1 3255 87 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 2 3253 38 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 3 6868 29 [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 4 6753 33 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 5 5936 35 TARGETING HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA AND HEPATITIS B VIRUS X PROTEIN: RECENT ADVANCES AND NEW APPROACHES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION REMAINS A WORLDWIDE CONCERN AND PUBLIC HEALTH PROBLEM. TWO KEY ASPECTS OF THE HBV LIFE CYCLE ARE ESSENTIAL FOR VIRAL REPLICATION AND THUS THE DEVELOPMENT OF CHRONIC INFECTIONS: THE ESTABLISHMENT OF THE VIRAL MINICHROMOSOME, COVALENTLY CLOSED CIRCULAR (CCC) DNA, WITHIN THE NUCLEUS OF INFECTED HEPATOCYTES AND THE EXPRESSION OF THE REGULATORY HEPATITIS B VIRUS X PROTEIN (HBX). INTERESTINGLY, NUCLEAR HBX REDIRECTS HOST EPIGENETIC MACHINERY TO ACTIVATE CCCDNA TRANSCRIPTION. IN THIS PERSPECTIVE, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN UNDERSTANDING THE REGULATION OF CCCDNA AND THE MECHANISTIC AND FUNCTIONAL ROLES OF HBX. WE ALSO DESCRIBE THE PROGRESS TOWARD TARGETING BOTH CCCDNA AND HBX FOR THERAPEUTIC PURPOSES. FINALLY, WE OUTLINE STANDING QUESTIONS IN THE FIELD AND PROPOSE COMPLEMENTARY CHEMICAL BIOLOGY APPROACHES TO ADDRESS THEM. 2019 6 1700 35 DYNAMIC EXPRESSION OF ZNF382 AND ITS TUMOR-SUPPRESSOR ROLE IN HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOGENESIS. HEPATITIS B VIRUS (HBV) INFECTION IS THE PRIMARY CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). ZINC-FINGER PROTEIN 382 (ZNF382), WHICH BELONGS TO ZINC-FINGER PROTEIN FAMILY, HAS BEEN DOCUMENTED TO BE DOWNREGULATED IN CERTAIN TYPES OF CANCER. HOWEVER, ITS ROLE IN HCC REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DEMONSTRATED THAT ZNF382 EXPRESSION WAS SIGNIFICANTLY ELEVATED IN HBV-INFECTED LIVER CIRRHOSIS TISSUES RELATIVE TO HBV-NEGATIVE NORMAL LIVER TISSUES AT PROTEIN LEVELS, BUT NOT AT MRNA LEVELS, AND WAS POSITIVELY CORRELATED WITH THE LEVELS OF HBV DNA AND HEPATITIS B VIRUS X PROTEIN (HBX). FURTHER STUDIES REVEALED THAT ZNF382 WAS A TARGET OF MIR-6867, AND HBX PROMOTED THE TRANSLATION OF ZNF382 DURING HBV CHRONIC INFECTION THROUGH ERK-MEDIATED MIR-6867 INHIBITION. IN ADDITION, OUR DATA SHOWED THAT ZNF382 WAS FREQUENTLY DOWNREGULATED BY PROMOTER METHYLATION IN HBV-RELATED HCCS RELATIVE TO HBV-INFECTED LIVER CIRRHOSIS TISSUES, AND DECREASED EXPRESSION OF ZNF382 WAS STRONGLY CORRELATED WITH POOR SURVIVAL IN EARLY-STAGE HCC PATIENTS. FUNCTIONAL STUDIES DEMONSTRATED THAT ZNF382 WAS A POTENT TUMOR SUPPRESSOR IN HCC CELLS THROUGH INHIBITING CELL PROLIFERATION, COLONY FORMATION, MIGRATION, INVASION, AND TUMORIGENIC POTENTIAL IN NUDE MICE, AND INDUCING CELL APOPTOSIS. MECHANISTICALLY, ZNF382 EXERTED ITS TUMOR-SUPPRESSOR FUNCTIONS IN HCC THROUGH TRANSCRIPTIONALLY REPRESSING ITS DOWNSTREAM TARGETS SUCH AS FOS PROTO-ONCOGENE (FOS), JUN PROTO-ONCOGENE (JUN), DISHEVELED SEGMENT POLARITY PROTEIN 2 (DVL2), AND FRIZZLED CLASS RECEPTOR 1 (FZD1), THEREBY IMPAIRING THE ACTIVITIES OF ACTIVATING PROTEIN 1 (AP-1) AND WNT/BETA-CATENIN PATHWAYS AND ACTIVATING P53 SIGNALING. ALTOGETHER, OUR DATA SHOW THAT ZNF382 ACTS AS A TUMOR SUPPRESSOR, AND IS CO-REGULATED BY HBX AND EPIGENETIC MECHANISM IN HBV-RELATED HEPATOCELLULAR CARCINOGENESIS. 2019 7 1646 28 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 8 3254 26 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 9 442 29 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 10 3185 26 HBC BINDS TO THE CPG ISLANDS OF HBV CCCDNA AND PROMOTES AN EPIGENETIC PERMISSIVE STATE. HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS THE TEMPLATE FOR THE TRANSCRIPTION OF HBV. HBV CORE PROTEIN (HBC) IS A MAIN COMPONENT OF THE HBV CCCDNA MINICHROMOSOME. HOWEVER, THE FUNCTION OF HBC IN CCCDNA IS NOT FULLY UNDERSTOOD. IN LIGHT OF RECENT FINDINGS THAT HBV CCCDNA MAY BE REGULATED EPIGENETICALLY, WE ANALYZED THE BINDING OF HBC TO CCCDNA AND THE IMPACT OF HBC ON CCCDNA EPIGENETIC PROFILE IN THE LIVER BIOPSY SAMPLES OF 22 PATIENTS WITH CHRONIC HEPATITIS B (CHB). WE FOUND THAT HBC BINDING TO HBV CCCDNA OCCURRED PREFERENTIALLY AT CPG ISLAND 2, AN IMPORTANT REGION FOR THE REGULATION OF HBV TRANSCRIPTION. FURTHERMORE, THE RELATIVE ABUNDANCES OF HBC BINDING TO CPG ISLAND 2 WERE POSITIVELY CORRELATED WITH THE RATIOS OF RELAXED CIRCULAR DNA TO CCCDNA AND THE LEVELS OF SERUM HBV DNA IN THOSE PATIENTS. INTERESTINGLY, THE RELATIVE ABUNDANCES OF HBC BINDING TO CPG ISLAND 2 WERE ASSOCIATED WITH THE BINDING OF CREB BINDING PROTEIN (CBP) AND WITH HYPOMETHYLATION IN CPG ISLAND 2 OF HBV CCCDNA MINICHROMOSOMES. HOWEVER, RELATIVELY HIGHER AMOUNTS OF HBC BINDING TO CPG ISLAND 2 OF CCCDNA WERE ACCOMPANIED BY LOWER AMOUNTS OF HDAC1 BINDING. MULTIVARIATE ANALYSIS REVEALED THAT THE ABUNDANCES OF HBC BINDING TO CPG ISLAND 2 OF CCCDNA AND POSITIVE HBEAG WERE INDEPENDENT FACTORS ASSOCIATED WITH THE REPLICATION OF HBV (P = 0.001 FOR BOTH). APPARENTLY, HBC IS A POSITIVE REGULATOR OF HBV TRANSCRIPTION AND REPLICATION, MAINTAINING THE PERMISSIVE EPIGENETIC STATE IN THE CRITICAL REGION OF THE HBV CCCDNA MINICHROMOSOMES. 2011 11 4131 34 MECHANISMS OF HBV-INDUCED HEPATOCELLULAR CARCINOMA. 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/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-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. 2016 12 6271 39 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 13 3186 35 HBV COVALENTLY CLOSED CIRCULAR DNA MINICHROMOSOMES IN DISTINCT EPIGENETIC TRANSCRIPTIONAL STATES DIFFER IN THEIR VULNERABILITY TO DAMAGE. BACKGROUND AND AIMS: HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IS A MAJOR OBSTACLE FOR A CURE OF CHRONIC HEPATITIS B. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MODIFICATIONS REGULATE THE TRANSCRIPTIONAL ACTIVITY OF CCCDNA MINICHROMOSOMES. HOWEVER, IT REMAINS UNCLEAR HOW THE EPIGENETIC STATE OF CCCDNA AFFECTS ITS STABILITY. APPROACHES AND RESULTS: BY USING HBV INFECTION CELL MODELS AND IN VITRO AND IN VIVO RECOMBINANT CCCDNA (RCCCDNA) AND HBVCIRCLE MODELS, THE REDUCTION RATE OF HBV CCCDNA AND THE EFFICACY OF APOLIPOPROTEIN B MRNA EDITING ENZYME CATALYTIC SUBUNIT 3A (APOBEC3A)-MEDIATED AND CRISPR/CRISPR-ASSOCIATED 9 (CAS9)-MEDIATED CCCDNA TARGETING WERE COMPARED BETWEEN CCCDNAS WITH DISTINCT TRANSCRIPTIONAL ACTIVITIES. INTERFERON-ALPHA TREATMENT AND HEPATITIS B X PROTEIN (HBX) DELETION WERE APPLIED AS TWO STRATEGIES FOR CCCDNA REPRESSION. CHROMATIN IMMUNOPRECIPITATION AND MICROCOCCAL NUCLEASE ASSAYS WERE PERFORMED TO DETERMINE THE EPIGENETIC PATTERN OF CCCDNA. HBV CCCDNA LEVELS REMAINED STABLE IN NONDIVIDING HEPATOCYTES; HOWEVER, THEY WERE SIGNIFICANTLY REDUCED DURING CELL DIVISION, AND THE REDUCTION RATE WAS SIMILAR BETWEEN CCCDNAS IN TRANSCRIPTIONALLY ACTIVE AND TRANSCRIPTIONALLY REPRESSED STATES. STRIKINGLY, HBV RCCCDNA WITHOUT HBX EXPRESSION EXHIBITED A SIGNIFICANTLY LONGER PERSISTENCE IN MICE. THE CCCDNA WITH LOW TRANSCRIPTIONAL ACTIVITY EXHIBITED AN EPIGENETICALLY INACTIVE PATTERN AND WAS MORE DIFFICULT TO ACCESS BY APOBEC3A AND ENGINEERED CRISPR-CAS9. THE EPIGENETIC REGULATOR ACTIVATING CCCDNA INCREASED ITS VULNERABILITY TO APOBEC3A. CONCLUSIONS: HBV CCCDNA MINICHROMOSOMES IN DISTINCT EPIGENETIC TRANSCRIPTIONAL STATES SHOWED A SIMILAR REDUCTION RATE DURING CELL DIVISION BUT SIGNIFICANTLY DIFFERED IN THEIR ACCESSIBILITY AND VULNERABILITY TO TARGETED NUCLEASES AND ANTIVIRAL AGENTS. EPIGENETIC SENSITIZATION OF CCCDNA MAKES IT MORE SUSCEPTIBLE TO DAMAGE AND MAY POTENTIALLY CONTRIBUTE TO AN HBV CURE. 2022 14 5689 41 SILENCING HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA: THE POTENTIAL OF AN EPIGENETIC THERAPY APPROACH. GLOBAL PROPHYLACTIC VACCINATION PROGRAMMES HAVE HELPED TO CURB NEW HEPATITIS B VIRUS (HBV) INFECTIONS. HOWEVER, IT IS ESTIMATED THAT NEARLY 300 MILLION PEOPLE ARE CHRONICALLY INFECTED AND HAVE A HIGH RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA. AS SUCH, HBV REMAINS A SERIOUS HEALTH PRIORITY AND THE DEVELOPMENT OF NOVEL CURATIVE THERAPEUTICS IS URGENTLY NEEDED. CHRONIC HBV INFECTION HAS BEEN ATTRIBUTED TO THE PERSISTENCE OF THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) WHICH ESTABLISHES ITSELF AS A MINICHROMOSOME IN THE NUCLEUS OF HEPATOCYTES. AS THE VIRAL TRANSCRIPTION INTERMEDIATE, THE CCCDNA IS RESPONSIBLE FOR PRODUCING NEW VIRIONS AND PERPETUATING INFECTION. HBV IS DEPENDENT ON VARIOUS HOST FACTORS FOR CCCDNA FORMATION AND THE MINICHROMOSOME IS AMENABLE TO EPIGENETIC MODIFICATIONS. TWO HBV PROTEINS, X (HBX) AND CORE (HBC) PROMOTE VIRAL REPLICATION BY MODULATING THE CCCDNA EPIGENOME AND REGULATING HOST CELL RESPONSES. THIS INCLUDES VIRAL AND HOST GENE EXPRESSION, CHROMATIN REMODELING, DNA METHYLATION, THE ANTIVIRAL IMMUNE RESPONSE, APOPTOSIS, AND UBIQUITINATION. ELIMINATION OF THE CCCDNA MINICHROMOSOME WOULD RESULT IN A STERILIZING CURE; HOWEVER, THIS MAY BE DIFFICULT TO ACHIEVE. EPIGENETIC THERAPIES COULD PERMANENTLY SILENCE THE CCCDNA MINICHROMOSOME AND PROMOTE A FUNCTIONAL CURE. THIS REVIEW EXPLORES THE CCCDNA EPIGENOME, HOW HOST AND VIRAL FACTORS INFLUENCE TRANSCRIPTION, AND THE RECENT EPIGENETIC THERAPIES AND EPIGENOME ENGINEERING APPROACHES THAT HAVE BEEN DESCRIBED. 2021 15 3794 38 INTERLEUKIN-33 MEDIATES BOTH IMMUNE-RELATED AND NON-IMMUNE-RELATED INHIBITORY EFFECTS AGAINST HEPATITIS B VIRUS. CHRONIC INFECTION BY HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH HIGH RISKS OF LIVER FIBROSIS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN THE NUCLEUS OF INFECTED HEPATOCYTE SERVES AS TRANSCRIPTION TEMPLATE. NEITHER NATURAL RESOLUTION OF ACUTE INFECTION NOR CURRENT TREATMENT OPTIONS FOR CHRONIC INFECTION ARE BELIEVED TO CAUSE CCCDNA CLEARANCE. WE PREVIOUSLY SHOWED THAT INJECTION OF IL-33-EXPRESSING PLASMID FACILITATED CLEARANCE OF INTRAHEPATIC HBV DNA IN A MOUSE MODEL OF HBV PERSISTENCE. IN THIS WORK, HBV-TARGETING THERAPEUTIC EFFECTS OF IL-33 WERE FURTHER EXPLORED. MURINE IL-33 DELIVERED BY RECOMBINANT ADENO-ASSOCIATED VIRUS (AAV-MIL-33) INDUCED CLEARANCE OF BOTH SERUM HBV MARKERS AND INTRAHEPATIC HBV DNA IN TWO MOUSE MODELS OF HBV PERSISTENCE BASED ON REPLICON PLASMID AND RECOMBINANT CCCDNA (RCCCDNA) RESPECTIVELY. CLEARANCE WAS ASSOCIATED WITH SERUM ALT ELEVATIONS AND LIVER INFILTRATIONS BY CD4(+) AND CD8(+) T CELLS, INDICATING IL-33-INDUCED CELLULAR IMMUNE RESPONSES AGAINST HBV-HARBORING CELLS. ADOPTIVE TRANSFER OF SPLENOCYTES FROM AAV-MIL-33-CURED MICE WAS INDEED SUFFICIENT TO ENGENDER SIMILAR CLEARANCE IN RECIPIENT MICE. IN VITRO, INTRACELLULAR, INSTEAD OF EXTRACELLULAR, IL-33 WAS MAINLY RESPONSIBLE FOR REPRESSING VIRAL TRANSCRIPTION, PROTEIN PRODUCTION AND GENOME REPLICATION IN HUH7 CELLS TRANSFECTED WITH HBV REPLICON OR RCCCDNA. IL-33 WAS SHOWN TO BE RECRUITED ONTO RCCCDNA MINICHROMOSOME ACCOMPANIED BY LOSS OF TRANSCRIPTIONAL ACTIVATION EPIGENETIC MARKS. FINALLY, TRANSFECTION OF IL-33 INTO HBV-INFECTED HEPG2/NTCP CELLS RESULTED IN REDUCED TRANSCRIPTION, ANTIGEN EXPRESSION AND GENOME REPLICATION, SUGGESTING REPRESSION OF CANONICAL CCCDNA. THESE DATA DEMONSTRATED DIVERSE INHIBITORY EFFECTS ON HBV AND HBV-INFECTED CELLS MEDIATED BY IL-33, AND SUGGEST IL-33 AS AN INTERESTING THERAPEUTIC CANDIDATE. 2022 16 6011 34 THE ANTIRESECTION ACTIVITY OF THE X PROTEIN ENCODED BY HEPATITIS VIRUS B. CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH AN INCREASED INCIDENCE OF HEPATOCELLULAR CARCINOMA (HCC). HBV ENCODES AN ONCOPROTEIN, HEPATITIS B X PROTEIN (HBX), THAT IS CRUCIAL FOR VIRAL REPLICATION AND INTERFERES WITH MULTIPLE CELLULAR ACTIVITIES INCLUDING GENE EXPRESSION, HISTONE MODIFICATIONS, AND GENOMIC STABILITY. TO DATE, IT REMAINS UNCLEAR HOW DISRUPTION OF THESE ACTIVITIES CONTRIBUTES TO HEPATOCARCINOGENESIS. HERE, WE REPORT THAT HBV EXHIBITS ANTIRESECTION ACTIVITY BY DISRUPTING DNA END RESECTION, THUS IMPAIRING THE INITIAL STEPS OF HOMOLOGOUS RECOMBINATION (HR). THIS ANTIRESECTION ACTIVITY OCCURS IN PRIMARY HUMAN HEPATOCYTES UNDERGOING A NATURAL VIRAL INFECTION-REPLICATION CYCLE AS WELL AS IN CELLS WITH INTEGRATED HBV GENOMES. AMONG THE SEVEN HBV-ENCODED PROTEINS, WE IDENTIFIED HBX AS THE SOLE VIRAL FACTOR THAT INHIBITS RESECTION. BY DISRUPTING AN EVOLUTIONARILY CONSERVED CULLIN4A-DAMAGE-SPECIFIC DNA BINDING PROTEIN 1-RING TYPE OF E3 LIGASE, CRL4(WDR70) , THROUGH ITS H-BOX, WE SHOW THAT HBX INHIBITS H2B MONOUBIQUITYLATION AT LYSINE 120 AT DOUBLE-STRAND BREAKS, THUS REDUCING THE EFFICIENCY OF LONG-RANGE RESECTION. WE FURTHER SHOW THAT DIRECTLY IMPAIRING H2B MONOUBIQUITYLATION ELICITED TUMORIGENESIS UPON ENGRAFTMENT OF DEFICIENT CELLS IN ATHYMIC MICE, CONFIRMING THAT THE IMPAIRMENT OF CRL4(WDR70) FUNCTION BY HBX IS SUFFICIENT TO PROMOTE CARCINOGENESIS. FINALLY, WE DEMONSTRATE THAT LACK OF H2B MONOUBIQUITYLATION IS MANIFEST IN HUMAN HBV-ASSOCIATED HCC WHEN COMPARED WITH HBV-FREE HCC, IMPLYING CORRESPONDING DEFECTS OF EPIGENETIC REGULATION AND END RESECTION. CONCLUSION: THE ANTIRESECTION ACTIVITY OF HBX INDUCES AN HR DEFECT AND GENOMIC INSTABILITY AND CONTRIBUTES TO TUMORIGENESIS OF HOST HEPATOCYTES. 2019 17 3274 40 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 18 3189 35 HBX RELIEVES CHROMATIN-MEDIATED TRANSCRIPTIONAL REPRESSION OF HEPATITIS B VIRAL CCCDNA INVOLVING SETDB1 HISTONE METHYLTRANSFERASE. BACKGROUND & AIMS: MAINTENANCE OF THE COVALENTLY CLOSED CIRCULAR HBV DNA (CCCDNA) THAT SERVES AS A TEMPLATE FOR HBV TRANSCRIPTION IS RESPONSIBLE FOR THE FAILURE OF ANTIVIRAL THERAPIES. WHILE STUDIES IN CHRONIC HEPATITIS PATIENTS HAVE SHOWN THAT HIGH VIREMIA CORRELATES WITH HYPERACETYLATION OF CCCDNA-ASSOCIATED HISTONES, THE MOLECULAR MECHANISMS CONTROLLING CCCDNA STABILITY AND TRANSCRIPTIONAL REGULATION ARE STILL POORLY UNDERSTOOD. THIS STUDY AIMED TO DECIPHER THE ROLE OF CHROMATIN AND CHROMATIN MODIFIER PROTEINS ON HBV TRANSCRIPTION. METHODS: WE ANALYZED THE CHROMATIN STRUCTURE OF ACTIVELY TRANSCRIBED OR SILENCED CCCDNA BY INFECTING PRIMARY HUMAN HEPATOCYTES AND DIFFERENTIATED HEPARG CELLS WITH WILD-TYPE VIRUS OR VIRUS DEFICIENT (HBVX-) FOR THE EXPRESSION OF HEPATITIS B VIRUS X PROTEIN (HBX), THAT IS REQUIRED FOR HBV EXPRESSION. RESULTS: IN THE ABSENCE OF HBX, HBV CCCDNA WAS TRANSCRIPTIONALLY SILENCED WITH THE CONCOMITANT DECREASE OF HISTONE 3 (H3) ACETYLATION AND H3K4ME3, INCREASE OF H3 DI- AND TRI-METHYLATION (H3K9ME) AND THE RECRUITMENT OF HETEROCHROMATIN PROTEIN 1 FACTORS (HP1) THAT CORRELATE WITH CONDENSED CHROMATIN. SETDB1 WAS FOUND TO BE THE MAIN HISTONE METHYLTRANSFERASE RESPONSIBLE FOR THE DEPOSITION OF H3K9ME3 AND HBV REPRESSION. FINALLY, FULL TRANSCRIPTIONAL REACTIVATION OF HBVX- UPON HBX RE-EXPRESSION CORRELATED WITH AN INCREASE OF HISTONE ACETYLATION AND H3K4ME3, AND A CONCOMITANT DECREASE OF HP1 BINDING AND OF H3K9ME3 ON THE CCCDNA. CONCLUSION: UPON HBV INFECTION, CELLULAR MECHANISMS INVOLVING SETDB1-MEDIATED H3K9ME3 AND HP1 INDUCE SILENCING OF HBV CCCDNA TRANSCRIPTION THROUGH MODULATION OF CHROMATIN STRUCTURE. HBX IS ABLE TO RELIEVE THIS REPRESSION AND ALLOW THE ESTABLISHMENT OF ACTIVE CHROMATIN. 2015 19 6486 31 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 20 1478 23 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