1 3272 274 HEPATOCELLULAR CARCINOMA: AN UPDATE. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF MALES IN THE WORLD, WITH AN INCIDENCE OF 1,000,000 NEW CASES A YEAR. IT IS ENDEMIC IN SOUTHEAST ASIA AND SUB-SAHARAN AFRICA. RISK FACTORS INCLUDE CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), AFLATOXIN B1 UPTAKE, HEMOCHROMATOSIS, AND ALPHA1 -ANTITRIPSIN DEFICIENCY. EPIDEMIOLOGICAL STUDIES PROVIDE EVIDENCE FOR THE ASSOCIATION OF HCC WITH HBV INFECTION. THE INCIDENCE OF HCC IS HIGH IN REGIONS HYPERENDEMIC FOR HBV. CHRONIC CARRIER STATE AND MATERNAL-INFANT TRANSMISSION ARE IMPORTANT FACTORS IN THE DEVELOPMENT OF HCC. EVIDENCE OF DIRECT ONCOGENIC EFFECT OF H BV IS WELL ESTABLISHED, HCCS CONTAIN VIRAL DNA SEQUENCES INTEGRATED INTO HEPATOCYTE DNA THAT ACT AS RANDOM INSERTIONAL MUTAGENS, AND THESE SITES ARE NEAR GENES INVOLVED IN THE CONTROL OF PROLIFERATION AND DIFFERENTIATION. THE MECHANISM OF HEPATITIS C VIRUS IN HEPATOCARCINOGENESIS IS STILL IMPRECISE BUT A HIGH PERCENTAGE OF CASES ARE RELATED TO THIS VIRUS. CHRONIC ALCOHOL CONSUMPTION AND CIRRHOSIS ARE COFACTORS THAT INCREASE THE DEVELOPMENT OF HCC IN PATIENTS WITH CHRONIC VIRAL INFECTION. IN EXPERIMENTAL CARCINOGENESIS A MULTIPOTENTIAL ELEMENT CALLED OVAL CELL PROLIFERATES IN THE EARLY STAGES. THE CELLULAR EVENTS ARE ACCOMPANIED BY INCREASED EXPRESSION OF SEVERAL GROWTH FACTORS THAT ENHANCE THE SURVIVAL OF CARCINOGEN-ACTIVATED CELLS BY SUPPRESSING APOPTOSIS AND INCREASING ELEMENTS ENTERING THE CELL CYCLE. HEPATIC CARCINOGENESIS IS A COMPLEX PROCESS ASSOCIATED WITH ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES THAT RUN THROUGH STEPS OF INITIATION, PROMOTION AND PROGRESSION. ACTIVATION OF ONCOGENES OF THE "RAS" FAMILY AND OTHERS HAS BEEN DETECTED DURING CHEMICALLY-INDUCED HCC IN RODENTS, BUT THERE IS LITTLE EVIDENCE OF SUCH ACTIVATION IN HUMAN TUMORS. THE ROLE OF TUMOR SUPRESSOR GENES SUCH AS RETINOBLASTOMA (RB) AND P53 GENES HAS BEEN DOCUMENTED. AFLATOXIN B1 THAT CONTAMINATES FOODS IN ENDEMIC AREAS HAS A CLEAR ROLE IN HEPATOCARCINOGENESIS. METABOLITES OF THIS TOXIN PROMOTE APURINIC SITES AND G TO T MUTATIONS IN CHROMOSOMAL DNA, THE THIRD BASE OF CODON 249 OF THE P53 GENE IS PREFERENTIALLY TARGETED TO FORM ADUCTS WITH AFLATOXIN B1, AND THIS MUTATION HAS BEEN SPECIFICALLY IDENTIFIED IN HBV INFECTION. HISTOLOGICAL AND CYTOLOGICAL CRITERIA FOR THE DIAGNOSIS OF HCC ARE WELL ESTABLISHED AND ARE BASED IN ARCHITECTURAL AND CYTOLOGICAL CHANGES. AN IMPORTANT ISSUE IS THE DIAGNOSIS OF LIVER "NODULES" DETECTED BY IMAGE, FROM WHICH SMALL BIOPSIES OR ASPIRATION MATERIAL IS OBTAINED. SPECIAL STUDIES SUCH AS RETICULIN, CD34, CYTOKERATIN PROFILE, AND MOC-31 CAN BE VERY USEFUL FOR THE DIFFERENTIAL DIAGNOSIS OF PRIMARY AND METASTATIC TUMORS. TELOMERASE ACTIVITY HAS BEEN FOUND IN HCC AND NEGATIVE IN PERICANCEROUS TISSUE. IT IS MORE PRONOUNCED IN POORLY DIFFERENTIATED TUMORS AND CORRELATES WITH FACTORS OF CLINICAL IMPORTANCE, SUCH AS PROGNOSIS AND RECURRENCES. CELLS OF WELL-DIFFERENTIATED HCC HAVE AN ULTRASTRUCTURAL APPEARANCE SIMILAR TO NORMAL HEPATOCYTES. DURING THE PROCESS OF DEDIFFERENTIATION, THERE IS PROGRESSIVE LOSS OF ORGANIZATION OF INTRACELLULAR ORGANELLES. THE CELL COHESION IS LOST, INTERCELLULAR GAPS WITH MICROVILLI APPEAR, THE SINUSOIDS BECOME CAPILLARIZED, AND REPARATIVE CHANGES ARE SEEN IN THE SPACES OF DISSE. A VARIETY OF INCLUSIONS, SUCH AS MALLORY BODIES, GRANULAR MATERIAL, SECONDARY LYSOSOMES, AND DUBIN-JOHNSON PIGMENT, HAVE BEEN DESCRIBED. FIBROLAMELLAR CARCINOMA HAS A CHARACTERISTIC HISTOLOGICAL PICTURE AND ULTRASTRUCTURALLY ONCOCYTIC FEATURES. NEUROENDOCRINE GRANULES AND COMBINATION OF HCC WITH BILE DUCT CARCINOMA ARE SEEN BY ELECTRON MICROSCOPY. 2001 2 4448 49 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 3 6486 65 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 4 5987 33 TGF-BETA SIGNAL SHIFTING BETWEEN TUMOR SUPPRESSION AND FIBRO-CARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES. PERTURBATION OF TRANSFORMING GROWTH FACTOR (TGF)-BETA SIGNALING IN HEPATOCYTES PERSISTENTLY INFECTED WITH HEPATITIS VIRUSES PROMOTES BOTH FIBROGENESIS AND CARCINOGENESIS (FIBRO-CARCINOGENESIS). INSIGHTS INTO HEPATOCYTIC FIBRO-CARCINOGENESIS HAVE EMERGED FROM RECENT DETAILED ANALYSES OF CONTEXT-DEPENDENT AND CELL TYPE-SPECIFIC TGF-BETA SIGNALING PROCESSES DIRECTED BY MULTIPLE PHOSPHORYLATED FORMS (PHOSPHO-ISOFORMS) OF SMAD MEDIATORS. IN THE COURSE OF HEPATITIS VIRUS-RELATED CHRONIC LIVER DISEASES, CHRONIC INFLAMMATION, ONGOING VIRAL INFECTION, AND HOST GENETIC/EPIGENETIC ALTERATIONS ADDITIVELY SHIFT HEPATOCYTIC SMAD PHOSPHO-ISOFORM SIGNALING FROM TUMOR SUPPRESSION TO FIBRO-CARCINOGENESIS, ACCELERATING LIVER FIBROSIS AND INCREASING RISK OF HEPATOCELLULAR CARCINOMA (HCC). AFTER SUCCESSFUL ANTIVIRAL THERAPY, PATIENTS WITH CHRONIC HEPATITIS CAN EXPERIENCE LESS RISK OF HCC OCCURRENCE BY REVERSING SMAD PHOSPHO-ISOFORM SIGNALING FROM FIBRO-CARCINOGENESIS TO TUMOR SUPPRESSION. HOWEVER, PATIENTS WITH CIRRHOSIS CAN STILL DEVELOP HCC OWING TO SUSTAINED, INTENSE FIBRO-CARCINOGENIC SIGNALING. RECENT PROGRESS IN UNDERSTANDING SMAD PHOSPHO-ISOFORM SIGNALING SHOULD PERMIT USE OF SMAD PHOSPHORYLATION AS A TOOL PREDICTING THE LIKELIHOOD OF LIVER DISEASE PROGRESSION, AND AS A BIOMARKER FOR ASSESSING THE EFFECTIVENESS OF INTERVENTIONS AIMED AT REDUCING FIBROSIS AND CANCER RISK. 2014 5 3190 46 HCV-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH LIVER CANCER RISK PERSIST AFTER SUSTAINED VIROLOGIC RESPONSE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE EFFECTIVE ANTIVIRAL THERAPIES, THE RISK FOR HCC IS DECREASED BUT NOT ELIMINATED AFTER A SUSTAINED VIROLOGIC RESPONSE (SVR) TO DIRECT-ACTING ANTIVIRAL (DAA) AGENTS, AND THE RISK IS HIGHER IN PATIENTS WITH ADVANCED FIBROSIS. WE INVESTIGATED HCV-INDUCED EPIGENETIC ALTERATIONS THAT MIGHT AFFECT RISK FOR HCC AFTER DAA TREATMENT IN PATIENTS AND MICE WITH HUMANIZED LIVERS. METHODS: WE PERFORMED GENOME-WIDE CHIPMENTATION-BASED CHIP-SEQ AND RNA-SEQ ANALYSES OF LIVER TISSUES FROM 6 PATIENTS WITHOUT HCV INFECTION (CONTROLS), 18 PATIENTS WITH CHRONIC HCV INFECTION, 8 PATIENTS WITH CHRONIC HCV INFECTION CURED BY DAA TREATMENT, 13 PATIENTS WITH CHRONIC HCV INFECTION CURED BY INTERFERON THERAPY, 4 PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION, AND 7 PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS IN EUROPE AND JAPAN. HCV-INDUCED EPIGENETIC MODIFICATIONS WERE MAPPED BY COMPARATIVE ANALYSES WITH MODIFICATIONS ASSOCIATED WITH OTHER LIVER DISEASE ETIOLOGIES. UPA/SCID MICE WERE ENGRAFTED WITH HUMAN HEPATOCYTES TO CREATE MICE WITH HUMANIZED LIVERS AND GIVEN INJECTIONS OF HCV-INFECTED SERUM SAMPLES FROM PATIENTS; MICE WERE GIVEN DAAS TO ERADICATE THE VIRUS. PATHWAYS ASSOCIATED WITH HCC RISK WERE IDENTIFIED BY INTEGRATIVE PATHWAY ANALYSES AND VALIDATED IN ANALYSES OF PAIRED HCC TISSUES FROM 8 PATIENTS WITH AN SVR TO DAA TREATMENT OF HCV INFECTION. RESULTS: WE FOUND CHRONIC HCV INFECTION TO INDUCE SPECIFIC GENOME-WIDE CHANGES IN H3K27AC, WHICH CORRELATED WITH CHANGES IN EXPRESSION OF MRNAS AND PROTEINS. THESE CHANGES PERSISTED AFTER AN SVR TO DAAS OR INTERFERON-BASED THERAPIES. INTEGRATIVE PATHWAY ANALYSES OF LIVER TISSUES FROM PATIENTS AND MICE WITH HUMANIZED LIVERS DEMONSTRATED THAT HCV-INDUCED EPIGENETIC ALTERATIONS WERE ASSOCIATED WITH LIVER CANCER RISK. COMPUTATIONAL ANALYSES ASSOCIATED INCREASED EXPRESSION OF SPHK1 WITH HCC RISK. WE VALIDATED THESE FINDINGS IN AN INDEPENDENT COHORT OF PATIENTS WITH HCV-RELATED CIRRHOSIS (N = 216), A SUBSET OF WHICH (N = 21) ACHIEVED VIRAL CLEARANCE. CONCLUSIONS: IN AN ANALYSIS OF LIVER TISSUES FROM PATIENTS WITH AND WITHOUT AN SVR TO DAA THERAPY, WE IDENTIFIED EPIGENETIC AND GENE EXPRESSION ALTERATIONS ASSOCIATED WITH RISK FOR HCC. THESE ALTERATIONS MIGHT BE TARGETED TO PREVENT LIVER CANCER IN PATIENTS TREATED FOR HCV INFECTION. 2019 6 442 38 ANTIVIRAL THERAPIES FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A CRITICAL RISK FACTOR FOR THE CARCINOGENESIS AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC). IT PROMOTES HCC DEVELOPMENT BY INDUCING LIVER FIBROGENESIS, GENETIC AND EPIGENETIC ALTERATIONS, AND THE EXPRESSION OF ACTIVE VIRAL-CODED PROTEINS. EFFECTIVE ANTIVIRAL TREATMENTS INHIBIT THE REPLICATION OF HBV, REDUCE SERUM VIRAL LOAD AND ACCELERATE HEPATITIS B E ANTIGEN SERUM CONVERSION. TIMELY INITIATION OF ANTIVIRAL TREATMENT IS NOT ONLY ESSENTIAL FOR PREVENTING THE INCIDENCE OF HCC IN CHRONIC HEPATITIS B PATIENTS, BUT ALSO IMPORTANT FOR REDUCING HBV REACTIVATION, IMPROVING LIVER FUNCTION, REDUCING OR DELAYING HCC RECURRENCE, AND PROLONGING OVERALL SURVIVAL OF HBV-RELATED HCC PATIENTS AFTER CURATIVE AND PALLIATIVE THERAPIES. THE SELECTION OF ANTIVIRAL DRUGS, MONITORING OF INDICATORS SUCH AS HBV DNA AND HEPATITIS B SURFACE ANTIGEN, AND TIMELY RESCUE TREATMENT WHEN NECESSARY, ARE ESSENTIAL IN ANTIVIRAL THERAPIES FOR HBV-RELATED HCC. 2015 7 5521 53 RISK OF HEPATOCELLULAR CARCINOMA AFTER HCV CLEARANCE BY DIRECT-ACTING ANTIVIRALS TREATMENT PREDICTIVE FACTORS AND ROLE OF EPIGENETICS. DIRECT-ACTING ANTIVIRALS (DAAS) INDUCE A RAPID VIROLOGIC RESPONSE (SVR) IN UP TO 99% OF CHRONIC HEPATITIS C PATIENTS. THE ROLE OF SVR BY DAAS ON THE INCIDENCE OR RECURRENCE OF HEPATOCELLULAR CARCINOMA (HCC) IS STILL A MATTER OF DEBATE, ALTHOUGH IT IS KNOWN THAT SVR DOES NOT ELIMINATE THE RISK OF HCC. IN THIS REVIEW, WE MADE AN UPDATED ANALYSIS OF THE LITERATURE DATA ON THE IMPACT OF SVR BY DAAS ON THE RISK OF HCC AS WELL AS AN ASSESSMENT OF RISK FACTORS AND THE ROLE OF EPIGENETICS. DATA SHOWED THAT SVR HAS NO IMPACT ON THE OCCURRENCE OF HCC IN THE SHORT-MEDIUM TERM BUT REDUCES THE RISK OF HCC IN THE MEDIUM-LONG TERM. A DIRECT ROLE OF DAAS IN THE DEVELOPMENT OF HCC HAS NOT BEEN DEMONSTRATED, WHILE THE HYPOTHESIS OF A REDUCTION IN IMMUNE SURVEILLANCE IN RESPONSE TO THE RAPID CLEARANCE OF HCV AND CHANGES IN THE CYTOKINE PATTERN INFLUENCING EARLY CARCINOGENESIS REMAINS TO BE FURTHER ELUCIDATED. HCV INDUCES EPIGENETIC ALTERATIONS SUCH AS MODIFICATIONS OF THE HISTONE TAIL AND DNA METHYLATION, WHICH ARE RISK FACTORS FOR HCC, AND SUCH CHANGES ARE MAINTAINED AFTER HCV CLEARANCE. FUTURE EPIGENETIC STUDIES COULD LEAD TO IDENTIFY USEFUL BIOMARKERS AND THERAPEUTIC TARGETS. CIRRHOSIS HAS BEEN IDENTIFIED AS A RISK FACTOR FOR HCC, PARTICULARLY IF ASSOCIATED WITH HIGH LIVER STIFFNESS AND ALPHA-FETOPROTEIN VALUES, DIABETES AND THE MALE SEX. CURRENTLY, CONSIDERING THE HIGH NUMBER AND HEALTH COST TO FOLLOW SUBJECTS' POST-HCV CLEARANCE BY DAAS, IT IS MANDATORY TO IDENTIFY THOSE AT HIGH RISK OF HCC TO OPTIMIZE MANAGEMENT. 2020 8 5731 39 SMAD3 PHOSPHO-ISOFORM SIGNALING IN HEPATITIS C VIRUS-RELATED CHRONIC LIVER DISEASES. THE RISK OF HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT INCREASES AS HEPATITIS VIRUS C (HCV)-RELATED LIVER DISEASES PROGRESS, ESPECIALLY IN PATIENTS WITH ACTIVE INFLAMMATION. INSIGHT INTO HEPATIC CARCINOGENESIS HAVE EMERGED FROM RECENT DETAILED ANALYSES OF TRANSFORMING GROWTH FACTOR-BETA AND C-JUN-N-TERMINAL KINASE SIGNALING PROCESSES DIRECTED BY MULTIPLE PHOSPHORYLATED (PHOSPHO)-ISOFORMS OF A SMAD3 MEDIATOR. IN THE COURSE OF HCV-RELATED CHRONIC LIVER DISEASES, CHRONIC INFLAMMATION AND HOST GENETIC/EPIGENETIC ALTERATIONS ADDITIVELY SHIFT THE HEPATOCYTIC SMAD3 PHOSPHO-ISOFORM SIGNALING FROM TUMOR SUPPRESSION TO CARCINOGENESIS, INCREASING THE RISK OF HCC. CHRONIC INFLAMMATION REPRESENTS AN EARLY CARCINOGENIC STEP THAT PROVIDES A NONMUTAGENIC TUMOR-PROMOTING STIMULUS. AFTER UNDERGOING SUCCESSFUL ANTIVIRAL THERAPY, PATIENTS WITH CHRONIC HEPATITIS C COULD EXPERIENCE A LOWER RISK OF HCC AS SMAD3 PHOSPHO-ISOFORM SIGNALING REVERSES FROM POTENTIAL CARCINOGENESIS TO TUMOR SUPPRESSION. EVEN AFTER HCV CLEARANCE, HOWEVER, PATIENTS WITH CIRRHOSIS COULD STILL DEVELOP HCC BECAUSE OF SUSTAINED, INTENSE CARCINOGENIC SMAD3 PHOSPHO-ISOFORM SIGNALING THAT IS POSSIBLY CAUSED BY GENETIC OR EPIGENETIC ALTERATIONS. SMAD3 PHOSPHO-ISOFORMS SHOULD ASSIST WITH EVALUATING THE EFFECTIVENESS OF INTERVENTIONS AIMED AT REDUCING HUMAN HCC. 2014 9 3271 46 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED. 2021 10 4815 59 OCCULT HEPATITIS B INFECTION AND HEPATOCELLULAR CARCINOMA: EPIDEMIOLOGY, VIROLOGY, HEPATOCARCINOGENESIS AND CLINICAL SIGNIFICANCE. OCCULT HEPATITIS B INFECTION (OBI) REFERS TO A CONDITION WHERE REPLICATION-COMPETENT HBV DNA IS PRESENT IN THE LIVER, WITH OR WITHOUT HBV DNA IN THE BLOOD, IN INDIVIDUALS WITH SERUM HBSAG NEGATIVITY ASSESSED BY CURRENTLY AVAILABLE ASSAYS. THE EPISOMAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN OBI IS IN A LOW REPLICATIVE STATE. VIRAL GENE EXPRESSION IS MEDIATED BY EPIGENETIC CONTROL OF HBV TRANSCRIPTION, INCLUDING THE HBV CPG ISLAND METHYLATION PATHWAY AND POST-TRANSLATIONAL MODIFICATION OF CCCDNA-BOUND HISTONE, WITH A DIFFERENT PATTERN FROM PATIENTS WITH CHRONIC HBV INFECTION. THE PREVALENCE OF OBI VARIES TREMENDOUSLY ACROSS PATIENT POPULATIONS OWING TO NUMEROUS FACTORS, SUCH AS GEOGRAPHIC LOCATION, ASSAY CHARACTERISTICS, HOST IMMUNE RESPONSE, COINFECTION WITH OTHER VIRUSES, AND VACCINATION STATUS. APART FROM THE RISK OF VIRAL REACTIVATION UPON IMMUNOSUPPRESSION AND THE RISK OF TRANSMISSION OF HBV, OBI HAS BEEN IMPLICATED IN HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN PATIENTS WITH CHRONIC HCV INFECTION, THOSE WITH CRYPTOGENIC OR KNOWN LIVER DISEASE, AND IN PATIENTS WITH HBSAG SEROCLEARANCE AFTER CHRONIC HBV INFECTION. AN INCREASING NUMBER OF PROSPECTIVE STUDIES AND META-ANALYSES HAVE REPORTED A HIGHER INCIDENCE OF HCC IN PATIENTS WITH HCV AND OBI, AS WELL AS MORE ADVANCED TUMOUR HISTOLOGICAL GRADES AND EARLIER AGE OF HCC DIAGNOSIS, COMPARED WITH PATIENTS WITHOUT OBI. THE PROPOSED PATHOGENETIC MECHANISMS OF OBI-RELATED HCC INCLUDE THE INFLUENCE OF HBV DNA INTEGRATION ON THE HEPATOCYTE CELL CYCLE, THE PRODUCTION OF PRO-ONCOGENIC PROTEINS (HBX PROTEIN AND MUTATED SURFACE PROTEINS), AND PERSISTENT LOW-GRADE NECROINFLAMMATION (CONTRIBUTING TO THE DEVELOPMENT OF FIBROSIS AND CIRRHOSIS). THERE REMAIN UNCERTAINTIES ABOUT EXACTLY HOW, AND IN WHAT ORDER, THESE MECHANISMS DRIVE THE DEVELOPMENT OF TUMOURS IN PATIENTS WITH OBI. 2020 11 1042 33 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 12 3931 27 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 13 3476 48 IDENTIFICATION OF A TRANSMEMBRANE PROTEIN INVOLVED IN SHEAR STRESS SIGNALING AND HEPATOCARCINOGENESIS AFTER A SUSTAINED VIROLOGICAL RESPONSE TO HEPATITIS C VIRUS. BACKGROUND & AIMS: THE RISK OF HEPATOCELLULAR CARCINOMA (HCC) REMAINS AFTER ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE (SVR) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC). EPIGENETIC ABNORMALITIES MIGHT BE KEY REGULATORS IN THE DEVELOPMENT OF HCC. THIS STUDY AIMED TO IDENTIFY THE GENES INVOLVED IN HEPATOCARCINOGENESIS AFTER AN SVR. METHODS: DNA METHYLATION IN LIVER TISSUE WAS COMPARED BETWEEN 21 CHC PATIENTS WITHOUT HCC AND 28 CHC PATIENTS WITH HCC, ALL OF WHOM HAD ACHIEVED AN SVR. ADDITIONAL COMPARISONS WITH 23 CHC PATIENTS BEFORE TREATMENT AND 10 NORMAL LIVERS WERE PERFORMED. THE CHARACTERISTICS OF A NEWLY IDENTIFIED GENE WERE EXPLORED IN VITRO AND IN VIVO. RESULTS: WE FOUND THAT THE TRANSMEMBRANE PROTEIN NO. 164 (TMEM164) GENE WAS DEMETHYLATED BY HEPATITIS C VIRUS INFECTION AND HCC DEVELOPMENT AFTER ACHIEVING AN SVR. TMEM164 WAS EXPRESSED MAINLY IN ENDOTHELIAL CELLS, ALPHA SMOOTH MUSCLE ACTIN-POSITIVE CELLS, AND SOME CAPILLARIZED LIVER SINUSOIDAL ENDOTHELIAL CELLS. TMEM164 EXPRESSION WAS SIGNIFICANTLY CORRELATED WITH LIVER FIBROSIS AND RELAPSE-FREE SURVIVAL IN HCC PATIENTS. TMEM164 WAS INDUCED BY SHEAR STRESS, INTERACTED WITH GRP78/BIP, ACCELERATED ATF6 (ACTIVATING TRANSCRIPTION FACTOR 6)-MEDIATED ENDOPLASMIC RETICULUM (ER) STRESS SIGNALING, AND ACTIVATED INTERLEUKIN-6/STAT3 (SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3) SIGNALING IN THE TMNK1 LIVER ENDOTHELIAL CELL LINE. THEREFORE, WE TERMED TMEM164 "SHEAR STRESS-INDUCED TRANSMEMBRANE PROTEIN ASSOCIATED WITH ER STRESS SIGNALING" (SHERMER). SHERMER KNOCKOUT MICE WERE PROTECTED AGAINST CCL4-INDUCED LIVER FIBROSIS. SHERMER OVEREXPRESSION IN TMNK1 CELLS ACCELERATED HCC GROWTH IN A XENOGRAFT MODEL. CONCLUSIONS: WE IDENTIFIED A NEW TRANSMEMBRANE PROTEIN, SHERMER, IN CHC PATIENTS WITH HCC AFTER ACHIEVING AN SVR. SHERMER WAS INDUCED BY SHEAR STRESS AND ACCELERATED ATF6-MEDIATED ER STRESS SIGNALING IN ENDOTHELIAL CELLS. THUS, SHERMER IS A NOVEL ENDOTHELIAL MARKER ASSOCIATED WITH LIVER FIBROSIS, HEPATOCARCINOGENESIS, AND PROGRESSION OF HCC. 2023 14 6868 41 [PATHOGENESIS OF HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCER WORLDWIDE. MOST OF THE HCC OCCUR IN DEVELOPING COUNTRIES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HCC DEVELOPMENT. HBV INDUCES IMMUNE-MEDIATED CHRONIC HEPATITIS, LIVER INJURY, REGENERATION AND SCAR FORMING RESPONSES, LEADING TO AN INFLAMMATORY, FIBROTIC AND IMMUNE DEFICIENT MICROENVIRONMENT. HBV MAY INTEGRATE INTO HOST GENOME, INDUCING GENETIC ABNORMALITY AND ALTERING THE EXPRESSION OF HCC-RELATED GENES. HBV ALSO EXPRESSES ACTIVE PROTEINS SUCH AS X (HBX) AND S PROTEINS, WHICH MAY TRANS-ACTIVATE HCC-RELATED PROTEINS EXPRESSION, INTERACT WITH INTRACELLULAR SPECIFIC PROTEINS, ACTIVATE A VARIETY OF SIGNALING PATHWAYS, AND INDUCE ABERRANT EPIGENETIC MODIFICATIONS. HBV MUTATION ALSO HAS IMPACT ON HBV RELATED HCC DEVELOPMENT. 2016 15 6848 69 [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 16 3245 32 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 17 3260 56 HEPATITIS C VIRUS LEAVES AN EPIGENETIC SIGNATURE POST CURE OF INFECTION BY DIRECT-ACTING ANTIVIRALS. THE INCREASING WORLDWIDE PREVALENCE OF HEPATOCELLULAR CARCINOMA (HCC), CHARACTERIZED BY RESISTANCE TO CONVENTIONAL CHEMOTHERAPY, POOR PROGNOSIS AND EVENTUALLY MORTALITY, PLACE IT AS A PRIME TARGET FOR NEW MODES OF PREVENTION AND TREATMENT. HEPATITIS C VIRUS (HCV) IS THE PREDOMINANT RISK FACTOR FOR HCC IN THE US AND EUROPE. MULTIPLE EPIDEMIOLOGICAL STUDIES SHOWED THAT SUSTAINED VIROLOGICAL RESPONSES (SVR) FOLLOWING TREATMENT WITH THE POWERFUL DIRECT ACTING ANTIVIRALS (DAAS), WHICH HAVE REPLACED INTERFERON-BASED REGIMES, DO NOT ELIMINATE TUMOR DEVELOPMENT. WE AIMED TO IDENTIFY AN HCV-SPECIFIC PATHOGENIC MECHANISM THAT PERSISTS POST SVR FOLLOWING DAAS TREATMENT. WE DEMONSTRATE THAT HCV INFECTION INDUCES GENOME-WIDE EPIGENETIC CHANGES BY PERFORMING CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT-GENERATION SEQUENCING (CHIP-SEQ) FOR HISTONE POST-TRANSLATIONAL MODIFICATIONS THAT ARE EPIGENETIC MARKERS FOR ACTIVE AND REPRESSED CHROMATIN. THE CHANGES IN HISTONE MODIFICATIONS CORRELATE WITH REPROGRAMED HOST GENE EXPRESSION AND ALTER SIGNALING PATHWAYS KNOWN TO BE ASSOCIATED WITH HCV LIFE CYCLE AND HCC. THESE EPIGENETIC ALTERATIONS REQUIRE THE PRESENCE OF HCV RNA OR/AND EXPRESSION OF THE VIRAL PROTEINS IN THE CELLS. IMPORTANTLY, THE EPIGENETIC CHANGES INDUCED FOLLOWING INFECTION PERSIST AS AN "EPIGENETIC SIGNATURE" AFTER VIRUS ERADICATION BY DAAS TREATMENT, AS DETECTED USING IN VITRO HCV INFECTION MODELS. THESE OBSERVATIONS LED TO THE IDENTIFICATION OF AN 8 GENE SIGNATURE THAT IS ASSOCIATED WITH HCC DEVELOPMENT AND DEMONSTRATE PERSISTENT EPIGENETIC ALTERATIONS IN HCV INFECTED AND POST SVR LIVER BIOPSY SAMPLES. THE EPIGENETIC SIGNATURE WAS REVERTED IN VITRO BY DRUGS THAT INHIBIT EPIGENETIC MODIFYING ENZYME AND BY THE EGFR INHIBITOR, ERLOTINIB. THIS EPIGENETIC "SCARRING" OF THE GENOME, PERSISTING FOLLOWING HCV ERADICATION, SUGGEST A NOVEL MECHANISM FOR THE PERSISTENT PATHOGENESIS OF HCV AFTER ITS ERADICATION BY DAAS. OUR STUDY OFFERS NEW AVENUES FOR PREVENTION OF THE PERSISTENT ONCOGENIC EFFECTS OF CHRONIC HEPATITIS INFECTIONS USING SPECIFIC DRUGS TO REVERT THE EPIGENETIC CHANGES TO THE GENOME. 2019 18 4903 41 P16 PROMOTER HYPERMETHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA WITH OR WITHOUT HEPATITIS VIRUS INFECTION. BACKGROUND: EPIGENETIC ALTERATION THROUGH METHYLATION IS ONE OF THE MOST IMPORTANT STEPS IN CARCINOGENESIS. HOWEVER, THE RELATION BETWEEN HEPATITIS VIRUS INFECTION AND EPIGENETIC ALTERATIONS IS POORLY UNDERSTOOD. METHODS: SIXTEEN PATIENTS WITHOUT HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) AND 35 PATIENTS WITH HBV OR HCV WHO UNDERWENT LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA (HCC) WERE STUDIED. MUTATION OF P53 WAS DETECTED BY DIRECT SEQUENCING. METHYLATION STATUS OF P16 WAS EVALUATED IN TUMOR AND NONCANCEROUS LIVER TISSUES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: IN HCC WITHOUT HBV AND HCV, P53 MUTATIONS WERE DETECTED IN 5 (31%) OF 16 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (25%) OF 8 MODERATELY DIFFERENTIATED HCCS, 6 (75%) OF 8 POORLY DIFFERENTIATED HCCS, AND NONE OF 16 NONCANCEROUS TISSUE SPECIMENS. IN HCC WITH HBV OR HCV, P53 MUTATIONS WERE DETECTED IN 8 (23%) OF 35 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (100%) OF 2 WELL-DIFFERENTIATED HCCS, 13 (76%) OF 17 MODERATELY DIFFERENTIATED HCCS, 12 (75%) OF 16 POORLY DIFFERENTIATED HCCS, AND 9 (26%) OF 35 NONCANCEROUS LIVER TISSUE SPECIMENS. CONCLUSIONS: OUR RESULTS SUGGEST THAT HEPATITIS VIRUSES MIGHT INDUCE METHYLATION OF P16 PROMOTER IN LIVER WITH CHRONIC INFLAMMATION, BEFORE APPEARANCE OF HCC. 2004 19 699 31 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 20 4890 44 OXIDATIVE STRESS AND HEPATIC NOX PROTEINS IN CHRONIC HEPATITIS C AND HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON LIVER CANCER AND A LEADING CAUSE OF CANCER-RELATED MORTALITY IN THE WORLD. HEPATITIS C VIRUS (HCV) IS A MAJOR ETIOLOGIC AGENT OF HCC. A MAJORITY OF HCV INFECTIONS LEAD TO CHRONIC INFECTION THAT CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, HCC AND LIVER FAILURE. A COMMON PATHOGENIC FEATURE PRESENT IN HCV INFECTION, AND OTHER CONDITIONS LEADING TO HCC, IS OXIDATIVE STRESS. HCV DIRECTLY INCREASES SUPEROXIDE AND H2O2 FORMATION IN HEPATOCYTES BY ELEVATING NOX PROTEIN EXPRESSION AND SENSITIZING MITOCHONDRIA TO REACTIVE OXYGEN SPECIES GENERATION WHILE DECREASING GLUTATHIONE. NITRIC OXIDE SYNTHESIS AND HEPATIC IRON ARE ALSO ELEVATED. FURTHERMORE, ACTIVATION OF PHAGOCYTIC NADPH OXIDASE (NOX) 2 OF HOST IMMUNE CELLS IS LIKELY TO EXACERBATE OXIDATIVE STRESS IN HCV-INFECTED PATIENTS. KEY MECHANISMS OF HCC INCLUDE GENOME INSTABILITY, EPIGENETIC REGULATION, INFLAMMATION WITH CHRONIC TISSUE INJURY AND SUSTAINED CELL PROLIFERATION, AND MODULATION OF CELL GROWTH AND DEATH. OXIDATIVE STRESS, OR NOX PROTEINS, PLAYS VARIOUS ROLES IN THESE MECHANISMS. NOX PROTEINS ALSO FUNCTION IN HEPATIC FIBROSIS, WHICH COMMONLY PRECEDES HCC, AND NOX4 ELEVATION BY HCV IS MEDIATED BY TRANSFORMING GROWTH FACTOR BETA. THIS REVIEW SUMMARIZES MECHANISMS OF ONCOGENESIS BY HCV, HIGHLIGHTING THE ROLES OF OXIDATIVE STRESS AND HEPATIC NOX ENZYMES IN HCC. 2014