1 1478 87 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 2 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 3 3394 28 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 4 6016 28 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 5 3187 27 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 6 3401 25 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 7 4133 31 MECHANISMS OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). THERE ARE APPROXIMATELY 250 MILLION PEOPLE IN THE WORLD THAT ARE CHRONICALLY INFECTED BY THIS VIRUS, RESULTING IN NEARLY 1 MILLION DEATHS EVERY YEAR. MANY OF THESE PATIENTS DIE FROM SEVERE LIVER DISEASES, INCLUDING HCC. HBV MAY INDUCE HCC THROUGH THE INDUCTION OF CHRONIC LIVER INFLAMMATION, WHICH CAN CAUSE OXIDATIVE STRESS AND DNA DAMAGE. HOWEVER, MANY STUDIES ALSO INDICATED THAT HBV COULD INDUCE HCC VIA THE ALTERATION OF HEPATOCELLULAR PHYSIOLOGY THAT MAY INVOLVE GENETIC AND EPIGENETIC CHANGES OF THE HOST DNA, THE ALTERATION OF CELLULAR SIGNALING PATHWAYS, AND THE INHIBITION OF DNA REPAIR MECHANISMS. THIS ALTERATION OF CELLULAR PHYSIOLOGY CAN LEAD TO THE ACCUMULATION OF DNA DAMAGES AND THE PROMOTION OF CELL CYCLES AND PREDISPOSE HEPATOCYTES TO ONCOGENIC TRANSFORMATION. 2021 8 2939 31 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 9 2980 32 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 10 4127 44 MECHANISMS OF DNA METHYLATION IN VIRUS-HOST INTERACTION IN HEPATITIS B INFECTION: PATHOGENESIS AND ONCOGENETIC PROPERTIES. HEPATITIS B VIRUS (HBV), THE WELL-STUDIED ONCOVIRUS THAT CONTRIBUTES TO THE MAJORITY OF HEPATOCELLULAR CARCINOMAS (HCC) WORLDWIDE, CAN CAUSE A SEVERE INFLAMMATORY MICROENVIRONMENT LEADING TO GENETIC AND EPIGENETIC CHANGES IN HEPATOCYTE CLONES. HBV REPLICATION CONTRIBUTES TO THE REGULATION OF DNA METHYLTRANSFERASE GENE EXPRESSION, PARTICULARLY BY X PROTEIN (HBX), AND SUBSEQUENT METHYLATION CHANGES MAY LEAD TO ABNORMAL TRANSCRIPTION ACTIVATION OF ADJACENT GENES AND GENOMIC INSTABILITY. UNDOUBTEDLY, THE ALTERED EXPRESSION OF THESE GENES HAS BEEN KNOWN TO CAUSE DIVERSE ASPECTS OF INFECTED HEPATOCYTES, INCLUDING APOPTOSIS, PROLIFERATION, REACTIVE OXYGEN SPECIES (ROS) ACCUMULATION, AND IMMUNE RESPONSES. ADDITIONALLY, POLLUTANT-INDUCED DNA METHYLATION CHANGES AND ABERRANT METHYLATION OF IMPRINTED GENES IN HEPATOCYTES ALSO COMPLICATE THE PROCESS OF TUMORIGENESIS. MEANWHILE, HEPATOCYTES ALSO CONTRIBUTE TO EPIGENETIC MODIFICATION OF THE VIRAL GENOME TO AFFECT HBV REPLICATION OR VIRAL PROTEIN PRODUCTION. MEANWHILE, METHYLATION LEVELS OF HBV INTEGRANTS AND SURROUNDING HOST REGIONS ALSO PLAY CRUCIAL ROLES IN THEIR ABILITY TO PRODUCE VIRAL PROTEINS IN AFFECTED HEPATOCYTES. BOTH HOST AND VIRAL CHANGES CAN PROVIDE NOVEL INSIGHTS INTO TUMORIGENESIS, INDIVIDUALIZED RESPONSES TO THERAPEUTIC INTERVENTION, DISEASE PROGRESS, AND EARLY DIAGNOSIS. AS SUCH, DNA METHYLATION-MEDIATED EPIGENETIC SILENCING OF CANCER-RELATED GENES AND VIRAL REPLICATION IS A COMPELLING THERAPEUTIC GOAL TO REDUCE MORBIDITY AND MORTALITY FROM LIVER CANCER CAUSED BY CHRONIC HBV INFECTION. IN THIS REVIEW, WE SUMMARIZE THE MOST RECENT RESEARCH ON ABERRANT DNA METHYLATION ASSOCIATED WITH HBV INFECTION, WHICH IS INVOLVED IN HCC DEVELOPMENT, AND PROVIDE AN OUTLOOK ON THE FUTURE DIRECTION OF THE RESEARCH. 2021 11 4449 38 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 12 4920 26 PARALLEL EPIGENETIC AND GENETIC CHANGES IN THE PATHOGENESIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST FREQUENT TUMOR TYPES IN THE WORLD, WITH SHORT SURVIVAL TIMES AND FEW TREATMENT OPTIONS. HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) ARE MAJOR ETIOLOGIC AGENTS OF HCC, ALTHOUGH THE ASSOCIATED MECHANISMS ARE INCOMPLETELY UNDERSTOOD. THE AVAILABLE EVIDENCE SUGGESTS THAT BOTH VIRUSES PROMOTE TUMORIGENESIS BY UP-REGULATING GENES THAT PROMOTE HEPATOCELLULAR GROWTH AND SURVIVAL, AND BY DOWN-REGULATING OTHER GENES THAT ACT AS TUMOR SUPPRESSORS AND NEGATIVE GROWTH REGULATORY MOLECULES. SIGNIFICANTLY, A NUMBER OF THE PATHWAYS THAT ARE ALTERED BY THESE VIRUSES ARE THE SAME ONES THAT ACCUMULATE GENETIC ALTERATIONS DURING TUMOR PROGRESSION. THIS SUGGESTS THAT THE PATHWAYS THAT PROMOTE VIRUS PERSISTENCE AND REPLICATION MAY ALSO PROMOTE CELL GROWTH AND SURVIVAL. FROM THE PERSPECTIVE OF THE VIRUS, THIS PROMOTES CHRONIC INFECTION, WHILE FROM THE PERSPECTIVE OF THE HOST, THIS PROMOTES TUMORIGENESIS. 2006 13 6850 30 [MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER DEATH WORLDWIDE. HCC NEARLY ALMOST ALWAYS DEVELOPS IN CONNECTION WITH CHRONIC HEPATITIS OR LIVER CIRRHOSIS, MAINLY DUE TO HEPATITIS B VIRUS OR HEPATITIS C VIRUS INFECTION. SEVERAL FACTORS ARE SUPPOSED TO PLAY KEY ROLES IN THE DEVELOPMENT OF HCC, SUCH AS ABERRANT VIRAL PROTEIN EXPRESSION, GENOMIC INSTABILITY WITH/WITHOUT INSERTIONS OF VIRAL DNAS, GENE MUTATIONS, EPIGENETIC GENE MODIFICATION, OXIDATIVE STRESS, AND ALTERATION OF THE MICROENVIRONMENT INCLUDING INFLAMMATION, FIBROSIS, AND EMERGENCE OF STEM/PROGENITOR CELLS AS A RESULT OF REPEATED NECROSIS AND REGENERATION OF HEPATOCYTES. THE ELUCIDATION OF MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS HAS SUCCESSFULLY PROVIDED SMALL MOLECULE INHIBITORS TARGETING ABERRANTLY ACTIVATED SIGNALING IN HCC. DEVELOPMENT OF NOVEL CLASSIFICATION SYSTEMS BASED ON THE MOLECULAR PROFILES AND DRUG SENSITIVITIES AGAINST MOLECULARLY TARGETED COMPOUNDS IS CURRENTLY UNDERWAY TO FACILITATE NOVEL STRATEGIES FOR EFFECTIVE ERADICATION OF HCC. 2010 14 3257 31 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 15 94 30 A PLEIOTROPIC ROLE OF THE HEPATITIS B VIRUS CORE PROTEIN IN HEPATOCARCINOGENESIS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ONE OF THE MOST COMMON FACTORS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC), WHICH IS THE SIXTH MOST PREVALENT CANCER AMONG ALL CANCERS WORLDWIDE. HOWEVER, THE PATHOGENESIS OF HBV-MEDIATED HEPATOCARCINOGENESIS IS UNCLEAR. EVIDENCE CURRENTLY AVAILABLE SUGGESTS THAT THE HBV CORE PROTEIN (HBC) PLAYS A POTENTIAL ROLE IN THE DEVELOPMENT OF HCC, SUCH AS THE HBV X PROTEIN. THE CORE PROTEIN, WHICH IS THE STRUCTURAL COMPONENT OF THE VIRAL NUCLEOCAPSID, CONTRIBUTES TO ALMOST EVERY STAGE OF THE HBV LIFE CYCLE AND OCCUPIES DIVERSE ROLES IN HBV REPLICATION AND PATHOGENESIS. RECENT STUDIES HAVE SHOWN THAT HBC WAS ABLE TO DISRUPT VARIOUS PATHWAYS INVOLVED IN LIVER CARCINOGENESIS: THE SIGNALING PATHWAYS IMPLICATED IN MIGRATION AND PROLIFERATION OF HEPATOMA CELLS, APOPTOSIS PATHWAYS, AND CELL METABOLIC PATHWAYS INDUCING THE DEVELOPMENT OF HCC; AND THE IMMUNE SYSTEM, THROUGH THE EXPRESSION AND PRODUCTION OF PROINFLAMMATORY CYTOKINES. IN ADDITION, HBC CAN MODULATE NORMAL FUNCTIONS OF HEPATOCYTES THROUGH DISRUPTING HUMAN HOST GENE EXPRESSION BY BINDING TO PROMOTER REGIONS. THIS HBV PROTEIN ALSO PROMOTES HCC METASTASIS THROUGH EPIGENETIC ALTERATIONS, SUCH AS MICRO-RNA. THIS REVIEW FOCUSES ON THE MOLECULAR PATHOGENESIS OF THE HBC PROTEIN IN HBV-INDUCED HCC. 2021 16 3251 24 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 4461 31 MOLECULAR MECHANISMS OF GENDER DISPARITY IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ONE OF THE MOST COMMON CAUSES OF HEPATOCELLULAR CARCINOMA (HCC), A MALIGNANT TUMOR WITH HIGH MORTALITY WORLDWIDE. ONE REMARKABLE CLINICAL FEATURE OF HBV-RELATED HCC IS THAT ITS INCIDENCE IS HIGHER IN MALES AND POSTMENOPAUSAL FEMALES COMPARED TO OTHER FEMALES. INCREASING EVIDENCE INDICATES THAT HBV-ASSOCIATED HCC MAY INVOLVE GENDER DISPARITY AND THAT IT MAY BE A TYPE OF HORMONE-RESPONSIVE MALIGNANT TUMOR. SEX HORMONES, SUCH AS ANDROGEN AND ESTROGEN, HAVE BEEN SHOWN TO PLAY VERY DIFFERENT ROLES IN THE PROGRESSION OF AN HBV INFECTION AND IN THE DEVELOPMENT OF HBV-RELATED HCC. THROUGH BINDING TO THEIR SPECIFIC CELLULAR RECEPTORS AND AFFECTING THE CORRESPONDING SIGNALING PATHWAYS, SEX HORMONES CAN REGULATE THE TRANSACTIVATION OF HBX, CAUSE THE CHRONIC RELEASE OF INFLAMMATORY CYTOKINES IN THE HEPATOCELLULAR MICROENVIRONMENT, AND PARTICIPATE IN EPIGENETIC AND GENETIC ALTERNATIONS IN HEPATOCYTES. ALL OF THESE FUNCTIONS MAY BE RELATED TO THE INITIATION AND PROGRESSION OF HBV-ASSOCIATED HCC. A THOROUGH INVESTIGATION OF THE MOLECULAR MECHANISMS UNDERLYING THE GENDER-RELATED DISPARITY IN HBV-RELATED HCC SHOULD PROVIDE A NEW PERSPECTIVE FOR BETTER UNDERSTANDING ITS PATHOGENESIS AND EXPLORING MORE EFFECTIVE METHODS FOR THE PREVENTION AND TREATMENT OF THIS DISEASE. 2014 18 4462 35 MOLECULAR MECHANISMS OF HBV-ASSOCIATED HEPATOCARCINOGENESIS. 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 THE LARGE ENVELOPE PROTEIN DEREGULATE THE CELLULAR TRANSCRIPTION PROGRAM AND PROLIFERATION CONTROL AND SENSITIZE LIVER CELLS TO CARCINOGENIC FACTORS. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY HBX THAT 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 AND P53 INACTIVATION BY MUTATIONS, OVEREXPRESS FETAL LIVER/HEPATIC PROGENITOR CELLS GENES, AND SHOW A SPECIFIC ACTIVATION OF THE AKT PATHWAY. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED, BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. ALL AVAILABLE EVIDENCE STRONGLY SUPPORTS THE NOTION THAT CHRONIC HBV INFECTION TRIGGERS BOTH COMMON AND ETIOLOGY-SPECIFIC ONCOGENIC PATHWAYS, THUS PLAYING A DIRECT ROLE BEYOND STIMULATION OF HOST IMMUNE RESPONSES AND CHRONIC NECROINFLAMMATORY LIVER DISEASE. 2013 19 4475 32 MOLECULAR PATHOGENESIS OF HEPATITIS C VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION WITH HEPATITIS C VIRUS (HCV) IS CAUSALLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HCV IS NOT CYTOLYTIC AND REPLICATES ENTIRELY IN THE CYTOPLASM. VIRAL INTERACTION WITH THE HOST LEADS TO SUBVERSION OF IMMUNE RESPONSE AND OTHER DEFENSE MECHANISMS. THE RECENT DEVELOPMENT OF ROBUST CELL CULTURE SYSTEMS FOR HCV INFECTION PROVIDES NEW OPPORTUNITIES FOR THE STUDY OF VIRUS-CELL INTERACTION AND VIRAL PATHOGENESIS. HCV INFECTION CAUSES ACTIVE INFLAMMATION AND FIBROSIS, WHICH ULTIMATELY PROGRESSES TO CIRRHOSIS. THE ONSET OF CIRRHOSIS USUALLY PRECEDES THE MULTISTAGE PROCESS OF TUMOR DEVELOPMENT, IN WHICH COMMON THEMES OF VIRAL CARCINOGENESIS CAN BE IDENTIFIED. WHILE CHRONIC INFLAMMATION AND CIRRHOSIS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN TUMOR INITIATION, THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. RECENT STUDIES HAVE REVEALED THAT INFECTION WITH HCV INDUCES GENOME INSTABILITY, LEADING TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS WHICH CONTRIBUTE TO THE FULL DEVELOPMENT OF HCC TUMOR. THE EXPRESSION OF VIRAL ONCOPROTEINS SUCH AS C AND NS5A IS CRITICALLY INVOLVED BOTH IN THE INDUCTION OF GENOME INSTABILITY AND IN DYSREGULATING CELLULAR CONTROL OF GROWTH AND SIGNAL TRANSDUCTION. A BETTER UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF HCV WILL REVEAL NOVEL STRATEGIES FOR THE PREVENTION AND TREATMENT OF RELATED DISEASES INCLUDING HCC. 2007 20 6797 35 [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