1 3365 117 HISTONE METHYLATION IN PRE-CANCEROUS LIVER DISEASES AND HEPATOCELLULAR CARCINOMA: RECENT OVERVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE PREVALENT FORM OF LIVER CANCER IN ADULTS AND THE FOURTH MOST COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. HCC PREDOMINANTLY ARISES IN THE CONTEXT OF CIRRHOSIS AS A RESULT OF CHRONIC LIVER DISEASE, INJURY AND INFLAMMATION. FULL-BLOWN HCC HAS POOR PROGNOSIS BECAUSE IT IS HIGHLY AGGRESSIVE AND RESISTANT TO THERAPY. CONSEQUENTLY, INTERVENTIONS THAT CAN PREVENT OR RESTRAIN HCC EMERGENCE FROM PRE-CANCEROUS DISEASED LIVER ARE A DESIRABLE STRATEGY. HISTONE METHYLATION IS A DYNAMIC, REVERSIBLE EPIGENETIC MODIFICATION INVOLVING THE ADDITION OR REMOVAL OF METHYL GROUPS FROM LYSINE, ARGININE OR GLUTAMINE RESIDUES. ABERRANT ACTIVITY OF HISTONE METHYLATION WRITERS, ERASES AND READERS HAS BEEN IMPLICATED IN SEVERAL CANCER TYPES, INCLUDING HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RESEARCH ON THE ROLE OF HISTONE METHYLATION IN PRE-CANCEROUS AND CANCEROUS HCC PUBLISHED OVER THE LAST 5 YEARS. IN PARTICULAR, WE PRESENT THE EVIDENCE LINKING ENVIRONMENTAL FACTORS SUCH AS DIET, VIRAL INFECTIONS AND CARCINOGENIC AGENTS WITH DYSREGULATION OF HISTONE METHYLATION DURING LIVER CANCER PROGRESSION WITH THE AIM TO HIGHLIGHT FUTURE THERAPEUTIC POSSIBILITIES. 2023 2 2166 46 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 3 2970 45 GENETIC AND EPIGENETIC SIGNATURES IN HUMAN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD MOST COMMON CAUSE OF CANCER DEATHS WORLDWIDE, AND THE INCIDENCE OF THIS FATAL DISEASE IS STILL ON RISE. THE MAJORITY OF HCCS EMERGE IN THE BACKGROUND OF A CHRONIC LIVER DISEASE, SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS. THE CURRENT UNDERSTANDING IS THAT MAJORITY OF HCCS EVOLVE AS A CONSEQUENCE OF CHRONIC INFLAMMATION AND DUE TO THE PRESENCE OF INFECTION WITH HEPATITIS VIRUSES. THESE UNDERLYING PATHOGENIC STIMULI SUBSEQUENTLY INDUCE A SPECTRUM OF GENETIC AND EPIGENETIC ALTERATIONS IN SEVERAL CANCER-RELATED GENES, WHICH ARE INVOLVED IN CELL-CYCLE REGULATION, CELL GROWTH AND ADHESION. SUCH WIDESPREAD GENOMIC ALTERATIONS CAUSE DISRUPTION OF NORMAL CELLULAR SIGNALING AND FINALLY LEAD TO THE ACQUISITION OF A MALIGNANT PHENOTYPE IN HCC. IN GENERAL, THE TYPE OF GENE ALTERATIONS, SUCH AS POINT MUTATIONS, DELETION OF CHROMOSOMAL REGIONS AND ABNORMAL METHYLATION OF GENE PROMOTERS DIFFER ACCORDING TO THE INDIVIDUAL TARGETED GENE. IN HCC, INCIDENCE OF GENETIC ALTERATIONS IS RELATIVELY RARE AND IS LIMITED TO A SUBSET OF FEW CANCER-SPECIFIC GENES, SUCH AS THE TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS THE CTNNB1. IN CONTRAST, EPIGENETIC CHANGES THAT INVOLVE ABERRANT METHYLATION OF GENES AND OTHER POST-TRANSCRIPTIONAL HISTONE MODIFICATIONS OCCUR FAR MORE FREQUENTLY, AND SOME OF THESE EPIGENETIC ALTERATIONS ARE NOW BEING EXPLOITED FOR THE DEVELOPMENT OF MOLECULAR DIAGNOSTIC SIGNATURES FOR HCC. IN ADDITION, RECENT FINDINGS OF UNIQUE MICRORNA EXPRESSION PROFILES ALSO PROVIDE AN EVIDENCE FOR THE EXISTENCE OF NOVEL MECHANISMS FOR GENE EXPRESSION REGULATION IN HCC. IN THIS REVIEW ARTICLE, WE WILL REVIEW THE CURRENT STATE OF KNOWLEDGE ON THE ACTIVATION OF VARIOUS ONCOGENIC PATHWAYS AND THE INACTIVATION OF TUMOR SUPPRESSOR PATHWAYS IN HCC THAT RESULT IN THE DISRUPTION OF CANCER-RELATED GENE FUNCTION. IN ADDITION, WE WILL SPECIFICALLY EMPHASIZE THE CLINICAL IMPLICATION OF SOME OF THESE GENETIC AND EPIGENETIC ALTERATIONS IN THE MANAGEMENT OF HEPATOCARCINOGENESIS. 2011 4 2538 30 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014 5 3932 30 LIVER REGENERATION, LIVER CANCERS AND CYCLINS. ACCUMULATING EVIDENCE HAS REVEALED THAT MALIGNANT CELL GROWTH IS REGULATED BY COMPLEX MECHANISMS INVOLVED IN GENETIC AND EPIGENETIC FACTORS. AMONG HUMAN CANCERS, CANCER IN THE LIVER (HEPATOCELLULAR CARCINOMA (HCC)) IS CHARACTERIZED BY THE EVIDENCE THAT IT IS USUALLY BASED ON CHRONIC LIVER DISEASES SUCH AS LIVER CIRRHOSIS OR CHRONIC HEPATITIS, IN WHICH THE LIVER IS PERSISTENTLY REGENERATING FOLLOWING HEPATIC INJURY. THIS RAISES THE POSSIBILITY THAT REPEATED HEPATOCYTE PROLIFERATION MAY CAUSE DISORDER OF GENES THAT ARE REGULATING THE CELL CYCLE IN HEPATOCYTES, THUS CAUSING HCC. IN THIS ARTICLE, RECENT STUDIES FOCUSING ON LIVER REGENERATION AND CANCER ARE REVIEWED FROM THE VIEWPOINT OF THE CELL CYCLE THAT IS REGULATED BY CYCLIN AND THE ASSOCIATED PROTEINS. 1998 6 2014 31 EPIGENETIC BIOMARKERS FOR THE DIAGNOSIS AND TREATMENT OF LIVER DISEASE. RESEARCH IN THE LAST DECADES HAS DEMONSTRATED THE RELEVANCE OF EPIGENETICS IN CONTROLLING GENE EXPRESSION TO MAINTAIN CELL HOMEOSTASIS, AND THE IMPORTANT ROLE PLAYED BY EPIGENOME ALTERATIONS IN DISEASE DEVELOPMENT. MOREOVER, THE REVERSIBILITY OF EPIGENETIC MARKS CAN BE HARNESSED AS A THERAPEUTIC STRATEGY, AND EPIGENETIC MARKS CAN BE USED AS DIAGNOSIS BIOMARKERS. EPIGENETIC ALTERATIONS IN DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND NON-CODING RNA (NCRNA) EXPRESSION HAVE BEEN ASSOCIATED WITH THE PROCESS OF HEPATOCARCINOGENESIS. HERE, WE SUMMARIZE EPIGENETIC ALTERATIONS INVOLVED IN THE PATHOGENESIS OF CHRONIC LIVER DISEASE (CLD), PARTICULARLY FOCUSING ON DNA METHYLATION. WE ALSO DISCUSS THEIR UTILITY AS EPIGENETIC BIOMARKERS IN LIQUID BIOPSY FOR THE DIAGNOSIS AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA (HCC). FINALLY, WE DISCUSS THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES FOR HCC TREATMENT. 2021 7 4687 33 NEW TOOLS FOR MOLECULAR THERAPY OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER, ARISING FROM NEOPLASTIC TRANSFORMATION OF HEPATOCYTES OR LIVER PRECURSOR/STEM CELLS. HCC IS OFTEN ASSOCIATED WITH PRE-EXISTING CHRONIC LIVER PATHOLOGIES OF DIFFERENT ORIGIN (MAINLY SUBSEQUENT TO HBV AND HCV INFECTIONS), SUCH AS FIBROSIS OR CIRRHOSIS. CURRENT THERAPIES ARE ESSENTIALLY STILL INEFFECTIVE, DUE BOTH TO THE TUMOR HETEROGENEITY AND THE FREQUENT LATE DIAGNOSIS, MAKING NECESSARY THE CREATION OF NEW THERAPEUTIC STRATEGIES TO INHIBIT TUMOR ONSET AND PROGRESSION AND IMPROVE THE SURVIVAL OF PATIENTS. A PROMISING STRATEGY FOR TREATMENT OF HCC IS THE TARGETED MOLECULAR THERAPY BASED ON THE RESTORATION OF TUMOR SUPPRESSOR PROTEINS LOST DURING NEOPLASTIC TRANSFORMATION. IN PARTICULAR, THE DELIVERY OF MASTER GENES OF EPITHELIAL/HEPATOCYTE DIFFERENTIATION, ABLE TO TRIGGER AN EXTENSIVE REPROGRAMMING OF GENE EXPRESSION, COULD ALLOW THE INDUCTION OF AN EFFICIENT ANTITUMOR RESPONSE THROUGH THE SIMULTANEOUS ADJUSTMENT OF MULTIPLE GENETIC/EPIGENETIC ALTERATIONS CONTRIBUTING TO TUMOR DEVELOPMENT. HERE, WE REPORT RECENT LITERATURE DATA SUPPORTING THE USE OF MEMBERS OF THE LIVER ENRICHED TRANSCRIPTION FACTOR (LETF) FAMILY, IN PARTICULAR HNF4ALPHA, AS TOOLS FOR GENE THERAPY OF HCC. 2015 8 5622 28 SEARCH FOR USEFUL BIOMARKERS IN HEPATOCELLULAR CARCINOMA, TUMOR FACTORS AND BACKGROUND LIVER FACTORS (REVIEW). HEPATOCARCINOGENESIS IS A COMPLEX AND MULTISTEP PROCESS THAT INVOLVES THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES. TO UNDERSTAND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CURRENT RESEARCH HAS UTILIZED IMPROVED ARRAY TECHNOLOGIES. THE IDENTIFICATION OF CANCER-RELATED MOLECULES COULD LEAD TO THE DEVELOPMENT OF NOVEL MOLECULAR TARGETS FOR TREATMENT AND BIOMARKERS FOR PREDICTING PROGNOSIS. HOWEVER, PROGNOSTIC PREDICTION IS INSUFFICIENT WHEN CONSIDERING ONLY TUMOR FACTORS, SINCE HEPATOCARCINOGENESIS IS ALSO GREATLY INFLUENCED BY THE STATUS OF THE BACKGROUND LIVER. CLINICAL BACKGROUND LIVER FACTORS, SUCH AS THE PRESENCE OF CHRONIC ACTIVE HEPATITIS OR CIRRHOSIS, ARE WELL KNOWN AS RISK FACTORS FOR DEVELOPING HCC. IN CONTRAST, GENETIC OR EPIGENETIC BACKGROUND LIVER FACTORS REMAIN UNKNOWN, ALBEIT THOSE ARE IMPORTANT TO UNDERSTAND THE DEVELOPING PROCESS OF HCC. INVESTIGATING BACKGROUND LIVER FACTORS COULD CONTRIBUTE TO THE DEVELOPMENT OF CARCINOGENIC MARKERS OF HCC AND TO THE PREVENTION OF THE DEVELOPMENT OF HCC. IN THE PRESENT STUDY, WE REVIEW THE CURRENTLY IDENTIFIED TUMOR FACTORS AND BACKGROUND LIVER FACTORS FROM A MOLECULAR BIOLOGICAL VIEWPOINT AND ALSO INTRODUCE OUR COMBINATION ARRAY ANALYSIS. 2017 9 3928 33 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021 10 4421 28 MOLECULAR AND FUNCTIONAL GENETICS OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER AND ONE OF THE LEADING CAUSES OF CANCER DEATH WORLDWIDE. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS DEVELOPING FROM NORMAL THROUGH CHRONIC HEPATITIS/CIRRHOSIS AND DYSPLASTIC NODULES TO HCC. ALTHOUGH WE HAVE INSUFFICIENT UNDERSTANDING TO PROPOSE A ROBUST GENERAL MODEL, WITH ADVANCES IN MOLECULAR METHODS, THERE IS A GROWING UNDERSTANDING OF THE MOLECULAR MECHANISMS IN THE DEVELOPMENT OF HCC. HEPATOCARCINOGENESIS IS STRONGLY LINKED TO INCREASES IN ALLELIC LOSSES, CHROMOSOMAL CHANGES, GENE MUTATIONS, EPIGENETIC ALTERATIONS, AND ALTERATIONS IN MOLECULAR CELLULAR PATHWAYS. SPECIAL EMPHASIS IN THIS REVIEW IS GIVEN TO THE GENETICS, EPIGENETICS, AND REGULATION OF MAJOR SIGNALING PATHWAYS INVOLVED IN HCC SUCH AS WNT/B-CATENIN, RAS, AND PI3K/AKT/MTOR PATHWAYS. A DETAILED UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS INVOLVED IN THE PROGRESSION OF HCC CAN IMPROVE OUR PREVENTION AND DIAGNOSTIC TOOLS FOR HCC AND BE AN IMPORTANT POTENTIAL SOURCE OF NOVEL MOLECULAR TARGETS FOR NEW THERAPIES. 2010 11 3250 33 HEPATITIS B VIRUS INFECTION, MICRORNAS AND LIVER DISEASE. HEPATITIS B VIRUS (HBV) ATTACKS THE LIVER AND CAN CAUSE BOTH ACUTE AS WELL AS CHRONIC LIVER DISEASES WHICH MIGHT LEAD TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. REGARDLESS OF THE AVAILABILITY OF A VACCINE AND NUMEROUS TREATMENT OPTIONS, HBV IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY ACROSS THE WORLD. RECENTLY,MICRORNAS (MIRNAS) HAVE EMERGED AS IMPORTANT MODULATORS OF GENE FUNCTION. STUDIES ON THE ROLE OF MIRNA IN THE REGULATION OF HEPATITIS B VIRUS GENE EXPRESSION HAVE BEEN THE FOCUS OF MODERN ANTIVIRAL RESEARCH. MIRNAS CAN REGULATE VIRAL REPLICATION AND PATHOGENESIS IN A NUMBER OF DIFFERENT WAYS, WHICH INCLUDEFACILITATION, DIRECT OR INDIRECT INHIBITION, ACTIVATION OF IMMUNE RESPONSE, EPIGENETIC MODULATION, ETC. NEVERTHELESS, THESE MECHANISMS CAN APPROPRIATELY BE USED WITH A DIAGNOSTICAND/OR THERAPEUTIC APPROACH. THE PRESENT REVIEW IS AN ATTEMPT TO CLASSIFY SPECIFIC MIRNAS THAT ARE REPORTED TO BE ASSOCIATED WITH VARIOUS ASPECTS OF HEPATITIS B BIOLOGY, IN ORDER TO PRECISELY PRESENT THE PARTICIPATION OF INDIVIDUAL MIRNAS IN MULTIPLE ASPECTS RELATING TO HBV. 2015 12 3244 43 HEPATIC STELLATE CELLS AND EXTRACELLULAR MATRIX IN HEPATOCELLULAR CARCINOMA: MORE COMPLICATED THAN EVER. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER DEATH. RECENT EPIDEMIOLOGICAL DATA INDICATE THAT THE MORTALITY RATE OF HCC WILL DOUBLE OVER THE NEXT DECADES IN THE USA AND EUROPE. LIVER CANCER PROGRESSES IN A LARGE PERCENTAGE OF CASES DURING THE CLINICAL COURSE OF CHRONIC FIBRO-INFLAMMATORY LIVER DISEASES LEADING TO CIRRHOSIS. THEREFORE, HCC DEVELOPMENT IS REGARDED AS THE RESULT OF DIFFERENT ENVIRONMENTAL RISK FACTORS EACH INVOLVING DIFFERENT GENETIC, EPIGENETIC- AND CHROMOSOMAL ALTERATIONS AND GENE MUTATIONS. DURING TUMOUR PROGRESSION, THE MALIGNANT HEPATOCYTES AND THE ACTIVATED HEPATIC STELLATE CELLS ARE ACCOMPANIED BY CANCER-ASSOCIATED FIBROBLASTS, MYOFIBROBLASTS AND IMMUNE CELLS GENERALLY CALLED TUMOUR STROMAL CELLS. THIS NEW AND DYNAMIC MILIEU FURTHER ENHANCES THE RESPONSIVENESS OF TUMOUR CELLS TOWARDS SOLUBLE MEDIATORS SECRETED BY TUMOUR STROMAL CELLS, THUS DIRECTLY AFFECTING THE MALIGNANT HEPATOCYTES. THIS RESULTS IN ALTERED MOLECULAR PATHWAYS WITH CELL PROLIFERATION AS THE MOST IMPORTANT MECHANISM OF LIVER CANCER PROGRESSION. GIVEN THIS CONTEXTUAL COMPLEXITY, IT IS OF UTMOST IMPORTANCE TO CHARACTERIZE THE MOLECULAR PATHOGENESIS OF HCC, AND TO IDENTIFY THE DOMINANT PATHWAYS/DRIVERS AND ABERRANT SIGNALLING PATHWAYS. THIS WILL ALLOW AN EFFECTIVE THERAPY FOR HCC THAT SHOULD COMBINE STRATEGIES AFFECTING BOTH CANCER AND THE TUMOUR STROMAL CELLS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT CHALLENGES AND ISSUES REGARDING HEPATIC STELLATE CELLS, EXTRACELLULAR MATRIX DYNAMICS, LIVER FIBROSIS/CIRRHOSIS AND THERAPY, TUMOUR MICROENVIRONMENT AND HCC. 2014 13 4888 34 OXIDATIVE DAMAGE IN THE PROGRESSION OF CHRONIC LIVER DISEASE TO HEPATOCELLULAR CARCINOMA: AN INTRICATE PATHWAY. THE HISTO-PATHOLOGIC AND MOLECULAR MECHANISMS LEADING TO INITIATION AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STILL ILL-DEFINED; HOWEVER, THERE IS INCREASING EVIDENCE THAT THE GRADUAL ACCUMULATION OF MUTATIONS, GENETIC AND EPIGENETIC CHANGES WHICH OCCUR IN PRENEOPLASTIC HEPATOCYTES RESULTS IN THE DEVELOPMENT OF DYSPLASTIC FOCI, NODULES, AND FINALLY, OVERT HCC. AS WELL AS MANY OTHER NEOPLASIAS, LIVER CANCER IS CONSIDERED AN "INFLAMMATORY CANCER", ARISING FROM A CONTEXT OF INFLAMMATION, AND CHARACTERIZED BY INFLAMMATION-RELATED MECHANISMS THAT FAVOR TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASION. MOLECULAR MECHANISMS THAT LINK INFLAMMATION AND NEOPLASIA HAVE BEEN WIDELY INVESTIGATED, AND IT HAS BEEN WELL ESTABLISHED THAT INFLAMMATORY CELLS RECRUITED AT THESE SITES WITH ONGOING INFLAMMATORY ACTIVITY RELEASE CHEMOKINES THAT ENHANCE THE PRODUCTION OF REACTIVE OXYGEN SPECIES. THE LATTER, IN TURN, PROBABLY HAVE A MAJOR PATHOGENIC ROLE IN THE CONTINUUM STARTING FROM HEPATITIS FOLLOWED BY CHRONIC INFLAMMATION, AND ULTIMATELY LEADING TO CANCER. THE RELATIONSHIP AMONGST CHRONIC LIVER INJURY, FREE RADICAL PRODUCTION, AND DEVELOPMENT OF HCC IS EXPLORED IN THE PRESENT REVIEW, PARTICULARLY IN THE LIGHT OF THE COMPLEX NETWORK THAT INVOLVES OXIDATIVE DNA DAMAGE, CYTOKINE SYNTHESIS, TELOMERE DYSFUNCTION, AND MICRORNA REGULATION. 2014 14 2341 35 EPIGENETIC REGULATION OF LIVER FIBROSIS. FIBROSIS IS A COMMON AND IMPORTANT PATHOLOGY ASSOCIATED WITH PROGRESSIVE CHRONIC LIVER DISEASES AND UNDERLIES THE DEVELOPMENT OF CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. RESEARCH INTO THE MOLECULAR REGULATION OF FIBROSIS HAS DISCOVERED THAT IT IS UNDER THE CONTROL OF A NUMBER OF EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND THE ACTIVITIES OF NON-CODING RNAS. A DEEPER UNDERSTANDING OF HOW EPIGENETIC REGULATORS SUCH AS DNA METHYLTRANSERASES, METHYL-DNA BINDING PROTEINS, HISTONE MODIFYING ENZYMES AND REGULATORY RNA MOLECULES IMPACT ON THE FIBROGENIC PROCESS IS EXPECTED TO RESULT IN NEW BIOMARKERS FOR DISEASE PROGRESSION AS WELL AS NOVEL THERAPEUTIC TARGETS. THE AIM OF THIS MINI-REVIEW IS TO BRIEFLY INTRODUCE THE READER TO THE MAJOR EPIGENETIC REGULATORS SO FAR IDENTIFIED AS BEING IMPLICATED IN FIBROSIS. 2015 15 4476 23 MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER AND THE THIRD LEADING CAUSE OF CANCER DEATH WORLDWIDE. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS EVOLVING FROM NORMAL THROUGH CHRONIC HEPATITIS/CIRRHOSIS AND DYSPLASTIC NODULES TO HCC. WITH ADVANCES IN MOLECULAR METHODS, THERE IS A GROWING UNDERSTANDING OF THE MOLECULAR MECHANISMS IN HEPATOCARCINOGENESIS. HEPATOCARCINOGENESIS IS STRONGLY LINKED TO INCREASES IN ALLELIC LOSSES, CHROMOSOMAL CHANGES, GENE MUTATIONS, EPIGENETIC ALTERATIONS AND ALTERATIONS IN MOLECULAR CELLULAR PATHWAYS. SOME OF THESE ALTERATIONS ARE ACCOMPANIED BY A STEPWISE INCREASE IN THE DIFFERENT PATHOLOGICAL DISEASE STAGES IN HEPATOCARCINOGENESIS. OVERALL, A DETAILED UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS INVOLVED IN THE PROGRESSION OF HCC IS OF FUNDAMENTAL IMPORTANCE TO THE DEVELOPMENT OF EFFECTIVE PREVENTION AND TREATMENT REGIMES FOR HCC. 2008 16 2182 35 EPIGENETIC MECHANISMS REGULATING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA AND THEIR PROMISE FOR THERAPEUTICS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS AROUND THE GLOBE AND THIRD MOST FATAL MALIGNANCY. CHRONIC LIVER DISORDERS SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS OFTEN LEAD TO THE DEVELOPMENT OF HCC. ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS ARE INVOLVED IN THE DEVELOPMENT OF HCC. GENETIC RESEARCH SPARKED BY RECENT DEVELOPMENTS IN NEXT GENERATION SEQUENCING HAS IDENTIFIED THE FREQUENCY OF GENETIC ALTERATIONS THAT OCCUR IN HCC AND HAS LED TO THE IDENTIFICATION OF GENETIC HOTSPOTS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC ABERRATIONS ARE STRONGLY ASSOCIATED WITH THE INITIATION AND DEVELOPMENT OF HCC. VARIOUS IMPORTANT GENES ENCODING TUMOR SUPPRESSORS INCLUDING P16, RASSF1A, DLC-1, RUNX3 AND SOCS-1 ARE TARGETS OF EPIGENETIC DYSREGULATION DURING THE DEVELOPMENT OF HCC. THE PRESENT REVIEW DISCUSSES THE IMPORTANCE OF EPIGENETIC REGULATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MEDIATED REGULATION OF GENE EXPRESSION DURING TUMORIGENESIS AND THEIR USE AS DISEASE BIOMARKERS. FURTHERMORE, THESE EPIGENETIC ALTERATIONS HAVE BEEN DISCUSSED IN RELATIONSHIP WITH PROMISING THERAPEUTIC PERSPECTIVES FOR HCC AND RELATED CANCERS. 2017 17 3621 37 IN VIVO AND IN VITRO MODELS OF HEPATOCELLULAR CARCINOMA: CURRENT STRATEGIES FOR TRANSLATIONAL MODELING. HEPATOCELLULAR CARCINOMA (HCC) IS THE SIXTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH GLOBALLY. HCC IS A COMPLEX MULTISTEP DISEASE AND USUALLY EMERGES IN THE SETTING OF CHRONIC LIVER DISEASES. THE MOLECULAR PATHOGENESIS OF HCC VARIES ACCORDING TO THE ETIOLOGY, MAINLY CAUSED BY CHRONIC HEPATITIS B AND C VIRUS INFECTIONS, CHRONIC ALCOHOL CONSUMPTION, AFLATOXIN-CONTAMINATED FOOD, AND NON-ALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH METABOLIC SYNDROME OR DIABETES MELLITUS. THE ESTABLISHMENT OF HCC MODELS HAS BECOME ESSENTIAL FOR BOTH BASIC AND TRANSLATIONAL RESEARCH TO IMPROVE OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY AND UNRAVEL NEW MOLECULAR DRIVERS OF THIS DISEASE. THE IDEAL MODEL SHOULD RECAPITULATE KEY EVENTS OBSERVED DURING HEPATOCARCINOGENESIS AND HCC PROGRESSION IN VIEW OF ESTABLISHING EFFECTIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO BE TRANSLATED INTO CLINICAL PRACTICE. DESPITE CONSIDERABLE EFFORTS CURRENTLY DEVOTED TO LIVER CANCER RESEARCH, ONLY A FEW ANTI-HCC DRUGS ARE AVAILABLE, AND PATIENT PROGNOSIS AND SURVIVAL ARE STILL POOR. THE PRESENT PAPER PROVIDES A STATE-OF-THE-ART OVERVIEW OF IN VIVO AND IN VITRO MODELS USED FOR TRANSLATIONAL MODELING OF HCC WITH A SPECIFIC FOCUS ON THEIR KEY MOLECULAR HALLMARKS. 2021 18 2165 35 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 19 4127 49 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 20 4104 31 MECHANISM AND THERAPEUTIC OPPORTUNITIES OF HISTONE MODIFICATIONS IN CHRONIC LIVER DISEASE. CHRONIC LIVER DISEASE (CLD) REPRESENTS A GLOBAL HEALTH PROBLEM, ACCOUNTING FOR THE HEAVY BURDEN OF DISABILITY AND INCREASED HEALTH CARE UTILIZATION. EPIGENOME ALTERATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF CLD. HISTONE MODIFICATIONS, WHICH INCLUDE ACETYLATION, METHYLATION, AND PHOSPHORYLATION, REPRESENT AN ESSENTIAL PART OF EPIGENETIC MODIFICATIONS THAT AFFECT THE TRANSCRIPTIONAL ACTIVITY OF GENES. DIFFERENT FROM GENETIC MUTATIONS, HISTONE MODIFICATIONS ARE PLASTIC AND REVERSIBLE. THEY CAN BE MODULATED PHARMACOLOGICALLY WITHOUT CHANGING THE DNA SEQUENCE. THUS, THERE MIGHT BE CHANCES TO ESTABLISH INTERVENTIONAL SOLUTIONS BY TARGETING HISTONE MODIFICATIONS TO REVERSE CLD. HERE WE SUMMARIZED THE ROLES OF HISTONE MODIFICATIONS IN THE CONTEXT OF ALCOHOLIC LIVER DISEASE (ALD), METABOLIC ASSOCIATED FATTY LIVER DISEASE (MAFLD), VIRAL HEPATITIS, AUTOIMMUNE LIVER DISEASE, DRUG-INDUCED LIVER INJURY (DILI), AND LIVER FIBROSIS OR CIRRHOSIS. THE POTENTIAL TARGETS OF HISTONE MODIFICATIONS FOR TRANSLATION INTO THERAPEUTICS WERE ALSO INVESTIGATED. IN PROSPECT, HIGH EFFICACY AND LOW TOXICITY DRUGS THAT ARE SELECTIVELY TARGETING HISTONE MODIFICATIONS ARE REQUIRED TO COMPLETELY REVERSE CLD AND PREVENT THE DEVELOPMENT OF LIVER CIRRHOSIS AND MALIGNANCY. 2021