HBV-ASSOCIATED HCC. EPIGENETIC MECHANISMS ARE DYNAMIC MOLECULAR PROCESSES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE HOST DNA, ACTING BY MODIFYING THE HOST CHROMATIN STRUCTURE VIA COVALENT POST-TRANSLATIONAL HISTONE MODIFICATIONS, CHANGING THE DNA METHYLATION STATUS, EXPRESSION OF NON-CODING RNAS SUCH AS MICRORNAS AND LONG NONCODING RNAS, AND ALTERING THE SPATIAL, 3-D ORGANIZATION OF THE CHROMATIN OF THE VIRUS-INFECTED CELL. HEREIN, STUDIES ARE DESCRIBED THAT PROVIDE EVIDENCE IN SUPPORT OF DEREGULATION OF EPIGENETIC MECHANISMS IN THE HBV-INFECTED/-REPLICATING HEPATOCYTE AND THEIR CONTRIBUTION TO HEPATOCYTE TRANSFORMATION. IN CONTRAST TO GENETIC MUTATIONS WHICH ARE PERMANENT, EPIGENETIC ALTERATIONS ARE DYNAMIC AND REVERSIBLE. ACCORDINGLY, THE IDENTIFICATION OF ESSENTIAL MOLECULAR EPIGENETIC TARGETS INVOLVED IN HBV-MEDIATED HCC PATHOGENESIS OFFERS THE OPPORTUNITY FOR THE DESIGN AND DEVELOPMENT OF NOVEL EPIGENETIC THERAPEUTIC APPROACHES. 2021 16 3251 34 HEPATITIS B VIRUS INFECTION: AN INSIGHT INTO THE CLINICAL CONNECTION AND MOLECULAR INTERACTION BETWEEN HEPATITIS B VIRUS AND HOST EXTRAHEPATIC CANCER RISK. THE EVIDENCE FOR CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND HEPATOCELLULAR CARCINOMA (HCC) OCCURRENCE IS WELL ESTABLISHED. THE HEPATOCYTE EPITHELIUM CARCINOGENESIS CAUSED BY HBV HAS BEEN INVESTIGATED AND REVIEWED IN DEPTH. NEVERTHELESS, RECENT FINDINGS FROM PRECLINICAL AND OBSERVATIONAL STUDIES SUGGESTED THAT CHRONIC HBV INFECTION IS EQUALLY IMPORTANT IN EXTRAHEPATIC CANCER OCCURRENCE AND SURVIVAL, SPECIFICALLY GASTROINTESTINAL SYSTEM-DERIVED CANCERS. IMMUNE MICROENVIRONMENT CHANGES (IMMUNE-SUPPRESSIVE CYTOKINE INFILTRATION), EPIGENETIC MODIFICATION (N6-METHYLADENOSINE), MOLECULAR SIGNALING PATHWAYS (PI3K-AKT AND WNT), AND SERUM BIOMARKERS SUCH AS HEPATITIS B VIRUS X (HBX) PROTEIN ARE POTENTIAL UNDERLYING MECHANISMS IN CHRONIC HBV INFECTION-INDUCED EXTRAHEPATIC CANCERS. THIS NARRATIVE REVIEW AIMED TO COMPREHENSIVELY SUMMARIZE THE MOST RECENT ADVANCES IN EVALUATING THE ASSOCIATION BETWEEN CHRONIC HBV INFECTION AND EXTRAHEPATIC CANCER RISK AND EXPLORE THE POTENTIAL UNDERLYING MOLECULAR MECHANISMS IN THE CARCINOGENESIS INDUCTION OF EXTRAHEPATIC CANCERS IN CHRONIC HBV CONDITIONS. 2023 17 6115 23 THE EPIGENETIC CONTROL OF HEPATITIS B VIRUS MODULATES THE OUTCOME OF INFECTION. EPIGENETIC MODIFICATIONS ARE STABLE ALTERATIONS IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS OF THE GENETIC SEQUENCE ITSELF. IT HAS BECOME INCREASINGLY CLEAR THAT EPIGENETIC FACTORS CONTRIBUTE TO THE OUTCOME OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION BY AFFECTING CELLULAR AND VIRION GENE EXPRESSION, VIRAL REPLICATION AND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. HBV PERSISTS IN THE NUCLEUS OF INFECTED HEPATOCYTES AS A STABLE NON-INTEGRATED COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) WHICH FUNCTIONS AS A MINICHROMOSOME. THERE ARE TWO MAJOR FORMS OF HBV EPIGENETIC REGULATION: POSTTRANSLATIONAL MODIFICATION OF HISTONE PROTEINS ASSOCIATED WITH THE CCCDNA MINICHROMOSOME AND DNA METHYLATION OF VIRAL AND HOST GENOMES. THIS REVIEW EXPLORES HOW HBV CAN INTERPHASE WITH HOST EPIGENETIC REGULATION IN ORDER TO EVADE HOST DEFENCES AND TO PROMOTE ITS OWN SURVIVAL AND PERSISTENCE. WE FOCUS ON THE EFFECT OF CCCDNA BOUND-HISTONE MODIFICATIONS AND THE METHYLATION STATUS OF HBV DNA IN REGULATING VIRAL REPLICATION. INVESTIGATION OF HBV EPIGENETIC CONTROL HAS IMPORTANT CLINICAL CORRELATES WITH REGARDS TO THE DEVELOPMENT OF POTENTIAL THERAPEUTIC REGIMENS THAT WILL SUCCESSFULLY ERADICATE HBV INFECTION AND DEAL WITH HBV REACTIVATION IN THOSE UNDERGOING TREATMENT WITH DEMETHYLATING AGENTS. 2015 18 915 27 CHRONIC HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS AND CANCER: SYNERGY BETWEEN VIRAL AND HOST FACTORS. HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTIONS REPRESENT MAJOR CAUSES OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. DESPITE INDUCING SHARED PATHOLOGICAL EVENTS LEADING TO ONCOGENIC TRANSFORMATION, THESE TWO VIRUSES PRESENT PROFOUND DIFFERENCES IN THEIR MOLECULAR FEATURES, LIFE CYCLE AND INTERPLAY WITH HOST FACTORS, WHICH SIGNIFICANTLY DIFFERENTIATE THE PROGNOSTIC AND THERAPEUTIC APPROACH TO THE RELATED DISEASES. IN THE PRESENT REVIEW, WE REPORT THE MAIN MECHANISMS INVOLVED IN THE MULTISTEP PROCESS LEADING FROM HCV/HBV INFECTION AND CANCER DEVELOPMENT, DISCUSSING SIDE-BY-SIDE THE ANALOGIES AND DIFFERENCES BETWEEN THE TWO VIRUSES. SUCH EVENTS CAN BE BROADLY CATEGORIZED INTO (A) DIRECT ONCOGENIC EFFECTS, INVOLVING INTEGRATION IN THE HOST GENOME (IN THE CASE OF HBV) AND CHROMOSOMAL INSTABILITY, INTERFERENCE WITH ONCOSUPPRESSOR PATHWAYS, INDUCTION OF OXIDATIVE STRESS, PROMOTION OF ANGIOGENESIS, EPITHELIAL-MESENCHYMAL TRANSITION, ALTERATIONS IN THE EPIGENETIC ASSET AND INTERACTION WITH NON-CODING RNAS; AND (B) INDIRECT ACTIVITIES MOSTLY MEDIATED BY HOST EVENTS, INCLUDING CHRONIC INFLAMMATION SUSTAINED BY PECULIAR CYTOKINE NETWORKS (SUCH AS INTERLEUKIN-6 AND LYMPHOTOXINS), METABOLIC DYSFUNCTIONS PROMOTED BY STEATOHEPATITIS, INTERPLAY WITH GUT MICROBIOTA AND FIBROTIC EVENTS (MAINLY IN HCV INFECTION). THIS SCENARIO SUGGESTS THAT THE INTEGRATED STUDY OF VIRAL AND HOST FACTORS MAY LEAD TO THE SUCCESSFUL DEVELOPMENT OF NOVEL BIOMARKERS AND TARGETS FOR THERAPY. 2015 19 1478 22 DIVERSE ROLES OF HEPATITIS B VIRUS IN LIVER CANCER. HEPATITIS B VIRUS (HBV) IS A WIDESPREAD HUMAN PATHOGEN RESPONSIBLE FOR ACUTE AND CHRONIC LIVER DISEASES. THE HEPATITIS B BURDEN IS PARTICULARLY HEAVY IN ENDEMIC COUNTRIES, WHERE LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA ARE LEADING CAUSES OF DEATH. HOWEVER, THE ONCOGENIC ROLE OF HBV REMAINS ENIGMATIC. AS THE VIRUS HAS NO CYTOPATHIC EFFECT, LIVER DAMAGE IS ATTRIBUTED TO IMMUNE RESPONSES THAT INDUCE INFLAMMATION, APOPTOSIS AND REGENERATION, FOSTERING THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN A MORE DIRECT ACTION, FREQUENT INTEGRATION OF HBV DNA INTO HOST CHROMOSOMES MAY LEAD TO INSERTIONAL MUTAGENESIS OF CANCER-RELATED GENES AND CHROMOSOMAL INSTABILITY. HBV PROTEINS, NOTABLY THE HBX TRANSACTIVATOR, PARTICIPATE AS CO-FACTORS IN ONCOGENESIS. BETTER UNDERSTANDING OF HEPATITIS B PATHOGENESIS IS MANDATORY FOR IMPROVING DISEASE MANAGEMENT. 2012 20 3256 25 HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA AND HEPATIC CANCER STEM CELLS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS LINKED TO HEPATOCELLULAR CARCINOMA (HCC) PATHOGENESIS. DESPITE THE AVAILABILITY OF A HBV VACCINE, CURRENT TREATMENTS FOR HCC ARE INADEQUATE. GLOBALLY, 257 MILLION PEOPLE ARE CHRONIC HBV CARRIERS, AND CHILDREN BORN FROM HBV-INFECTED MOTHERS BECOME CHRONIC CARRIERS, DESTINED TO DEVELOP LIVER CANCER. THUS, NEW THERAPEUTIC APPROACHES ARE NEEDED TO TARGET ESSENTIAL PATHWAYS INVOLVED IN HCC PATHOGENESIS. ACCUMULATING EVIDENCE SUPPORTS EXISTENCE OF HEPATIC CANCER STEM CELLS (HCSCS), WHICH CONTRIBUTE TO CHEMOTHERAPY RESISTANCE AND CANCER RECURRENCE AFTER TREATMENT OR SURGERY. UNDERSTANDING HOW HCSCS FORM WILL ENABLE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO PREVENT THEIR FORMATION. RECENT STUDIES HAVE IDENTIFIED AN EPIGENETIC MECHANISM INVOLVING THE DOWNREGULATION OF THE CHROMATIN MODIFYING POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) DURING HBV INFECTION, WHICH RESULTS IN RE-EXPRESSION OF HCSC MARKER GENES IN INFECTED HEPATOCYTES AND HBV-ASSOCIATED LIVER TUMORS. HOWEVER, THE GENESIS OF HCSCS REQUIRES, IN ADDITION TO THE EXPRESSION OF HCSC MARKERS CELLULAR CHANGES, REWIRING OF METABOLISM, CELL SURVIVAL, ESCAPE FROM PROGRAMMED CELL DEATH, AND IMMUNE EVASION. HOW THESE CHANGES OCCUR IN CHRONICALLY HBV-INFECTED HEPATOCYTES IS NOT YET UNDERSTOOD. IN THIS REVIEW, WE WILL PRESENT THE BASICS ABOUT HBV INFECTION AND HEPATOCARCINOGENESIS. NEXT, WE WILL DISCUSS STUDIES DESCRIBING THE MUTATIONAL LANDSCAPE OF LIVER CANCERS AND HOW EPIGENETIC MECHANISMS LIKELY ORCHESTRATE CELLULAR REPROGRAMING OF HEPATOCYTES TO ENABLE FORMATION OF HCSCS. 2018