1 2970 158 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 2 2166 58 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 5360 59 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY. 2013 4 4687 41 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 5 5622 40 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 6 4477 40 MOLECULAR PATHOGENESIS OF HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCARCINOGENESIS IS A SLOW PROCESS DURING WHICH GENOMIC CHANGES PROGRESSIVELY ALTER THE HEPATOCELLULAR PHENOTYPE TO PRODUCE CELLULAR INTERMEDIATES THAT EVOLVE INTO HEPATOCELLULAR CARCINOMA. DURING THE LONG PRENEOPLASTIC STAGE, IN WHICH THE LIVER IS OFTEN THE SITE OF CHRONIC HEPATITIS, CIRRHOSIS, OR BOTH, HEPATOCYTE CYCLING IS ACCELERATED BY UPREGULATION OF MITOGENIC PATHWAYS, IN PART THROUGH EPIGENETIC MECHANISMS. THIS LEADS TO THE PRODUCTION OF MONOCLONAL POPULATIONS OF ABERRANT AND DYSPLASTIC HEPATOCYTES THAT HAVE TELOMERE EROSION AND TELOMERASE RE-EXPRESSION, SOMETIMES MICROSATELLITE INSTABILITY, AND OCCASIONALLY STRUCTURAL ABERRATIONS IN GENES AND CHROMOSOMES. DEVELOPMENT OF DYSPLASTIC HEPATOCYTES IN FOCI AND NODULES AND EMERGENCE OF HEPATOCELLULAR CARCINOMA ARE ASSOCIATED WITH THE ACCUMULATION OF IRREVERSIBLE STRUCTURAL ALTERATIONS IN GENES AND CHROMOSOMES, BUT THE GENOMIC BASIS OF THE MALIGNANT PHENOTYPE IS HETEROGENEOUS. THE MALIGNANT HEPATOCYTE PHENOTYPE MAY BE PRODUCED BY THE DISRUPTION OF A NUMBER OF GENES THAT FUNCTION IN DIFFERENT REGULATORY PATHWAYS, PRODUCING SEVERAL MOLECULAR VARIANTS OF HEPATOCELLULAR CARCINOMA. NEW STRATEGIES SHOULD ENABLE THESE VARIANTS TO BE CHARACTERIZED. 2002 7 4421 46 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 8 4888 42 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 9 3932 34 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 10 4479 46 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 11 4920 40 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 12 4476 40 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 13 4134 52 MECHANISMS OF HUMAN HEPATOCARCINOGENESIS. THE MAJOR RISK FACTORS AND ETIOLOGICAL AGENTS RESPONSIBLE FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN HUMANS HAVE BEEN IDENTIFIED AND CHARACTERIZED. AMONG THESE ARE CHRONIC INFECTION WITH HEPATITIS B VIRUS OR HEPATITIS C VIRUS, EXPOSURE TO AFLATOXIN B1, AND CIRRHOSIS OF ANY ETIOLOGY (INCLUDING ALCOHOLIC CIRRHOSIS AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES). BOTH CHRONIC HEPATITIS AND CIRRHOSIS REPRESENT MAJOR PRENEOPLASTIC CONDITIONS OF THE LIVER AS THE MAJORITY OF HEPATOCELLULAR CARCINOMAS ARISE IN THESE PATHOLOGICAL SETTINGS. HEPATOCARCINOGENESIS REPRESENTS A LINEAR AND PROGRESSIVE PROCESS IN WHICH SUCCESSIVELY MORE ABERRANT MONOCLONAL POPULATIONS OF HEPATOCYTES EVOLVE. REGENERATIVE HEPATOCYTES IN FOCAL LESIONS IN THE INFLAMED LIVER (CHRONIC HEPATITIS OR CIRRHOSIS) GIVE RISE TO HYPERPLASTIC HEPATOCYTE NODULES, AND THESE PROGRESS TO DYSPLASTIC NODULES, WHICH ARE THOUGHT TO BE THE DIRECT PRECURSOR OF HEPATOCELLULAR CARCINOMA. IN MOST CASES, THE NEOPLASTIC TRANSFORMATION OF HEPATOCYTES RESULTS FROM ACCUMULATION OF GENETIC DAMAGE DURING THE REPETITIVE CELLULAR PROLIFERATION THAT OCCURS IN THE INJURED LIVER IN RESPONSE TO PARACRINE GROWTH FACTOR AND CYTOKINE STIMULATION. HEPATOCELLULAR CARCINOMAS EXHIBIT NUMEROUS GENETIC ABNORMALITIES (INCLUDING CHROMOSOMAL DELETIONS, REARRANGEMENTS, ANEUPLOIDY, GENE AMPLIFICATIONS, AND MUTATIONS), AS WELL AS EPIGENETIC ALTERATIONS (INCLUDING MODULATION OF DNA METHYLATION). THESE GENETIC AND EPIGENETIC ALTERATIONS COMBINE TO ACTIVATE POSITIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING CELLULAR PROTO-ONCOGENES AND THEIR MITOGENIC SIGNALING PATHWAYS) AND INACTIVATE NEGATIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING TUMOR SUPPRESSOR GENES), RESULTING IN CELLS WITH AUTONOMOUS GROWTH POTENTIAL. HOWEVER, HEPATOCELLULAR CARCINOMAS EXHIBIT A HIGH DEGREE OF GENETIC HETEROGENEITY, SUGGESTING THAT MULTIPLE MOLECULAR PATHWAYS MAY BE INVOLVED IN THE GENESIS OF SUBSETS OF HEPATOCELLULAR NEOPLASMS. CONTINUED INVESTIGATION OF THE MECHANISMS OF HEPATOCARCINOGENESIS WILL REFINE OUR CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR BASIS FOR NEOPLASTIC TRANSFORMATION IN LIVER, ENABLING THE DEVELOPMENT OF EFFECTIVE STRATEGIES FOR PREVENTION AND/OR MORE EFFECTIVE TREATMENT OF HEPATOCELLULAR CARCINOMA. 2003 14 2538 36 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 15 2172 51 EPIGENETIC MECHANISMS INVOLVED IN HCV-INDUCED HEPATOCELLULAR CARCINOMA (HCC). HEPATOCELLULAR CARCINOMA (HCC), IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS, WHICH IS LARGELY CAUSED BY VIRUS INFECTION. ABOUT 80% OF THE VIRUS-INFECTED PEOPLE DEVELOP A CHRONIC INFECTION THAT EVENTUALLY LEADS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). WITH APPROXIMATELY 71 MILLION HCV CHRONIC INFECTED PATIENTS WORLDWIDE, THEY STILL HAVE A HIGH RISK OF HCC IN THE NEAR FUTURE. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES. HEPATITIS C VIRUS (HCV) INFECTION LARGELY CAUSES HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE WITH 3 TO 4 MILLION NEWLY INFECTED CASES DIAGNOSED EACH YEAR. IT IS URGENT TO EXPLORE ITS UNDERLYING MOLECULAR MECHANISMS FOR THERAPEUTIC TREATMENT AND BIOMARKER DISCOVERY. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES. 2021 16 2182 49 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 2854 41 FROM HEPATITIS TO HEPATOCELLULAR CARCINOMA: A PROPOSED MODEL FOR CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS. INFLAMMATION REPRESENTS THE BODY'S NATURAL RESPONSE TO TISSUE DAMAGE; HOWEVER, CHRONIC INFLAMMATION MAY ACTIVATE CELL PROLIFERATION AND INDUCE DEREGULATION OF CELL DEATH IN AFFECTED TISSUES. CHRONIC INFLAMMATION IS AN IMPORTANT FACTOR IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), ALTHOUGH THE PRECISE UNDERLYING MECHANISM REMAINS UNKNOWN. EPIGENETIC EVENTS, WHICH ARE CONSIDERED KEY MECHANISMS IN THE REGULATION OF GENE ACTIVITY STATES, ARE ALSO COMMONLY DEREGULATED IN HCC. HERE, WE REVIEW THE EVIDENCE THAT CHRONIC INFLAMMATION MIGHT DEREGULATE EPIGENETIC PROCESSES, THUS PROMOTING ONCOGENIC TRANSFORMATION, AND WE PROPOSE A WORKING HYPOTHESIS THAT EPIGENETIC DEREGULATION IS AN UNDERLYING MECHANISM BY WHICH INFLAMMATION MIGHT PROMOTE HCC DEVELOPMENT. IN THIS SCENARIO, DIFFERENT COMPONENTS OF THE INFLAMMATORY RESPONSE MIGHT DIRECTLY AND INDIRECTLY INDUCE CHANGES IN EPIGENETIC MACHINERIES ('EPIGENETIC SWITCH'), INCLUDING THOSE INVOLVED IN SETTING AND PROPAGATING NORMAL PATTERNS OF DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS IN HEPATOCYTES. WE DISCUSS THE POSSIBILITY THAT SELF-REINFORCING CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS MIGHT AMPLIFY INFLAMMATORY SIGNALS AND MAINTAIN A CHRONIC STATE OF INFLAMMATION CULMINATING IN CANCER DEVELOPMENT. THE POTENTIAL ROLE OF INFLAMMATION-EPIGENOME INTERACTIONS IN THE EMERGENCE AND MAINTENANCE OF CANCER STEM CELLS IS ALSO DISCUSSED. 2012 18 3244 49 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 19 5770 38 SPECIFIC MOLECULAR SIGNATURES OF NON-TUMOR LIVER TISSUE MAY PREDICT A RISK OF HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON HUMAN CANCERS AND A MAJOR CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE BLEAK OUTCOMES OF HCC PATIENTS EVEN AFTER CURATIVE TREATMENT HAVE BEEN, AT LEAST PARTIALLY, ATTRIBUTED TO ITS MULTICENTRIC ORIGIN. THEREFORE, IT IS NECESSARY TO EXAMINE NOT ONLY TUMOR TISSUE BUT ALSO NON-TUMOR LIVER TISSUE TO INVESTIGATE THE MOLECULAR MECHANISMS OPERATING DURING HEPATOCARCINOGENESIS BASED ON THE CONCEPT OF "FIELD CANCERIZATION". SEVERAL STUDIES PREVIOUSLY INVESTIGATED THE ASSOCIATION OF MOLECULAR ALTERATIONS IN NON-TUMOR LIVER TISSUE WITH CLINICAL FEATURES AND PROGNOSIS IN HCC PATIENTS ON A GENOME-WIDE SCALE. IN PARTICULAR, SPECIFIC ALTERATIONS OF DNA METHYLATION PROFILES HAVE BEEN CONFIRMED IN NON-TUMOR LIVER TISSUE. THIS REVIEW FOCUSES ON THE POSSIBLE CLINICAL VALUE OF ARRAY-BASED COMPREHENSIVE ANALYSES OF MOLECULAR ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IN NON-TUMOR LIVER TISSUE TO CLARIFY THE RISK OF HEPATOCARCINOGENESIS. CARCINOGENETIC RISK ESTIMATION BASED ON SPECIFIC METHYLATION SIGNATURES MAY BE ADVANTAGEOUS FOR CLOSE FOLLOW-UP OF PATIENTS WHO ARE AT HIGH RISK OF HCC DEVELOPMENT. FURTHERMORE, EPIGENETIC THERAPIES FOR PATIENTS WITH CHRONIC LIVER DISEASES MAY BE HELPFUL TO REDUCE THE RISK OF HCC DEVELOPMENT BECAUSE EPIGENETIC ALTERATIONS ARE POTENTIALLY REVERSIBLE, AND THUS PROVIDE PROMISING MOLECULAR TARGETS FOR THERAPEUTIC INTERVENTION. 2014 20 2122 44 EPIGENETIC IMPACT OF INFECTION ON CARCINOGENESIS: MECHANISMS AND APPLICATIONS. VIRAL AND BACTERIAL INFECTIONS ARE INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS, SUCH AS LIVER, NASOPHARYNGEAL, CERVICAL, HEAD AND NECK, AND GASTRIC CANCERS. ABERRANT DNA METHYLATION IS FREQUENTLY PRESENT IN THESE CANCERS, AND SOME OF THE ABERRANTLY METHYLATED GENES ARE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. NOTABLY, ABERRANT DNA METHYLATION CAN BE PRESENT EVEN IN NON-CANCEROUS OR PRECANCEROUS TISSUES, AND ITS LEVELS CORRELATE WITH THE RISK OF CANCER DEVELOPMENT, PRODUCING A SO-CALLED 'EPIGENETIC FIELD FOR CANCERIZATION'. MECHANISTICALLY, MOST VIRAL OR BACTERIAL INFECTIONS INDUCE DNA METHYLATION INDIRECTLY VIA CHRONIC INFLAMMATION, BUT RECENT STUDIES HAVE INDICATED THAT SOME VIRUSES HAVE DIRECT EFFECTS ON THE EPIGENETIC MACHINERY OF HOST CELLS. FROM A TRANSLATIONAL VIEWPOINT, A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THAT ASSESSMENT OF THE EXTENT OF ALTERATIONS IN DNA METHYLATION IN NON-CANCEROUS TISSUES CAN BE USED TO PREDICT CANCER RISK. FURTHERMORE, SUPPRESSION OF ABERRANT DNA METHYLATION WAS SHOWN TO BE A USEFUL STRATEGY FOR CANCER PREVENTION IN AN ANIMAL MODEL. HERE, WE REVIEW THE INVOLVEMENT OF ABERRANT DNA METHYLATION IN VARIOUS TYPES OF INFECTION-ASSOCIATED CANCERS, ALONG WITH INDIVIDUAL INDUCTION MECHANISMS, AND WE DISCUSS THE APPLICATION OF THESE FINDINGS FOR CANCER PREVENTION, DIAGNOSIS, AND THERAPY. 2016