1 4929 151 PAST, PRESENT, AND FUTURE OF CHEMICALLY INDUCED HEPATOCARCINOGENESIS RODENT MODELS: PERSPECTIVES CONCERNING CLASSIC AND NEW CANCER HALLMARKS. HEPATOCELLULAR CARCINOMA (HCC), THE MAIN PRIMARY LIVER CANCER, ACCOUNTS FOR 5 % OF ALL INCIDENT CASES AND 8.4 % OF ALL CANCER-RELATED DEATHS WORLDWIDE. HCC DISPLAYS A SPECTRUM OF ENVIRONMENTAL RISK FACTORS (VIRAL CHRONIC INFECTIONS, AFLATOXIN EXPOSURE, ALCOHOLIC- AND NONALCOHOLIC FATTY LIVER DISEASES) THAT RESULT IN MOLECULAR COMPLEXITY AND HETEROGENEITY, CONTRIBUTING TO A RISING EPIDEMIOLOGICAL BURDEN, POOR PROGNOSIS, AND NON-SATISFACTORY TREATMENT OPTIONS. THE EMERGENCE OF HCC (I.E., HEPATOCARCINOGENESIS) IS A MULTISTEP AND COMPLEX PROCESS THAT ADDRESSES MANY (EPI)GENETIC ALTERATIONS AND PHENOTYPIC TRAITS, THE SO-CALLED CANCER HALLMARKS. "POLYMORPHIC MICROBIOMES", "EPIGENETIC REPROGRAMMING", "SENESCENT CELLS" AND "UNLOCKING PHENOTYPIC PLASTICITY" ARE TRENDING HALLMARKS/ENABLING FEATURES IN CANCER BIOLOGY. AS THE MAIN MOLECULAR DRIVERS OF HCC ARE STILL UNDRUGGABLE, CHEMICALLY INDUCED IN VIVO MODELS OF HEPATOCARCINOGENESIS ARE USEFUL TOOLS IN PRECLINICAL RESEARCH. THUS, THIS NARRATIVE REVIEW AIMED AT RECAPITULATING THE BASIC FEATURES OF CHEMICALLY INDUCED RODENT MODELS OF HEPATOCARCINOGENESIS, ELICITING THEIR PERMANENT TRANSLATIONAL VALUE REGARDING THE "CLASSIC" AND THE "NEW" CANCER HALLMARKS/ENABLING FEATURES. WE GATHERED STATE-OF-ART PRECLINICAL EVIDENCE ON NON-CIRRHOTIC, INFLAMMATION-, ALCOHOLIC LIVER DISEASE- AND NONALCOHOLIC FATTY LIVER-ASSOCIATED HCC MODELS, DEMONSTRATING THAT THESE BIOASSAYS INDEED EXPRESS THE RECENTLY ADDED HALLMARKS, AS WELL AS REFLECT THE INTERPLAY BETWEEN CLASSICAL AND NEW CANCER TRAITS. OUR REVIEW DEMONSTRATED THAT THESE PROTOCOLS REMAIN VALUABLE FOR TRANSLATIONAL PRECLINICAL APPLICATION, AS THEY RECAPITULATE TRENDING FEATURES OF CANCER SCIENCE. FURTHER "OMICS-BASED" APPROACHES ARE WARRANTED WHILE MULTIMODEL INVESTIGATIONS ARE ENCOURAGED IN ORDER TO AVOID "MODEL-BIASED" RESPONSES. 2023 2 251 33 ADVANCED THERAPEUTIC MODALITIES IN HEPATOCELLULAR CARCINOMA: NOVEL INSIGHTS. HEPATOCELLULAR CARCINOMA (HCC), THE MOST COMMON TYPE OF LIVER CANCER, IS USUALLY A LATENT AND ASYMPTOMATIC MALIGNANCY CAUSED BY DIFFERENT AETIOLOGIES, WHICH IS A RESULT OF VARIOUS ABERRANT MOLECULAR HETEROGENEITY AND OFTEN DIAGNOSED AT ADVANCED STAGES. THE INCIDENCE AND PREVALENCE HAVE SIGNIFICANTLY INCREASED BECAUSE OF SEDENTARY LIFESTYLE, DIABETES, CHRONIC INFECTION WITH HEPATOTROPIC VIRUSES AND EXPOSURE TO AFLATOXINS. DUE TO ADVANCED INTRA- OR EXTRAHEPATIC METASTASIS, RECURRENCE IS VERY COMMON EVEN AFTER RADICAL RESECTION. IN THIS PAPER, WE HIGHLIGHTED NOVEL THERAPEUTIC MODALITIES, SUCH AS MOLECULAR-TARGETED THERAPIES, TARGETED RADIONUCLIDE THERAPIES AND EPIGENETIC MODIFICATION-BASED THERAPIES. THESE TOPICS ARE TRENDING HEADLINES AND THEIR COMBINATION WITH CELL-BASED IMMUNOTHERAPIES, AND GENE THERAPY HAS PROVIDED PROMISING PROSPECTS FOR THE FUTURE OF HCC TREATMENT. MOREOVER, A COMPREHENSIVE OVERVIEW OF CURRENT AND ADVANCED THERAPEUTIC APPROACHES IS DISCUSSED AND THE ADVANTAGES AND LIMITATIONS OF EACH STRATEGY ARE DESCRIBED. FINALLY, VERY RECENT AND APPROVED NOVEL COMBINED THERAPIES AND THEIR PROMISING RESULTS IN HCC TREATMENT HAVE BEEN INTRODUCED. 2021 3 3270 28 HEPATOCELLULAR CARCINOMA IN THE CONTEXT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH): RECENT ADVANCES IN THE PATHOGENIC MECHANISMS. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER. HCC IS PARTICULARLY AGGRESSIVE AND IS ONE OF THE LEADING CAUSES OF CANCER MORTALITY. IN RECENT DECADES, THE EPIDEMIOLOGICAL LANDSCAPE OF HCC HAS UNDERGONE SIGNIFICANT CHANGES. WHILE CHRONIC VIRAL HEPATITIS AND EXCESSIVE ALCOHOL CONSUMPTION HAVE LONG BEEN IDENTIFIED AS THE MAIN RISK FACTORS FOR HCC, NON-ALCOHOLIC STEATOHEPATITIS (NASH), PARALLELING THE WORLDWIDE EPIDEMIC OF OBESITY AND TYPE 2 DIABETES, HAS BECOME A GROWING CAUSE OF HCC IN THE US AND EUROPE. HERE, WE REVIEW THE RECENT ADVANCES IN EPIDEMIOLOGICAL, GENETIC, EPIGENETIC AND PATHOGENIC MECHANISMS AS WELL AS EXPERIMENTAL MOUSE MODELS THAT HAVE IMPROVED THE UNDERSTANDING OF NASH PROGRESSION TOWARD HCC. WE ALSO DISCUSS THE CLINICAL MANAGEMENT OF PATIENTS WITH NASH-RELATED HCC AND POSSIBLE THERAPEUTIC APPROACHES. 2020 4 1042 26 CLINICAL AND MOLECULAR BASIS OF HEPATOCELLULAR CARCINOMA AFTER HEPATITIS C VIRUS ERADICATION. HEPATOCELLULAR CARCINOMA (HCC) ARISES IN THE BACKGROUND OF CHRONIC LIVER DISEASES, INCLUDING HEPATITIS AND LIVER CIRRHOSIS CAUSED BY HEPATITIS C VIRUS (HCV) INFECTION. IT IS WELL KNOWN THAT HCV ERADICATION USING ANTIVIRAL DRUGS CAN EFFICIENTLY INHIBIT HEPATOCARCINOGENESIS. RECENT ADVANCES IN AND DEVELOPMENT OF DIRECT-ACTING ANTIVIRAL (DAA) DRUGS HAS REVOLUTIONIZED THE TREATMENT OF HCV INFECTION, AND THE VAST MAJORITY OF HCV PATIENTS CAN ACHIEVE HCV ERADICATION USING DAAS. HOWEVER, MOUNTING EVIDENCE CLEARLY INDICATES THAT HCC INEVITABLY OCCURS IN A SUBSET OF PATIENTS AFTER SUCCESSFUL VIRAL ERADICATION USING DAA THERAPY. CANCER IS A GENETIC DISEASE, AND THE ACCUMULATION OF GENETIC AND EPIGENETIC ABERRATIONS MAY CAUSE HEPATOCARCINOGENESIS IN CHRONICALLY DAMAGED LIVER, EVEN AFTER VIRUS ELIMINATION. IN THIS REVIEW, WE HIGHLIGHT HCC DEVELOPMENT AFTER HCV ERADICATION AND DISCUSS THE CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS OF TUMORIGENESIS AFTER VIRUS ELIMINATION, FOCUSING ON THE GENETIC AND EPIGENETIC BACKGROUND OF CHRONICALLY DAMAGED LIVER TISSUES. 2022 5 3621 43 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 6 4454 28 MOLECULAR MECHANISMS DRIVING PROGRESSION OF LIVER CIRRHOSIS TOWARDS HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B AND C INFECTIONS: A REVIEW. ALMOST ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC), A MAJOR TYPE OF PRIMARY LIVER CANCER, ALSO HAVE LIVER CIRRHOSIS, THE SEVERITY OF WHICH HAMPERS EFFECTIVE TREATMENT FOR HCC DESPITE RECENT PROGRESS IN THE EFFICACY OF ANTICANCER DRUGS FOR ADVANCED STAGES OF HCC. HERE, WE REVIEW RECENT KNOWLEDGE CONCERNING THE MOLECULAR MECHANISMS OF LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC FROM GENETIC AND EPIGENOMIC POINTS OF VIEW. BECAUSE ~70% OF PATIENTS WITH HCC HAVE HEPATITIS B VIRUS (HBV) AND/OR HEPATITIS C VIRUS (HCV) INFECTION, WE FOCUSED ON HBV- AND HCV-ASSOCIATED HCC. THE LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC FACTORS, SUCH AS MICRORNAS, PLAY A ROLE IN LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC, AND THAT HBV- AND HCV-ENCODED PROTEINS APPEAR TO BE INVOLVED IN HEPATOCARCINOGENESIS. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE MECHANISMS, INCLUDING IMMUNE CHECKPOINTS AND MOLECULAR TARGETS OF KINASE INHIBITORS, ASSOCIATED WITH LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC. 2019 7 1942 40 EPIDEMIOLOGY OF LIVER CANCER IN AFRICA: CURRENT AND FUTURE TRENDS. HEPATOCELLULAR CARCINOMA (HCC) IS A DISEASE OF GLOBAL PUBLIC HEALTH SIGNIFICANCE WITH MORTALITY ON THE RISE, DESPITE THE PREVENTABLE NATURE OF ITS RISK FACTORS ESPECIALLY IN AFRICA. IT IS NOW THE SIXTH MOST COMMON CANCER WORLDWIDE, FIFTH IN MALES, AND NINTH IN FEMALES. HCC INCIDENCE AND MORTALITY ARE PREDICTED TO INCREASE IN AFRICAN COUNTRIES CONSTRAINED BY LIMITED RESOURCES TO COMBAT ENDEMIC LEVELS OF VIRAL INFECTION AND SYNERGISTIC ENVIRONMENTAL RISK FACTORS. THE CHANGING NATURE OF HCC ETIOLOGY IS PARTICULARLY ILLUSTRATED HERE WITH THE TRADITIONAL RISK FACTORS LIKE VIRAL HEPATITIS COEXISTING ALONGSIDE HIGH HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVALENCE AND RAPIDLY INCREASING URBANIZATION THAT HAVE PROMOTED A SHARP INCREASE IN ADDITIONAL RISK FACTORS LIKE COINFECTION, TYPE 2 DIABETES MELLITUS, AND OBESITY. ALTHOUGH THERE ARE SOME DIFFERENCES IN ETIOLOGY BETWEEN NORTH AFRICA AND SUB-SAHARAN AFRICA, RISK FACTORS LIKE CHRONIC VIRAL HEPATITIS B AND C, AFLATOXIN EXPOSURE, AND IRON OVERLOAD PREDOMINATE. AGGRESSIVE HEPATITIS B GENOTYPES, COMBINED WITH HEPATITIS B VIRUS/HEPATITIS C VIRUS/HIV COINFECTIONS AND AFLATOXIN EXPOSURE, PROMOTE A MORE AGGRESSIVE MOLECULAR PHENOTYPE. IN PARALLEL TO A BETTER UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF HCC, POLICY AND PLANNING INITIATIVES TO ADDRESS THE BURDEN OF HCC MUST BE ANCHORED WITHIN THE REALITY OF THE LIMITED RESOURCES AVAILABLE. ESTABLISHMENT AND COORDINATION OF CANCER REGISTRIES ACROSS AFRICA IS NEEDED TO IMPROVE THE QUALITY OF DATA NECESSARY TO GALVANIZE ACTION. PREVENTIVE MEASURES INCLUDING HEPATITIS B VACCINATION PROGRAMS, MEASURES TO PREVENT MATERNAL-TO-CHILD AND CHILD-TO-CHILD TRANSMISSION, DELIVERY OF UNIVERSALLY ACCESSIBLE ANTIRETROVIRAL AND ANTIVIRAL TREATMENTS, AND REDUCTION OF DIETARY AFLATOXIN EXPOSURE CAN CONTRIBUTE MARKEDLY TO REDUCE HCC INCIDENCE. FINALLY, THE DEVELOPMENT OF BIOMARKERS AND NEW THERAPEUTIC INTERVENTIONS WILL NEED A BETTER UNDERSTANDING OF THE UNIQUE GENETIC AND EPIGENETIC CHARACTERISTICS OF HCC ON THE CONTINENT. WE PRESENT A NARRATIVE REVIEW OF HCC IN AFRICA, DISCUSSING PRESENT AND FUTURE TRENDS. 2020 8 3269 34 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER DISEASE-ONE OF A KIND OR TWO DIFFERENT ENEMIES? HEPATOCELLULAR CANCER (HCC) IS A CANCER WITH AN OVERALL POOR PROGNOSIS AND AN ALARMING GLOBALLY RISING INCIDENCE. WHILE VIRAL ETIOLOGY OF CHRONIC LIVER DISEASE AND HCC IS DOWN-TRENDING, ALCOHOL AND EXCESS CALORIE INTAKE HAVE EMERGED AS MAJOR CULPRITS. ALCOHOL RELATED LIVER DISEASE (ALD) AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) SHARE SIMILAR PATHOGENETIC MECHANISM OF HEPATIC INJURY AND IN PROMOTING DEVELOPMENT OF HCC; YET SOME GENETIC AND EPIGENETIC FEATURES ARE DISTINCT AND MAY PROMISE CLINICAL UTILITY. POPULATION BASED INTERVENTION ARE URGENTLY NEEDED TO REDUCE ALCOHOL USE AND IMPROVE METABOLIC FACTORS SUCH AS OBESITY AND DIABETES. THE GOAL IS TO IDENTIFY AT-RISK PATIENTS, TO LINK THESE PATIENTS TO CARE AND TO PROVIDE EFFECTIVE MANAGEMENT OF CHRONIC LIVER DISEASE AND HCC. THIS REVIEW FOCUSES ON THE EPIDEMIOLOGY, PATHOPHYSIOLOGY INCLUDING GENETIC AND EPIGENETIC ALTERCATION AS WELL AS CLINICAL ASPECTS OF ALD AND NAFLD ASSOCIATED HCC. 2019 9 5807 35 STRATEGIES, MODELS AND BIOMARKERS IN EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE RESEARCH. NON-ALCOHOLIC FATTY LIVER DISEASE ENCOMPASSES A SPECTRUM OF LIVER DISEASES, INCLUDING SIMPLE STEATOSIS, STEATOHEPATITIS, LIVER FIBROSIS AND CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NON-ALCOHOLIC FATTY LIVER DISEASE IS CURRENTLY THE MOST DOMINANT CHRONIC LIVER DISEASE IN WESTERN COUNTRIES DUE TO THE FACT THAT HEPATIC STEATOSIS IS ASSOCIATED WITH INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME AND DRUG-INDUCED INJURY. A VARIETY OF CHEMICALS, MAINLY DRUGS, AND DIETS IS KNOWN TO CAUSE HEPATIC STEATOSIS IN HUMANS AND RODENTS. EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE MODELS RELY ON THE APPLICATION OF A DIET OR THE ADMINISTRATION OF DRUGS TO LABORATORY ANIMALS OR THE EXPOSURE OF HEPATIC CELL LINES TO THESE DRUGS. MORE RECENTLY, GENETICALLY MODIFIED RODENTS OR ZEBRAFISH HAVE BEEN INTRODUCED AS NON-ALCOHOLIC FATTY LIVER DISEASE MODELS. CONSIDERABLE INTEREST NOW LIES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL NON-INVASIVE BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, WITH SPECIFIC FOCUS ON HEPATIC STEATOSIS. EXPERIMENTAL DIAGNOSTIC BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, SUCH AS (EPI)GENETIC PARAMETERS AND '-OMICS'-BASED READ-OUTS ARE STILL IN THEIR INFANCY, BUT SHOW GREAT PROMISE. IN THIS PAPER, THE ARRAY OF TOOLS AND MODELS FOR THE STUDY OF LIVER STEATOSIS IS DISCUSSED. FURTHERMORE, THE CURRENT STATE-OF-ART REGARDING EXPERIMENTAL BIOMARKERS SUCH AS EPIGENETIC, GENETIC, TRANSCRIPTOMIC, PROTEOMIC AND METABONOMIC BIOMARKERS WILL BE REVIEWED. 2015 10 6486 34 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 11 3928 29 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 12 3259 24 HEPATITIS C VIRUS AND HEPATOCELLULAR CARCINOMA: WHEN THE HOST LOSES ITS GRIP. CHRONIC INFECTION WITH HEPATITIS C VIRUS (HCV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). NOVEL TREATMENTS WITH DIRECT-ACTING ANTIVIRALS ACHIEVE HIGH RATES OF SUSTAINED VIROLOGIC RESPONSE; HOWEVER, THE HCC RISK REMAINS ELEVATED IN CURED PATIENTS, ESPECIALLY THOSE WITH ADVANCED LIVER DISEASE. LONG-TERM HCV INFECTION CAUSES A PERSISTENT AND ACCUMULATING DAMAGE OF THE LIVER DUE TO A COMBINATION OF DIRECT AND INDIRECT PRO-ONCOGENIC MECHANISMS. THIS REVIEW DESCRIBES THE PROCESSES INVOLVED IN VIRUS-INDUCED DISEASE PROGRESSION BY VIRAL PROTEINS, DERAILED SIGNALING, IMMUNITY, AND PERSISTENT EPIGENETIC DEREGULATION, WHICH MAY BE INSTRUMENTAL TO DEVELOP URGENTLY NEEDED PROGNOSTIC BIOMARKERS AND AS TARGETS FOR NOVEL CHEMOPREVENTIVE THERAPIES. 2020 13 6848 36 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 14 6797 35 [EPIDEMIOLOGY, NATURAL HISTORY AND PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE MAIN TYPE OF PRIMARY LIVER CANCERS AND THE THIRD MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. IN FRANCE, RISING NUMBER BETWEEN 5000 AND 6000 CASES ARE DIAGNOSED EACH YEAR. THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IS CHRONIC HEPATITIS: VIRAL HEPATITIS B, VIRAL HEPATITIS C, CONSUMPTION OF ALCOHOL, HEMOCHROMATOSIS. HEPATOCELLULAR CARCINOMA IS CLOSELY ASSOCIATED TO LIVER CIRRHOSIS, WHICH IS A TRUE PRECANCEROUS STATE. BECAUSE HEPATOCARCINOGENESIS IS A LONG AND HETEROGENEOUS PROCESS, THERE IS STILL MUCH TO UNDERSTAND. MANY GENETIC AND EPIGENETIC ALTERATIONS ARE DESCRIBED LEADING TO CHANGES IN CELLULAR SIGNALLING CASCADES INVOLVED IN REGULATION OF GROWTH, DIFFERENTIATION, APOPTOSIS, MOTILITY. HEPATITIS VIRUSES PLAY A DIRECT ONCOGENIC ROLE THROUGH THE INTERACTION BETWEEN VIRAL AND CELLULAR PROTEINS, WHICH CONTROL CELL HOMEOSTASIS, OR BY THE INTEGRATION OF HEPATITIS B VIRUS GENOME INTO THE HOST GENOME. FURTHERMORE, HEPATITIS VIRUSES PLAY AN INDIRECT ONCOGENIC ROLE BY CAUSING CHRONIC INFLAMMATION AND HEPATOCYTE REGENERATION RELATED TO VIRAL HEPATOPATHY. IN EXPECTATION OF A BETTER UNDERSTANDING OF HEPATOCARCINOGENESIS AND NEW TREATMENTS, PREVENTION FROM RISK FACTORS AND ULTRASONOGRAPHIC SCREENING OF PATIENTS WITH CIRRHOSIS SHOULD INCREASE PROGNOSIS. 2011 15 4478 32 MOLECULAR PATHOGENESIS OF NONALCOHOLIC STEATOHEPATITIS- (NASH-) RELATED HEPATOCELLULAR CARCINOMA. THE PROPORTION OF OBESE OR DIABETIC POPULATION HAS BEEN ANTICIPATED TO INCREASE IN THE UPCOMING DECADES, WHICH RISES THE PREVALENCE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND ITS PROGRESSION TO NONALCOHOLIC STEATOHEPATITIS (NASH). RECENT EVIDENCE INDICATES THAT NASH IS THE MAIN CAUSE OF CHRONIC LIVER DISEASES AND IT IS AN IMPORTANT RISK FACTOR FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH THE LITERATURE ADDRESSING NASH-HCC IS GROWING RAPIDLY, LIMITED DATA IS AVAILABLE ABOUT THE ETIOLOGY OF NASH-RELATED HCC. EXPERIMENTAL STUDIES ON THE MOLECULAR MECHANISM OF HCC DEVELOPMENT IN NASH REVEAL THAT THE CARCINOGENESIS IS RELEVANT TO COMPLEX CHANGES IN SIGNALING PATHWAYS THAT MEDIATE CELL PROLIFERATION AND ENERGY METABOLISM. GENETIC OR EPIGENETIC MODIFICATIONS AND ALTERATIONS IN METABOLIC, IMMUNOLOGIC, AND ENDOCRINE PATHWAYS HAVE BEEN SHOWN TO BE CLOSELY RELATED TO INFLAMMATION, LIVER INJURY, AND FIBROSIS IN NASH ALONG WITH ITS SUBSEQUENT PROGRESSION TO HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW ON THE CURRENT KNOWLEDGE OF NASH-RELATED HCC DEVELOPMENT AND EMPHASIZE MOLECULAR SIGNALING PATHWAYS REGARDING THEIR MECHANISM OF ACTION IN NASH-DERIVED HCC. 2018 16 4108 21 MECHANISMS AND DISEASE CONSEQUENCES OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CHRONIC LIVER DISEASE WORLDWIDE. ITS MORE ADVANCED SUBTYPE, NONALCOHOLIC STEATOHEPATITIS (NASH), CONNOTES PROGRESSIVE LIVER INJURY THAT CAN LEAD TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HERE WE PROVIDE AN IN-DEPTH DISCUSSION OF THE UNDERLYING PATHOGENETIC MECHANISMS THAT LEAD TO PROGRESSIVE LIVER INJURY, INCLUDING THE METABOLIC ORIGINS OF NAFLD, THE EFFECT OF NAFLD ON HEPATIC GLUCOSE AND LIPID METABOLISM, BILE ACID TOXICITY, MACROPHAGE DYSFUNCTION, AND HEPATIC STELLATE CELL ACTIVATION, AND CONSIDER THE ROLE OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT PROMOTE FIBROSIS PROGRESSION AND RISK OF HEPATOCELLULAR CARCINOMA IN NASH. 2021 17 3394 32 HOST EPIGENETIC ALTERATIONS AND HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST FREQUENT PRIMARY MALIGNANCY OF THE LIVER AND A LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH MUCH PROGRESS HAS BEEN MADE IN HCC DRUG DEVELOPMENT IN RECENT YEARS, TREATMENT OPTIONS REMAIN LIMITED. THE MAJOR CAUSE OF HCC IS CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. DESPITE THE EXISTENCE OF A VACCINE, MORE THAN 250 MILLION INDIVIDUALS ARE CHRONICALLY INFECTED BY HBV. CURRENT ANTIVIRAL THERAPIES CAN REPRESS VIRAL REPLICATION BUT TO DATE THERE IS NO CURE FOR CHRONIC HEPATITIS B. OF NOTE, INHIBITION OF VIRAL REPLICATION REDUCES BUT DOES NOT ELIMINATE THE RISK OF HCC DEVELOPMENT. HBV CONTRIBUTES TO LIVER CARCINOGENESIS BY DIRECT AND INDIRECT EFFECTS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF HBV-INDUCED HOST EPIGENETIC ALTERATIONS AND THEIR ASSOCIATION WITH HCC, WITH AN EMPHASIS ON THE INTERACTIONS BETWEEN HBV PROTEINS AND THE HOST CELL EPIGENETIC MACHINERY LEADING TO MODULATION OF GENE EXPRESSION. 2021 18 6829 29 [HEPATITIS C VIRUS INFECTION AND HEPATOCARCINOGENESIS]. HEPATITIS C VIRUS INFECTION CAUSES APPROXIMATELY 4 MILLION NEW INFECTIONS WORLDWIDE, AND 399 000 DEATHS DUE TO ITS COMPLICATIONS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MICROENVIRONMENTAL CHANGES, CHRONIC INFLAMMATION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS CAUSED BY HCV INFECTION, VIA GENETIC AND EPIGENETIC CHANGES CAN RESULT IN PRIMARY LIVER CANCER DURING DECADES. THE DIRECT ONCOGENIC PROPERTY OF HCV IS WELLKNOWN. THE TRANSFORMING EFFECT OF FOUR HCV PROTEINS (CORE, NS3, NS4B, NS5A) HAS BEEN PROVEN. EFFECTIVE ANTIVIRAL THERAPY, SUSTAINED VIRAL RESPONSE DECREASES THE HCV-RELATED GENERAL AND LIVER-RELATED MORTALITY. INTERFERON-BASED THERAPY REDUCES THE RISK OF HCC DEVELOPMENT. SHORTER THERAPY WITH DIRECT ACTING ANTIVIRAL AGENTS (DAA) HAS HIGHER EFFICACY, FEWER SIDE-EFFECTS. PUBLICATIONS HAVE REPORTED THE UNEXPECTED EFFECTS OF DAA. THE AUTHORS REVIEW THE ARTICLES FOCUSING ON THE OCCURRENCE OF HCC IN CONNECTION WITH DAA THERAPIES. THERE IS A NEED FOR PROSPECTIVE, MULTICENTRIC STUDIES WITH LONGER FOLLOW-UP TO EXAMINE THE RISK OF HCC FORMATION. AFTER ANTIVIRAL THERAPY, HCC SURVEILLANCE IS OF HIGH IMPORTANCE WHICH MEANS ABDOMINAL ULTRASOUND EVERY 3-6-12 MONTHS IN SUSTAINED VIRAL RESPONSE PATIENTS AS WELL. ORV HETIL. 2019; 160(22): 846-853. 2019 19 3263 35 HEPATITIS VIRUS AND HEPATOCELLULAR CARCINOMA: RECENT ADVANCES. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL HEALTH CHALLENGE, CAUSING 600,000 DEATHS EACH YEAR. INFECTIOUS FACTORS, INCLUDING HEPATITIS B VIRUS (HBV), HEPATITIS C VIRUS (HCV) AND HEPATITIS D VIRUS (HDV), HAVE LONG BEEN CONSIDERED THE MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF HCC. THESE PATHOGENS INDUCE HEPATOCYTE TRANSFORMATION THROUGH A VARIETY OF MECHANISMS, INCLUDING INSERTIONAL MUTATIONS CAUSED BY VIRAL GENE INTEGRATION, EPIGENETIC CHANGES, AND THE INDUCTION OF LONG-TERM IMMUNE DYSFUNCTION. THE DISCOVERY OF THESE MECHANISMS, WHILE ADVANCING OUR UNDERSTANDING OF THE DISEASE, ALSO PROVIDES TARGETS FOR NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. IN ADDITION, THE DISCOVERY AND RESEARCH OF CHRONIC HEV INFECTION OVER THE PAST DECADE INDICATE THAT THIS COMMON HEPATITIS VIRUS ALSO SEEMS TO HAVE THE POTENTIAL TO INDUCE HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT STUDIES ON THE LINK BETWEEN HEPATITIS VIRUS AND HCC, AS WELL AS NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO HCC BASED ON THESE FINDINGS. FINALLY, WE ALSO DISCUSS THE POTENTIAL RELATIONSHIP BETWEEN HEV AND HCC. IN CONCLUSION, THESE ASSOCIATIONS WILL FURTHER OPTIMIZE THE DIAGNOSIS AND TREATMENT OF INFECTION-ASSOCIATED HCC AND CALL FOR BETTER MANAGEMENT POLICIES. 2023 20 6798 35 [EPIDEMIOLOGY, RISK FACTORS AND MOLECULAR PATHOGENESIS OF PRIMARY LIVER CANCER]. PRIMARY LIVER CANCER IS THE FIFTH MOST COMMON CANCER WORLDWIDE. HEPATOCELLULAR CARCINOMA ACCOUNTS FOR 85-90% OF PRIMARY LIVER CANCERS. DISTRIBUTION OF HEPATOCELLULAR CARCINOMA SHOWS VARIATIONS AMONG GEOGRAPHIC REGIONS AND ETHNIC GROUPS. MALES HAVE HIGHER LIVER CANCER RATES THAN FEMALES. HEPATOCELLULAR CARCINOMA OCCURS WITHIN AN ESTABLISHED BACKGROUND OF CHRONIC LIVER DISEASE AND CIRRHOSIS (70-90%). MAJOR CAUSES (80%) OF HEPATOCELLULAR CARCINOMA ARE HEPATITIS B, C VIRUS INFECTION, AND AFLATOXIN EXPOSITION. ITS DEVELOPMENT IS A MULTISTEP PROCESS. WE HAVE A GROWING UNDERSTANDING ON THE MOLECULAR PATHOGENESIS. GENETIC AND EPIGENETIC CHANGES ACTIVATE ONCOGENES, INHIBIT TUMORSUPPRESSOR GENES, WHICH RESULT IN AUTONOMOUS CELL PROLIFERATION. THE CHROMOSOMAL INSTABILITY CAUSED BY TELOMERE DYSFUNCTION, THE GROWTH-RETRAINED ENVIRONMENT AND THE ALTERATIONS OF THE MICRO- AND MACROENVIRONMENT HELP THE EXPANSION OF THE MALIGNANT CELLS. UNDERSTANDING THE MOLECULAR MECHANISMS COULD IMPROVE THE SCREENING OF PATIENTS WITH CHRONIC LIVER DISEASE, OR CIRRHOSIS, AND THE PREVENTION AS WELL AS TREATMENT OF HEPATOCELLULAR CARCINOMA. 2008