1 3567 103 IMPACT OF HEPATITIS VIRUS AND AGING ON DNA METHYLATION IN HUMAN HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) USUALLY DEVELOPS ON THE BASIS OF CHRONIC HEPATITIS AND LIVER CIRRHOSIS, WHERE INACTIVATION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) TAKES PLACE VIA METHYLATION OF THE PROMOTER. INTERESTINGLY, THESE METHYLATION EVENTS ARE MORE PREVALENT IN A BACKGROUND LIVER AT HIGH RISK OF HCC THAN ONE AT LOW RISK. ABNORMAL METHYLATION IS ALSO OBSERVED IN PRECANCEROUS NODULES SUCH AS DYSPLASTIC NODULES AND ADENOMAS, SUGGESTING THAT EPIGENETIC ALTERATION IS AN EARLY EVENT FOR HCC CARCINOGENESIS. IT IS POSSIBLE THAT INFECTION WITH THE HEPATITIS VIRUS INDUCES ALTERATION OF METHYLATION AT PROMOTERS OF TSGS. SOME STUDIES SUGGESTED THAT VIRAL PROTEINS INTERFERE WITH DNA METHYLTRANSFERASE IN CHRONIC HEPATITIS B. INDUCTION OF EPIGENETIC ALTERATION IN CHRONIC HEPATITIS C MIGHT, HOWEVER, MIGHT BE A CONSEQUENCE OF OXIDATIVE STRESS. IN ADDITION, WE PROPOSED AGE SHOULD BE TAKEN INTO CONSIDERATION FOR HCC DEVELOPMENT VIA EPIGENETIC PATHWAYS. FURTHER INVESTIGATIONS ARE REQUIRED TO UNDERSTAND THE MECHANISM OF INDUCING EPIGENETIC INSTABILITY DURING HEPATOCARCINOGENESIS. 2010 2 332 46 ALTERATION OF EPIGENETIC PROFILE IN HUMAN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL IMPLICATIONS. HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON CANCER WORLDWIDE AND DEVELOPS AGAINST A BACKGROUND OF CHRONIC LIVER DAMAGE. A VARIETY OF HCC-RELATED GENES ARE KNOWN TO BE ALTERED BY GENETIC AND EPIGENETIC MECHANISMS. THEREFORE, INFORMATION REGARDING ALTERATION OF THE GENETIC AND EPIGENETIC PROFILES IN HCC IS ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF THIS TYPE OF TUMOR. METHYLATION AT CPG SITES IN GENE PROMOTERS IS KNOWN TO AFFECT THE TRANSCRIPTION OF THE CORRESPONDING GENES. ABNORMAL REGIONAL HYPERMETHYLATION IS OBSERVED IN THE 5' REGION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) IN HCC, AND THIS HYPERMETHYLATION MAY PROMOTE CARCINOGENESIS THROUGH THE TRANSCRIPTIONAL INACTIVATION OF DOWNSTREAM TSGS. THE DNA DAMAGE INDUCED BY OXIDATION IS A TRIGGER OF ABNORMAL DNA METHYLATION AND INACTIVATION OF TSGS THROUGH RECRUITMENT OF THE POLYCOMB REPRESSIVE COMPLEX TO THE PROMOTER SEQUENCE. THUS, OXIDATIVE STRESS MAY BE RESPONSIBLE FOR THE EMERGENCE OF HCC FROM CHRONIC HEPATITIS AND LIVER CIRRHOSIS THROUGH THE EPIGENETIC ALTERATION OF TSGS. THERE HAVE BEEN SEVERAL ATTEMPTS TO APPLY EPIGENETIC INFORMATION TO THE DIAGNOSIS AND TREATMENT OF HCC. THE PREDICTIVE VALUE OF SELECTED METHYLATION EVENTS ON SURVIVAL IN HCC PATIENTS HAS BEEN REPORTED, AND THE METHYLATION PROFILE OF BACKGROUND LIVER COULD BE ASSOCIATED WITH RECURRENCE-FREE SURVIVAL OF HCC PATIENTS WHO HAVE UNDERGONE HEPATECTOMY. ANOTHER STUDY DETECTED METHYLATED DNA FROM HCC CELLS IN SERUM, AND THE CIRCULATING TUMOR DNA WAS REGARDED AS A POTENTIAL TUMOR MARKER. IN ADDITION, SEVERAL TRIALS OF HCC THERAPY HAVE TARGETED THE EPIGENETIC MACHINERY AND WERE BASED UPON COMPREHENSIVE ANALYSES OF DNA METHYLATION OF THIS TYPE OF TUMOR. HERE, WE PRESENT AN OVERVIEW OF RESEARCH REGARDING DNA METHYLATION STATUS IN HUMAN HCC AND DESCRIBE THE CLINICAL APPLICATION OF EPIGENETIC INFORMATION TO HCC. 2014 3 1543 36 DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. AS FOR MANY OTHER TUMORS, DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES, LEADING TO ACTIVATION OF ONCOGENES AND INACTIVATION OR LOSS OF TUMOR SUPPRESSOR GENES (TSG). IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC INACTIVATION OF (TUMOR SUPPRESSOR) GENES BY PROMOTER HYPERMETHYLATION HAS BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMORIGENESIS. IN HCC, ABERRANT METHYLATION OF PROMOTER SEQUENCES OCCURS NOT ONLY IN ADVANCED TUMORS, IT HAS BEEN ALSO OBSERVED IN PREMALIGNANT CONDITIONS JUST AS CHRONIC VIRAL HEPATITIS B OR C AND CIRRHOTIC LIVER. THIS REVIEW DISCUSSES THE EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FOCUSING DNA METHYLATION. 2008 4 5360 43 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 5 4920 33 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 6 2172 36 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 7 4134 47 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 8 2166 48 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 9 5622 32 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 10 2970 46 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 11 6640 41 UNRAVELING THE MOLECULAR MECHANISMS INVOLVED IN HCV-INDUCED CARCINOGENESIS. CANCER INDUCED BY A VIRAL INFECTION IS AMONG THE LEADING CAUSES OF CANCER. HEPATITIS C VIRUS (HCV) IS A HEPATOTROPIC ONCOGENIC POSITIVE-SENSE RNA VIRUS THAT LEADS TO CHRONIC INFECTION, EXPOSING THE LIVER TO A CONTINUOUS PROCESS OF DAMAGE AND REGENERATION AND PROMOTING HEPATOCARCINOGENESIS. THE VIRUS PROMOTES THE DEVELOPMENT OF CARCINOGENESIS THROUGH INDIRECT AND DIRECT MOLECULAR MECHANISMS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, STEATOSIS, GENETIC ALTERATIONS, EPITHELIAL-MESENCHYMAL TRANSITION, PROLIFERATION, AND APOPTOSIS, AMONG OTHERS. RECENTLY, DIRECT-ACTING ANTIVIRALS (DAAS) SHOWED SUSTAINED VIROLOGIC RESPONSE IN 95% OF CASES. NEVERTHELESS, PATIENTS TREATED WITH DAAS HAVE REPORTED AN UNEXPECTED INCREASE IN THE EARLY INCIDENCE OF HEPATOCELLULAR CARCINOMA (HCC). STUDIES SUGGEST THAT HCV INDUCES EPIGENETIC REGULATION THROUGH NON-CODING RNAS, DNA METHYLATION, AND CHROMATIN REMODELING, WHICH MODIFY GENE EXPRESSIONS AND INDUCE GENOMIC INSTABILITY RELATED TO HCC DEVELOPMENT THAT PERSISTS WITH THE INFECTION'S CLEARANCE. THE NEED FOR A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS ASSOCIATED WITH THE DEVELOPMENT OF CARCINOGENESIS IS EVIDENT. THE AIM OF THIS REVIEW WAS TO UNRAVEL THE MOLECULAR PATHWAYS INVOLVED IN THE DEVELOPMENT OF CARCINOGENESIS BEFORE, DURING, AND AFTER THE VIRAL INFECTION'S RESOLUTION, AND HOW THESE PATHWAYS WERE REGULATED BY THE VIRUS, TO FIND CONTROL POINTS THAT CAN BE USED AS POTENTIAL THERAPEUTIC TARGETS. 2022 12 4461 35 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 13 4477 33 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 14 4476 25 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 15 4127 39 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 16 3932 25 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 17 4133 30 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 18 4677 30 NEW LNCRNAS IN CHRONIC HEPATITIS C PROGRESSION: FROM FIBROSIS TO HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH IN THE WORLD, AND ABOUT 80% OF THE CASES ARE ASSOCIATED WITH HEPATITIS B OR C. GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED OVER DECADES OF CHRONIC INJURY AND MAY AFFECT THE FUNCTIONING OF TUMOR SUPPRESSOR GENES AND PROTOONCOGENES. STUDIES HAVE EVIDENCED THE ROLE OF LONG NON-CODING RNAS (LNCRNA) WITH ONCOGENIC OR TUMOR SUPPRESSOR ACTIVITIES, SUGGESTING A GREAT POTENTIAL IN THE TREATMENT, DIAGNOSIS OR INDICATOR OF PROGNOSIS IN CANCER. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO EVALUATE THE GLOBAL EXPRESSION PROFILE LNCRNA IN HEPATIC TISSUE SAMPLES WITH DIFFERENT STAGES OF FIBROSIS ASSOCIATED WITH CHRONIC HEPATITIS C, HCC AND NORMAL LIVER, IN ORDER TO IDENTIFY NEW LNCRNAS THAT COULD CONTRIBUTE TO STUDY THE PROGRESSION OF HEPATIC FIBROSIS TO HCC ASSOCIATED WITH CHRONIC HEPATITIS C. RNA-SEQ WAS PERFORMED ON ILLUMINA NEXTSEQ PLATFORM TO IDENTIFY LNCRNAS EXPRESSED DIFFERENTLY IN 15 PATIENTS WITH CHRONIC HEPATITIS C, THREE PATIENTS WITH HCC AND THREE NORMAL LIVER SPECIMENS. WHEN THE PATHOLOGICAL TISSUES (FIBROSIS AND CARCINOMA) WERE COMPARED TO NORMAL HEPATIC TISSUE, WERE IDENTIFIED 2, 6 E 34 DIFFERENTIALLY EXPRESSED LNCRNAS IN MODERATE FIBROSIS, ADVANCED FIBROSIS AND HCC, RESPECTIVELY. THE CARCINOMA GROUP HAD THE HIGHEST PROPORTION OF DIFFERENTIALLY EXPRESSED LNCRNA (34) AND OF THESE, 29 WERE EXCLUSIVE IN THIS TYPE OF TISSUE. A HEAT MAP OF THE DEREGULATED LNCRNA REVEALED DIFFERENT EXPRESSION PATTERNS ALONG THE PROGRESSION OF FIBROSIS TO HCC. THE RESULTS SHOWED THE DEREGULATION OF SOME LNCRNA ALREADY CLASSIFIED AS TUMOR SUPPRESSORS IN HCC AND OTHER CANCERS, AS WELL AS SOME UNPUBLISHED LNCRNA WHOSE FUNCTION IS UNKNOWN. SOME OF THESE LNCRNAS ARE DYSREGULATED SINCE THE EARLY STAGES OF LIVER INJURY IN PATIENTS WITH HEPATITIS C, OTHERS OVEREXPRESSED ONLY IN TUMOR TISSUE, INDICATING THEMSELVES AS CANDIDATES OF MARKERS OF FIBROSIS PROGRESSION OR TUMOR, WITH POTENTIAL CLINICAL APPLICATIONS IN PROGNOSIS AS WELL AS A THERAPEUTIC TARGET. ALTHOUGH THERE ARE ALREADY STUDIES ON LNCRNA IN HEPATOCELLULAR CARCINOMA, THIS IS THE FIRST STUDY CONDUCTED IN SAMPLES EXCLUSIVELY OF HCV-RELATED LIVER AND HCV HCC. 2020 19 5770 36 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 6850 33 [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