1 6486 146 TP53 AND LIVER CARCINOGENESIS. PRIMARY HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES AND HAS THE FOURTH HIGHEST MORTALITY RATE WORLDWIDE. THE MAJOR RISK FACTORS, INCLUDING CHRONIC INFECTIONS WITH THE HEPATITIS B OR C VIRUS, ARE EXPOSURE TO DIETARY AFLATOXIN B1(AFB1), VINYL CHLORIDE, OR ALCOHOL CONSUMPTION. SOUTHERN CHINA AND SUB-SAHARAN AFRICA HAVE THE HIGHEST DIETARY AFB1 EXPOSURE, MAKING IT AND HEPATITIS B VIRUS (HBV) THE MAJOR CAUSES OF CANCER MORTALITY IN THESE GEOGRAPHIC AREAS. RECENT STUDIES HAVE DISCOVERED GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, INCLUDING SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53). AFB1 INDUCES TYPICAL G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF P53. CHRONIC ACTIVE HEPATITIS B AND C (HCV) INFECTION, AND FURTHER INFLAMMATORY AND OXYRADICAL DISORDERS INCLUDING WILSON DISEASE (WD) OR HEMOCHROMATOSIS, GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN DAMAGE DNA AND MUTATE THE P53 GENE. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC. THE INTEGRATED HBX IS FREQUENTLY MUTATED AND HAS A DIMINISHED ABILITY TO FUNCTION AS A TRANSCRIPTIONAL COTRANSACTIVATOR AND TO ACTIVATE THE NF-KAPPA B PATHWAY. HOWEVER, THE MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO AND ABROGATE P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY AND MOLECULAR PATHOGENESIS OF HCC. THE RESULTANT MOLECULAR CHANGES IN THE RAS AND WNT SIGNAL-TRANSDUCTION PATHWAYS, AND THE P53 AND RB TUMOR SUPPRESSOR PATHWAYS SIGNIFICANTLY CONTRIBUTE TO LIVER CARCINOGENESIS 2003 2 6487 104 TP53 MUTATIONS AND HEPATOCELLULAR CARCINOMA: INSIGHTS INTO THE ETIOLOGY AND PATHOGENESIS OF LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES WORLDWIDE AND THE MAJOR RISK FACTORS INCLUDE CHRONIC INFECTIONS WITH THE HEPATITIS B (HBV) OR C (HCV) VIRUS, AND EXPOSURE TO DIETARY AFLATOXIN B(1) (AFB(1)) OR ALCOHOL CONSUMPTION. MULTIPLE GENETIC AND EPIGENETIC CHANGES ARE INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, FOR EXAMPLE, SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53) AND THE ACTIVATION OF THE WNT SIGNAL TRANSDUCTION PATHWAY. AFB(1) FREQUENTLY INDUCES G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF TP53 AND COOPERATES WITH HBV IN CAUSING P53 MUTATIONS IN HCC. THE DETECTION OF TP53 MUTANT DNA IN PLASMA IS A BIOMARKER OF BOTH AFB(1) EXPOSURE AND HCC RISK. CHRONIC INFECTION WITH HBV AND HCV VIRUSES, AND OXYRADICAL DISORDERS INCLUDING HEMOCHROMATOSIS, ALSO GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN BOTH DAMAGE DNA AND MUTATE CANCER-RELATED GENES SUCH AS TP53. CERTAIN MUTANT P53 PROTEINS MAY EXHIBIT A 'GAIN OF ONCOGENIC FUNCTION'. THE P53 BIOLOGICAL NETWORK IS A KEY RESPONDER TO THIS OXIDATIVE AND NITROSATIVE STRESS. DEPENDING ON THE EXTENT OF THE DNA DAMAGE, P53 REGULATES THE TRANSCRIPTION OF PROTECTIVE ANTIOXIDANT GENES AND WITH EXTENSIVE DNA DAMAGE, TRANSACTIVATES PRO-OXIDANT GENES THAT CONTRIBUTE TO APOPTOSIS. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC AND THE INTEGRATED HBX IS FREQUENTLY MUTATED. MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO P53, AND ATTENUATE DNA REPAIR AND P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY OF TP53 MUTATIONS DURING THE MOLECULAR PATHOGENESIS OF HCC. 2007 3 3272 65 HEPATOCELLULAR CARCINOMA: AN UPDATE. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF MALES IN THE WORLD, WITH AN INCIDENCE OF 1,000,000 NEW CASES A YEAR. IT IS ENDEMIC IN SOUTHEAST ASIA AND SUB-SAHARAN AFRICA. RISK FACTORS INCLUDE CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), AFLATOXIN B1 UPTAKE, HEMOCHROMATOSIS, AND ALPHA1 -ANTITRIPSIN DEFICIENCY. EPIDEMIOLOGICAL STUDIES PROVIDE EVIDENCE FOR THE ASSOCIATION OF HCC WITH HBV INFECTION. THE INCIDENCE OF HCC IS HIGH IN REGIONS HYPERENDEMIC FOR HBV. CHRONIC CARRIER STATE AND MATERNAL-INFANT TRANSMISSION ARE IMPORTANT FACTORS IN THE DEVELOPMENT OF HCC. EVIDENCE OF DIRECT ONCOGENIC EFFECT OF H BV IS WELL ESTABLISHED, HCCS CONTAIN VIRAL DNA SEQUENCES INTEGRATED INTO HEPATOCYTE DNA THAT ACT AS RANDOM INSERTIONAL MUTAGENS, AND THESE SITES ARE NEAR GENES INVOLVED IN THE CONTROL OF PROLIFERATION AND DIFFERENTIATION. THE MECHANISM OF HEPATITIS C VIRUS IN HEPATOCARCINOGENESIS IS STILL IMPRECISE BUT A HIGH PERCENTAGE OF CASES ARE RELATED TO THIS VIRUS. CHRONIC ALCOHOL CONSUMPTION AND CIRRHOSIS ARE COFACTORS THAT INCREASE THE DEVELOPMENT OF HCC IN PATIENTS WITH CHRONIC VIRAL INFECTION. IN EXPERIMENTAL CARCINOGENESIS A MULTIPOTENTIAL ELEMENT CALLED OVAL CELL PROLIFERATES IN THE EARLY STAGES. THE CELLULAR EVENTS ARE ACCOMPANIED BY INCREASED EXPRESSION OF SEVERAL GROWTH FACTORS THAT ENHANCE THE SURVIVAL OF CARCINOGEN-ACTIVATED CELLS BY SUPPRESSING APOPTOSIS AND INCREASING ELEMENTS ENTERING THE CELL CYCLE. HEPATIC CARCINOGENESIS IS A COMPLEX PROCESS ASSOCIATED WITH ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES THAT RUN THROUGH STEPS OF INITIATION, PROMOTION AND PROGRESSION. ACTIVATION OF ONCOGENES OF THE "RAS" FAMILY AND OTHERS HAS BEEN DETECTED DURING CHEMICALLY-INDUCED HCC IN RODENTS, BUT THERE IS LITTLE EVIDENCE OF SUCH ACTIVATION IN HUMAN TUMORS. THE ROLE OF TUMOR SUPRESSOR GENES SUCH AS RETINOBLASTOMA (RB) AND P53 GENES HAS BEEN DOCUMENTED. AFLATOXIN B1 THAT CONTAMINATES FOODS IN ENDEMIC AREAS HAS A CLEAR ROLE IN HEPATOCARCINOGENESIS. METABOLITES OF THIS TOXIN PROMOTE APURINIC SITES AND G TO T MUTATIONS IN CHROMOSOMAL DNA, THE THIRD BASE OF CODON 249 OF THE P53 GENE IS PREFERENTIALLY TARGETED TO FORM ADUCTS WITH AFLATOXIN B1, AND THIS MUTATION HAS BEEN SPECIFICALLY IDENTIFIED IN HBV INFECTION. HISTOLOGICAL AND CYTOLOGICAL CRITERIA FOR THE DIAGNOSIS OF HCC ARE WELL ESTABLISHED AND ARE BASED IN ARCHITECTURAL AND CYTOLOGICAL CHANGES. AN IMPORTANT ISSUE IS THE DIAGNOSIS OF LIVER "NODULES" DETECTED BY IMAGE, FROM WHICH SMALL BIOPSIES OR ASPIRATION MATERIAL IS OBTAINED. SPECIAL STUDIES SUCH AS RETICULIN, CD34, CYTOKERATIN PROFILE, AND MOC-31 CAN BE VERY USEFUL FOR THE DIFFERENTIAL DIAGNOSIS OF PRIMARY AND METASTATIC TUMORS. TELOMERASE ACTIVITY HAS BEEN FOUND IN HCC AND NEGATIVE IN PERICANCEROUS TISSUE. IT IS MORE PRONOUNCED IN POORLY DIFFERENTIATED TUMORS AND CORRELATES WITH FACTORS OF CLINICAL IMPORTANCE, SUCH AS PROGNOSIS AND RECURRENCES. CELLS OF WELL-DIFFERENTIATED HCC HAVE AN ULTRASTRUCTURAL APPEARANCE SIMILAR TO NORMAL HEPATOCYTES. DURING THE PROCESS OF DEDIFFERENTIATION, THERE IS PROGRESSIVE LOSS OF ORGANIZATION OF INTRACELLULAR ORGANELLES. THE CELL COHESION IS LOST, INTERCELLULAR GAPS WITH MICROVILLI APPEAR, THE SINUSOIDS BECOME CAPILLARIZED, AND REPARATIVE CHANGES ARE SEEN IN THE SPACES OF DISSE. A VARIETY OF INCLUSIONS, SUCH AS MALLORY BODIES, GRANULAR MATERIAL, SECONDARY LYSOSOMES, AND DUBIN-JOHNSON PIGMENT, HAVE BEEN DESCRIBED. FIBROLAMELLAR CARCINOMA HAS A CHARACTERISTIC HISTOLOGICAL PICTURE AND ULTRASTRUCTURALLY ONCOCYTIC FEATURES. NEUROENDOCRINE GRANULES AND COMBINATION OF HCC WITH BILE DUCT CARCINOMA ARE SEEN BY ELECTRON MICROSCOPY. 2001 4 6848 58 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 5 6797 46 [EPIDEMIOLOGY, NATURAL HISTORY AND PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE MAIN TYPE OF PRIMARY LIVER CANCERS AND THE THIRD MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. IN FRANCE, RISING NUMBER BETWEEN 5000 AND 6000 CASES ARE DIAGNOSED EACH YEAR. THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IS CHRONIC HEPATITIS: VIRAL HEPATITIS B, VIRAL HEPATITIS C, CONSUMPTION OF ALCOHOL, HEMOCHROMATOSIS. HEPATOCELLULAR CARCINOMA IS CLOSELY ASSOCIATED TO LIVER CIRRHOSIS, WHICH IS A TRUE PRECANCEROUS STATE. BECAUSE HEPATOCARCINOGENESIS IS A LONG AND HETEROGENEOUS PROCESS, THERE IS STILL MUCH TO UNDERSTAND. MANY GENETIC AND EPIGENETIC ALTERATIONS ARE DESCRIBED LEADING TO CHANGES IN CELLULAR SIGNALLING CASCADES INVOLVED IN REGULATION OF GROWTH, DIFFERENTIATION, APOPTOSIS, MOTILITY. HEPATITIS VIRUSES PLAY A DIRECT ONCOGENIC ROLE THROUGH THE INTERACTION BETWEEN VIRAL AND CELLULAR PROTEINS, WHICH CONTROL CELL HOMEOSTASIS, OR BY THE INTEGRATION OF HEPATITIS B VIRUS GENOME INTO THE HOST GENOME. FURTHERMORE, HEPATITIS VIRUSES PLAY AN INDIRECT ONCOGENIC ROLE BY CAUSING CHRONIC INFLAMMATION AND HEPATOCYTE REGENERATION RELATED TO VIRAL HEPATOPATHY. IN EXPECTATION OF A BETTER UNDERSTANDING OF HEPATOCARCINOGENESIS AND NEW TREATMENTS, PREVENTION FROM RISK FACTORS AND ULTRASONOGRAPHIC SCREENING OF PATIENTS WITH CIRRHOSIS SHOULD INCREASE PROGNOSIS. 2011 6 6868 42 [PATHOGENESIS OF HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCER WORLDWIDE. MOST OF THE HCC OCCUR IN DEVELOPING COUNTRIES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HCC DEVELOPMENT. HBV INDUCES IMMUNE-MEDIATED CHRONIC HEPATITIS, LIVER INJURY, REGENERATION AND SCAR FORMING RESPONSES, LEADING TO AN INFLAMMATORY, FIBROTIC AND IMMUNE DEFICIENT MICROENVIRONMENT. HBV MAY INTEGRATE INTO HOST GENOME, INDUCING GENETIC ABNORMALITY AND ALTERING THE EXPRESSION OF HCC-RELATED GENES. HBV ALSO EXPRESSES ACTIVE PROTEINS SUCH AS X (HBX) AND S PROTEINS, WHICH MAY TRANS-ACTIVATE HCC-RELATED PROTEINS EXPRESSION, INTERACT WITH INTRACELLULAR SPECIFIC PROTEINS, ACTIVATE A VARIETY OF SIGNALING PATHWAYS, AND INDUCE ABERRANT EPIGENETIC MODIFICATIONS. HBV MUTATION ALSO HAS IMPACT ON HBV RELATED HCC DEVELOPMENT. 2016 7 4890 40 OXIDATIVE STRESS AND HEPATIC NOX PROTEINS IN CHRONIC HEPATITIS C AND HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON LIVER CANCER AND A LEADING CAUSE OF CANCER-RELATED MORTALITY IN THE WORLD. HEPATITIS C VIRUS (HCV) IS A MAJOR ETIOLOGIC AGENT OF HCC. A MAJORITY OF HCV INFECTIONS LEAD TO CHRONIC INFECTION THAT CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, HCC AND LIVER FAILURE. A COMMON PATHOGENIC FEATURE PRESENT IN HCV INFECTION, AND OTHER CONDITIONS LEADING TO HCC, IS OXIDATIVE STRESS. HCV DIRECTLY INCREASES SUPEROXIDE AND H2O2 FORMATION IN HEPATOCYTES BY ELEVATING NOX PROTEIN EXPRESSION AND SENSITIZING MITOCHONDRIA TO REACTIVE OXYGEN SPECIES GENERATION WHILE DECREASING GLUTATHIONE. NITRIC OXIDE SYNTHESIS AND HEPATIC IRON ARE ALSO ELEVATED. FURTHERMORE, ACTIVATION OF PHAGOCYTIC NADPH OXIDASE (NOX) 2 OF HOST IMMUNE CELLS IS LIKELY TO EXACERBATE OXIDATIVE STRESS IN HCV-INFECTED PATIENTS. KEY MECHANISMS OF HCC INCLUDE GENOME INSTABILITY, EPIGENETIC REGULATION, INFLAMMATION WITH CHRONIC TISSUE INJURY AND SUSTAINED CELL PROLIFERATION, AND MODULATION OF CELL GROWTH AND DEATH. OXIDATIVE STRESS, OR NOX PROTEINS, PLAYS VARIOUS ROLES IN THESE MECHANISMS. NOX PROTEINS ALSO FUNCTION IN HEPATIC FIBROSIS, WHICH COMMONLY PRECEDES HCC, AND NOX4 ELEVATION BY HCV IS MEDIATED BY TRANSFORMING GROWTH FACTOR BETA. THIS REVIEW SUMMARIZES MECHANISMS OF ONCOGENESIS BY HCV, HIGHLIGHTING THE ROLES OF OXIDATIVE STRESS AND HEPATIC NOX ENZYMES IN HCC. 2014 8 1478 35 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 9 4903 30 P16 PROMOTER HYPERMETHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA WITH OR WITHOUT HEPATITIS VIRUS INFECTION. BACKGROUND: EPIGENETIC ALTERATION THROUGH METHYLATION IS ONE OF THE MOST IMPORTANT STEPS IN CARCINOGENESIS. HOWEVER, THE RELATION BETWEEN HEPATITIS VIRUS INFECTION AND EPIGENETIC ALTERATIONS IS POORLY UNDERSTOOD. METHODS: SIXTEEN PATIENTS WITHOUT HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) AND 35 PATIENTS WITH HBV OR HCV WHO UNDERWENT LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA (HCC) WERE STUDIED. MUTATION OF P53 WAS DETECTED BY DIRECT SEQUENCING. METHYLATION STATUS OF P16 WAS EVALUATED IN TUMOR AND NONCANCEROUS LIVER TISSUES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: IN HCC WITHOUT HBV AND HCV, P53 MUTATIONS WERE DETECTED IN 5 (31%) OF 16 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (25%) OF 8 MODERATELY DIFFERENTIATED HCCS, 6 (75%) OF 8 POORLY DIFFERENTIATED HCCS, AND NONE OF 16 NONCANCEROUS TISSUE SPECIMENS. IN HCC WITH HBV OR HCV, P53 MUTATIONS WERE DETECTED IN 8 (23%) OF 35 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (100%) OF 2 WELL-DIFFERENTIATED HCCS, 13 (76%) OF 17 MODERATELY DIFFERENTIATED HCCS, 12 (75%) OF 16 POORLY DIFFERENTIATED HCCS, AND 9 (26%) OF 35 NONCANCEROUS LIVER TISSUE SPECIMENS. CONCLUSIONS: OUR RESULTS SUGGEST THAT HEPATITIS VIRUSES MIGHT INDUCE METHYLATION OF P16 PROMOTER IN LIVER WITH CHRONIC INFLAMMATION, BEFORE APPEARANCE OF HCC. 2004 10 1942 43 EPIDEMIOLOGY OF LIVER CANCER IN AFRICA: CURRENT AND FUTURE TRENDS. HEPATOCELLULAR CARCINOMA (HCC) IS A DISEASE OF GLOBAL PUBLIC HEALTH SIGNIFICANCE WITH MORTALITY ON THE RISE, DESPITE THE PREVENTABLE NATURE OF ITS RISK FACTORS ESPECIALLY IN AFRICA. IT IS NOW THE SIXTH MOST COMMON CANCER WORLDWIDE, FIFTH IN MALES, AND NINTH IN FEMALES. HCC INCIDENCE AND MORTALITY ARE PREDICTED TO INCREASE IN AFRICAN COUNTRIES CONSTRAINED BY LIMITED RESOURCES TO COMBAT ENDEMIC LEVELS OF VIRAL INFECTION AND SYNERGISTIC ENVIRONMENTAL RISK FACTORS. THE CHANGING NATURE OF HCC ETIOLOGY IS PARTICULARLY ILLUSTRATED HERE WITH THE TRADITIONAL RISK FACTORS LIKE VIRAL HEPATITIS COEXISTING ALONGSIDE HIGH HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVALENCE AND RAPIDLY INCREASING URBANIZATION THAT HAVE PROMOTED A SHARP INCREASE IN ADDITIONAL RISK FACTORS LIKE COINFECTION, TYPE 2 DIABETES MELLITUS, AND OBESITY. ALTHOUGH THERE ARE SOME DIFFERENCES IN ETIOLOGY BETWEEN NORTH AFRICA AND SUB-SAHARAN AFRICA, RISK FACTORS LIKE CHRONIC VIRAL HEPATITIS B AND C, AFLATOXIN EXPOSURE, AND IRON OVERLOAD PREDOMINATE. AGGRESSIVE HEPATITIS B GENOTYPES, COMBINED WITH HEPATITIS B VIRUS/HEPATITIS C VIRUS/HIV COINFECTIONS AND AFLATOXIN EXPOSURE, PROMOTE A MORE AGGRESSIVE MOLECULAR PHENOTYPE. IN PARALLEL TO A BETTER UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF HCC, POLICY AND PLANNING INITIATIVES TO ADDRESS THE BURDEN OF HCC MUST BE ANCHORED WITHIN THE REALITY OF THE LIMITED RESOURCES AVAILABLE. ESTABLISHMENT AND COORDINATION OF CANCER REGISTRIES ACROSS AFRICA IS NEEDED TO IMPROVE THE QUALITY OF DATA NECESSARY TO GALVANIZE ACTION. PREVENTIVE MEASURES INCLUDING HEPATITIS B VACCINATION PROGRAMS, MEASURES TO PREVENT MATERNAL-TO-CHILD AND CHILD-TO-CHILD TRANSMISSION, DELIVERY OF UNIVERSALLY ACCESSIBLE ANTIRETROVIRAL AND ANTIVIRAL TREATMENTS, AND REDUCTION OF DIETARY AFLATOXIN EXPOSURE CAN CONTRIBUTE MARKEDLY TO REDUCE HCC INCIDENCE. FINALLY, THE DEVELOPMENT OF BIOMARKERS AND NEW THERAPEUTIC INTERVENTIONS WILL NEED A BETTER UNDERSTANDING OF THE UNIQUE GENETIC AND EPIGENETIC CHARACTERISTICS OF HCC ON THE CONTINENT. WE PRESENT A NARRATIVE REVIEW OF HCC IN AFRICA, DISCUSSING PRESENT AND FUTURE TRENDS. 2020 11 442 28 ANTIVIRAL THERAPIES FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A CRITICAL RISK FACTOR FOR THE CARCINOGENESIS AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC). IT PROMOTES HCC DEVELOPMENT BY INDUCING LIVER FIBROGENESIS, GENETIC AND EPIGENETIC ALTERATIONS, AND THE EXPRESSION OF ACTIVE VIRAL-CODED PROTEINS. EFFECTIVE ANTIVIRAL TREATMENTS INHIBIT THE REPLICATION OF HBV, REDUCE SERUM VIRAL LOAD AND ACCELERATE HEPATITIS B E ANTIGEN SERUM CONVERSION. TIMELY INITIATION OF ANTIVIRAL TREATMENT IS NOT ONLY ESSENTIAL FOR PREVENTING THE INCIDENCE OF HCC IN CHRONIC HEPATITIS B PATIENTS, BUT ALSO IMPORTANT FOR REDUCING HBV REACTIVATION, IMPROVING LIVER FUNCTION, REDUCING OR DELAYING HCC RECURRENCE, AND PROLONGING OVERALL SURVIVAL OF HBV-RELATED HCC PATIENTS AFTER CURATIVE AND PALLIATIVE THERAPIES. THE SELECTION OF ANTIVIRAL DRUGS, MONITORING OF INDICATORS SUCH AS HBV DNA AND HEPATITIS B SURFACE ANTIGEN, AND TIMELY RESCUE TREATMENT WHEN NECESSARY, ARE ESSENTIAL IN ANTIVIRAL THERAPIES FOR HBV-RELATED HCC. 2015 12 4815 45 OCCULT HEPATITIS B INFECTION AND HEPATOCELLULAR CARCINOMA: EPIDEMIOLOGY, VIROLOGY, HEPATOCARCINOGENESIS AND CLINICAL SIGNIFICANCE. OCCULT HEPATITIS B INFECTION (OBI) REFERS TO A CONDITION WHERE REPLICATION-COMPETENT HBV DNA IS PRESENT IN THE LIVER, WITH OR WITHOUT HBV DNA IN THE BLOOD, IN INDIVIDUALS WITH SERUM HBSAG NEGATIVITY ASSESSED BY CURRENTLY AVAILABLE ASSAYS. THE EPISOMAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN OBI IS IN A LOW REPLICATIVE STATE. VIRAL GENE EXPRESSION IS MEDIATED BY EPIGENETIC CONTROL OF HBV TRANSCRIPTION, INCLUDING THE HBV CPG ISLAND METHYLATION PATHWAY AND POST-TRANSLATIONAL MODIFICATION OF CCCDNA-BOUND HISTONE, WITH A DIFFERENT PATTERN FROM PATIENTS WITH CHRONIC HBV INFECTION. THE PREVALENCE OF OBI VARIES TREMENDOUSLY ACROSS PATIENT POPULATIONS OWING TO NUMEROUS FACTORS, SUCH AS GEOGRAPHIC LOCATION, ASSAY CHARACTERISTICS, HOST IMMUNE RESPONSE, COINFECTION WITH OTHER VIRUSES, AND VACCINATION STATUS. APART FROM THE RISK OF VIRAL REACTIVATION UPON IMMUNOSUPPRESSION AND THE RISK OF TRANSMISSION OF HBV, OBI HAS BEEN IMPLICATED IN HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN PATIENTS WITH CHRONIC HCV INFECTION, THOSE WITH CRYPTOGENIC OR KNOWN LIVER DISEASE, AND IN PATIENTS WITH HBSAG SEROCLEARANCE AFTER CHRONIC HBV INFECTION. AN INCREASING NUMBER OF PROSPECTIVE STUDIES AND META-ANALYSES HAVE REPORTED A HIGHER INCIDENCE OF HCC IN PATIENTS WITH HCV AND OBI, AS WELL AS MORE ADVANCED TUMOUR HISTOLOGICAL GRADES AND EARLIER AGE OF HCC DIAGNOSIS, COMPARED WITH PATIENTS WITHOUT OBI. THE PROPOSED PATHOGENETIC MECHANISMS OF OBI-RELATED HCC INCLUDE THE INFLUENCE OF HBV DNA INTEGRATION ON THE HEPATOCYTE CELL CYCLE, THE PRODUCTION OF PRO-ONCOGENIC PROTEINS (HBX PROTEIN AND MUTATED SURFACE PROTEINS), AND PERSISTENT LOW-GRADE NECROINFLAMMATION (CONTRIBUTING TO THE DEVELOPMENT OF FIBROSIS AND CIRRHOSIS). THERE REMAIN UNCERTAINTIES ABOUT EXACTLY HOW, AND IN WHAT ORDER, THESE MECHANISMS DRIVE THE DEVELOPMENT OF TUMOURS IN PATIENTS WITH OBI. 2020 13 6753 39 WILD TYPE HBX AND TRUNCATED HBX: PLEIOTROPIC REGULATORS DRIVING SEQUENTIAL GENETIC AND EPIGENETIC STEPS OF HEPATOCARCINOGENESIS AND PROGRESSION OF HBV-ASSOCIATED NEOPLASMS. HEPATITIS B VIRUS (HBV) IS ONE OF THE CAUSATIVE AGENTS OF HEPATOCELLULAR CARCINOMA. THE MOLECULAR MECHANISMS OF TUMORIGENESIS ARE COMPLEX. ONE OF THE HOST FACTORS INVOLVED IS APPARENTLY THE LONG-LASTING INFLAMMATORY REACTION WHICH ACCOMPANIES CHRONIC HBV INFECTION. ALTHOUGH HBV LACKS A TYPICAL VIRAL ONCOGENE, THE HBX GENE ENCODING A PLEIOTROPIC REGULATORY PROTEIN EMERGED AS A MAJOR PLAYER IN LIVER CARCINOGENESIS. HERE WE REVIEW THE TUMORIGENIC FUNCTIONS OF HBX WITH AN EMPHASIS ON WILD TYPE AND TRUNCATED HBX VARIANTS, AND THEIR ROLE IN THE TRANSCRIPTIONAL DYSREGULATION AND EPIGENETIC REPROGRAMMING OF THE HOST CELL GENOME. WE SUGGEST THAT HBX ACQUIRED BY THE HBV GENOME DURING EVOLUTION ACTS LIKE A CELLULAR PROTO-ONC GENE THAT IS ACTIVATED BY DELETION DURING HEPATOCARCINOGENESIS. THE RESULTING VIRAL ONCOGENE (V-ONC GENE) CODES FOR A TRUNCATED HBX PROTEIN THAT FACILITATES TUMOR PROGRESSION. COPYRIGHT (C) 2015 JOHN WILEY & SONS, LTD. 2016 14 1646 39 DOES THE HEPATITIS B ANTIGEN HBX PROMOTE THE APPEARANCE OF LIVER CANCER STEM CELLS? HEPATITIS B VIRUS (HBV) IS A MAJOR ETIOLOGIC AGENT OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV-ENCODED X ANTIGEN, HBX, AND PATHWAYS IMPLICATED IN THE SELF-RENEWAL OF STEM CELLS CONTRIBUTE TO HCC, BUT IT IS NOT CLEAR WHETHER HBX EXPRESSION PROMOTES "STEMNESS." THUS, EXPERIMENTS WERE DESIGNED TO TEST THE HYPOTHESIS THAT HBX TRIGGERS MALIGNANT TRANSFORMATION BY PROMOTING PROPERTIES THAT ARE CHARACTERISTIC OF CANCER STEM CELLS (CSC). TO TEST THIS HYPOTHESIS, HEPG2 CELLS WERE STABLY TRANSDUCED WITH HBX AND THEN ASSAYED FOR PHENOTYPIC AND MOLECULAR CHARACTERISTICS OF "STEMNESS." THE RELATIONSHIP BETWEEN HBX AND "STEMNESS"-ASSOCIATED MARKERS WAS ALSO EVALUATED BY IMMUNOHISTOCHEMICAL STAINING OF LIVER AND TUMOR TISSUE SECTIONS FROM HBV-INFECTED PATIENTS. THE RESULTS SHOWED THAT OCT-4, NANOG, KLF-4, BETA-CATENIN, AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) WERE ACTIVATED BY HBX IN VITRO AND IN VIVO. EPCAM WAS DETECTED IN THE NUCLEI OF HUMAN HCC CELLS FROM INFECTED PATIENTS. HBX PROMOTES "STEMNESS" BY ACTIVATING BETA-CATENIN AND EPIGENETIC UPREGULATION OF MIR-181, BOTH OF WHICH TARGET EPCAM. HBX EXPRESSION WAS ALSO ASSOCIATED WITH DEPRESSED LEVELS OF E-CADHERIN. MOREOVER, HBX STIMULATED CELL MIGRATION, GROWTH IN SOFT AGAR, AND SPHEROID FORMATION. THIS WORK IS THE FIRST TO PROPOSE THAT HBV PROMOTES "STEMNESS" IN THE PATHOGENESIS OF HCC. HBX-ASSOCIATED UPREGULATED EXPRESSION OF MULTIPLE "STEMNESS" MARKERS SUPPORTS THE HYPOTHESIS THAT HBX CONTRIBUTES TO HEPATOCARCINOGENESIS, AT LEAST IN PART, BY PROMOTING CHANGES IN GENE EXPRESSION THAT ARE CHARACTERISTICS OF CSCS. 2011 15 6271 41 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 16 3257 40 HEPATITIS B X ANTIGEN (HBX) IS AN IMPORTANT THERAPEUTIC TARGET IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A HUMAN PATHOGEN THAT HAS INFECTED AN ESTIMATED TWO BILLION PEOPLE WORLDWIDE. DESPITE THE AVAILABILITY OF HIGHLY EFFICACIOUS VACCINES, UNIVERSAL SCREENING OF THE BLOOD SUPPLY FOR VIRUS, AND POTENT DIRECT ACTING ANTI-VIRAL DRUGS, THERE ARE MORE THAN 250 MILLION CARRIERS OF HBV WHO ARE AT RISK FOR THE SEQUENTIAL DEVELOPMENT OF HEPATITIS, FIBROSIS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MORE THAN 800,000 DEATHS PER YEAR ARE ATTRIBUTED TO CHRONIC HEPATITIS B. MANY DIFFERENT THERAPEUTIC APPROACHES HAVE BEEN DEVELOPED TO BLOCK VIRUS REPLICATION, AND ALTHOUGH EFFECTIVE, NONE ARE CURATIVE. THESE TREATMENTS HAVE LITTLE OR NO IMPACT UPON THE PORTIONS OF INTEGRATED HBV DNA, WHICH OFTEN ENCODE THE VIRUS REGULATORY PROTEIN, HBX. ALTHOUGH GIVEN LITTLE ATTENTION, HBX IS AN IMPORTANT THERAPEUTIC TARGET BECAUSE IT CONTRIBUTES IMPORTANTLY TO (A) HBV REPLICATION, (B) IN PROTECTING INFECTED CELLS FROM IMMUNE MEDIATED DESTRUCTION DURING CHRONIC INFECTION, AND (C) IN THE DEVELOPMENT OF HCC. THUS, THE DEVELOPMENT OF THERAPIES TARGETING HBX, COMBINED WITH OTHER ESTABLISHED THERAPIES, WILL PROVIDE A FUNCTIONAL CURE THAT WILL TARGET VIRUS REPLICATION AND FURTHER REDUCE OR ELIMINATE BOTH THE MORBIDITY AND MORTALITY ASSOCIATED WITH CHRONIC LIVER DISEASE AND HCC. SIMULTANEOUS TARGETING OF ALL THESE CHARACTERISTICS UNDERSCORES THE IMPORTANCE OF DEVELOPING THERAPIES AGAINST HBX. 2021 17 42 41 A COMPREHENSIVE GENOME-WIDE PROFILING COMPARISON BETWEEN HBV AND HCV INFECTED HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS WORLDWIDE, ESPECIALLY IN EAST ASIA. EVEN WITH THE PROGRESS IN THERAPY, 5-YEAR SURVIVAL RATES REMAIN UNSATISFIED. CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) HAS BEEN EPIDEMIOLOGICALLY ASSOCIATED WITH HCC AND IS THE MAJOR ETIOLOGY IN THE EAST ASIAN POPULATION. THE DETAILED MECHANISM, ESPECIALLY THE CHANGES OF DNA METHYLATION AND GENE EXPRESSION BETWEEN THE TWO TYPES OF VIRUS-RELATED HCC, AND THEIR CONTRIBUTIONS TO THE HCC DEVELOPMENT, METASTASIS, AND RECURRENCE REMAIN LARGELY UNKNOWN. METHODS: IN THIS INTEGRATED ANALYSIS, WE CHARACTERIZED GENOME-SCALE PROFILES OF HBV AND HCV INFECTED HCC BY COMPARING THEIR GENE EXPRESSION PATTERN, METHYLATION PROFILES, AND COPY NUMBER VARIATIONS FROM THE PUBLICLY ACCESSIBLE DATA OF THE CANCER GENOME ATLAS PROGRAM (TCGA). RESULTS: THE HLA-A, STAT1, AND OAS2 GENES WERE HIGHLY ENRICHED AND UP-REGULATED DISCOVERED IN THE HCV-INFECTED HCC. HYPOMETHYLATION BUT NOT COPY NUMBER VARIATIONS MIGHT BE THE MAJOR FACTOR FOR THE UP-REGULATION OF THESE IMMUNE-RELATED GENES IN HCV-INFECTED HCC. CONCLUSIONS: THE RESULTS INDICATED THE DIFFERENT EPIGENETIC CHANGES OF HBV/HCV RELATED HEPATOCARCINOGENESIS. THE TOP UP-REGULATED GENES IN HCV GROUP WERE SIGNIFICANTLY CLUSTERED IN THE IMMUNE-RELATED AND DEFENSE RESPONSE PATHWAYS. THESE FINDINGS WILL HELP US TO UNDERSTAND THE PATHOGENESIS OF HBV/HCV ASSOCIATED HEPATOCELLULAR CARCINOMA. 2019 18 1042 28 CLINICAL AND MOLECULAR BASIS OF HEPATOCELLULAR CARCINOMA AFTER HEPATITIS C VIRUS ERADICATION. HEPATOCELLULAR CARCINOMA (HCC) ARISES IN THE BACKGROUND OF CHRONIC LIVER DISEASES, INCLUDING HEPATITIS AND LIVER CIRRHOSIS CAUSED BY HEPATITIS C VIRUS (HCV) INFECTION. IT IS WELL KNOWN THAT HCV ERADICATION USING ANTIVIRAL DRUGS CAN EFFICIENTLY INHIBIT HEPATOCARCINOGENESIS. RECENT ADVANCES IN AND DEVELOPMENT OF DIRECT-ACTING ANTIVIRAL (DAA) DRUGS HAS REVOLUTIONIZED THE TREATMENT OF HCV INFECTION, AND THE VAST MAJORITY OF HCV PATIENTS CAN ACHIEVE HCV ERADICATION USING DAAS. HOWEVER, MOUNTING EVIDENCE CLEARLY INDICATES THAT HCC INEVITABLY OCCURS IN A SUBSET OF PATIENTS AFTER SUCCESSFUL VIRAL ERADICATION USING DAA THERAPY. CANCER IS A GENETIC DISEASE, AND THE ACCUMULATION OF GENETIC AND EPIGENETIC ABERRATIONS MAY CAUSE HEPATOCARCINOGENESIS IN CHRONICALLY DAMAGED LIVER, EVEN AFTER VIRUS ELIMINATION. IN THIS REVIEW, WE HIGHLIGHT HCC DEVELOPMENT AFTER HCV ERADICATION AND DISCUSS THE CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS OF TUMORIGENESIS AFTER VIRUS ELIMINATION, FOCUSING ON THE GENETIC AND EPIGENETIC BACKGROUND OF CHRONICALLY DAMAGED LIVER TISSUES. 2022 19 3253 41 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 20 3394 34 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