1 3538 99 IMMUNE REGULATION IN CHRONIC HEPATITIS C VIRUS INFECTION. THE IMMUNOLOGICAL RESULT OF INFECTION WITH HEPATITIS C VIRUS (HCV) DEPENDS ON THE DELICATE BALANCE BETWEEN A VIGOROUS IMMUNE RESPONSE THAT MAY CLEAR THE INFECTION, BUT WITH A RISK OF UNSPECIFIC INFLAMMATION AND, OR A LESS INFLAMMATORY RESPONSE THAT LEADS TO CHRONIC INFECTION. IN GENERAL, EXHAUSTION AND IMPAIRMENT OF CYTOTOXIC FUNCTION OF HCV-SPECIFIC T CELLS AND NK CELLS ARE FOUND IN PATIENTS WITH CHRONIC HCV INFECTION. IN CONTRAST, AN INCREASE IN IMMUNE REGULATORY FUNCTIONS IS FOUND PRIMARILY IN FORM OF INCREASED IL-10 PRODUCTION POSSIBLY DUE TO INCREASED LEVEL AND FUNCTION OF ANTI-INFLAMMATORY TREGS. THUS, THE MAJOR IMMUNE PLAYERS DURING CHRONIC HCV INFECTION ARE CHARACTERIZED BY A DECREASE OF CYTOTOXIC FUNCTION AND INCREASE OF INHIBITORY FUNCTIONS. THIS MAY BE AN APPROACH TO DIMINISH INTRAHEPATIC AND SYSTEMIC INFLAMMATION. FINALLY, THERE HAS BEEN INCREASING AWARENESS OF REGULATORY FUNCTIONS OF EPIGENETIC CHANGES IN CHRONIC HCV INFECTION. A VAST AMOUNT OF STUDIES HAVE REVEALED THE COMPLEXITY OF IMMUNE REGULATION IN CHRONIC HCV INFECTION, BUT THE INTERPLAY BETWEEN IMMUNE REGULATION IN VIRUS AND HOST REMAINS INCOMPLETELY UNDERSTOOD. THIS REVIEW PROVIDES AN OVERVIEW OF REGULATORY FUNCTIONS OF HCV-SPECIFIC T CELLS, NK CELLS, TREGS, IL-10, AND TGF-BETA, AS WELL AS EPIGENETIC CHANGES IN THE SETTING OF CHRONIC HCV INFECTION. 2016 2 2036 24 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 3 6365 28 THE ROLE OF METABOLIC DYSFUNCTION IN T-CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION. T CELLS ARE IMPORTANT COMPONENTS OF ADAPTIVE IMMUNITY THAT PROTECT THE HOST AGAINST INVADING PATHOGENS DURING INFECTION. UPON RECOGNIZING THE ACTIVATION SIGNALS, NAIVE AND/OR MEMORY T CELLS WILL INITIATE CLONAL EXPANSION, TRIGGER DIFFERENTIATION INTO EFFECTOR POPULATIONS AND TRAFFIC TO THE INFLAMED SITES TO ELIMINATE PATHOGENS. HOWEVER, IN CHRONIC VIRAL INFECTIONS, SUCH AS THOSE CAUSED BY HUMAN IMMUNODEFICIENCY VIRUS (HIV), HEPATITIS B AND C (HBV AND HCV), T CELLS EXHIBIT IMPAIRED FUNCTION AND BECOME DIFFICULT TO CLEAR PATHOGENS IN A STATE KNOWN AS T-CELL EXHAUSTION. THE ACTIVATION AND FUNCTION PERSISTENCE OF T CELLS DEMAND FOR DYNAMIC CHANGES IN CELLULAR METABOLISM TO MEET THEIR BIOENERGETIC AND BIOSYNTHETIC DEMANDS, ESPECIALLY THE AUGMENTATION OF AEROBIC GLYCOLYSIS, WHICH NOT ONLY PROVIDE EFFICIENT ENERGY GENERATION, BUT ALSO FUEL MULTIPLE BIOCHEMICAL INTERMEDIATES THAT ARE ESSENTIAL FOR NUCLEOTIDE, AMINO ACID, FATTY ACID SYNTHESIS AND MITOCHONDRIA FUNCTION. CHANGES IN CELLULAR METABOLISM ALSO AFFECT THE FUNCTION OF EFFECTORS T CELLS THROUGH MODIFYING EPIGENETIC SIGNATURES. IT IS WIDELY ACCEPTED THAT THE DYSFUNCTION OF T CELL METABOLISM CONTRIBUTES GREATLY TO T-CELL EXHAUSTION. HERE, WE REVIEWED RECENT FINDINGS ON T CELLS METABOLISM UNDER CHRONIC VIRAL INFECTION, SEEKING TO REVEAL THE ROLE OF METABOLIC DYSFUNCTION PLAYED IN T-CELL EXHAUSTION. 2022 4 2854 26 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 5 6641 30 UNRAVELING THE MULTIFACETED NATURE OF CD8 T CELL EXHAUSTION PROVIDES THE MOLECULAR BASIS FOR THERAPEUTIC T CELL RECONSTITUTION IN CHRONIC HEPATITIS B AND C. IN CHRONIC HEPATITIS B AND C VIRUS INFECTIONS PERSISTENTLY ELEVATED ANTIGEN LEVELS DRIVE CD8+ T CELLS TOWARD A PECULIAR DIFFERENTIATION STATE KNOWN AS T CELL EXHAUSTION, WHICH POSES CRUCIAL CONSTRAINTS TO ANTIVIRAL IMMUNITY. AVAILABLE EVIDENCE INDICATES THAT T CELL EXHAUSTION IS ASSOCIATED WITH A SERIES OF METABOLIC AND SIGNALING DEREGULATIONS AND WITH A VERY PECULIAR EPIGENETIC STATUS WHICH ALL TOGETHER LEAD TO REDUCED EFFECTOR FUNCTIONS. A CLEAR MECHANISTIC NETWORK EXPLAINING HOW INTRACELLULAR METABOLIC DERANGEMENTS, TRANSCRIPTIONAL AND SIGNALING ALTERATIONS SO FAR DESCRIBED ARE INTERCONNECTED IN A COMPREHENSIVE AND UNIFIED VIEW OF THE T CELL EXHAUSTION DIFFERENTIATION PROFILE IS STILL LACKING. ADDRESSING THIS ISSUE IS OF KEY IMPORTANCE FOR THE DEVELOPMENT OF INNOVATIVE STRATEGIES TO BOOST HOST IMMUNITY IN ORDER TO ACHIEVE VIRAL CLEARANCE. THIS REVIEW WILL DISCUSS THE CURRENT KNOWLEDGE IN HBV AND HCV INFECTIONS, ADDRESSING HOW INNATE IMMUNITY, METABOLIC DERANGEMENTS, EXTENSIVE STRESS RESPONSES AND ALTERED EPIGENETIC PROGRAMS MAY BE TARGETED TO RESTORE FUNCTIONALITY AND RESPONSIVENESS OF VIRUS-SPECIFIC CD8 T CELLS IN THE CONTEXT OF CHRONIC VIRUS INFECTIONS. 2021 6 5412 28 REGULATION OF ANTITUMOR IMMUNITY BY INFLAMMATION-INDUCED EPIGENETIC ALTERATIONS. CHRONIC INFLAMMATION PROMOTES TUMOR DEVELOPMENT, PROGRESSION, AND METASTATIC DISSEMINATION AND CAUSES TREATMENT RESISTANCE. THE ACCUMULATION OF GENETIC ALTERATIONS AND LOSS OF NORMAL CELLULAR REGULATORY PROCESSES ARE NOT ONLY ASSOCIATED WITH CANCER GROWTH AND PROGRESSION BUT ALSO RESULT IN THE EXPRESSION OF TUMOR-SPECIFIC AND TUMOR-ASSOCIATED ANTIGENS THAT MAY ACTIVATE ANTITUMOR IMMUNITY. THIS ANTAGONISM BETWEEN INFLAMMATION AND IMMUNITY AND THE ABILITY OF CANCER CELLS TO AVOID IMMUNE DETECTION AFFECT THE COURSE OF CANCER DEVELOPMENT AND TREATMENT OUTCOMES. WHILE INFLAMMATION, PARTICULARLY ACUTE INFLAMMATION, SUPPORTS T-CELL PRIMING, ACTIVATION, AND INFILTRATION INTO INFECTED TISSUES, CHRONIC INFLAMMATION IS MOSTLY IMMUNOSUPPRESSIVE. HOWEVER, THE MAIN MECHANISMS THAT DICTATE THE OUTCOME OF THE INFLAMMATION-IMMUNITY INTERPLAY ARE NOT WELL UNDERSTOOD. RECENT DATA SUGGEST THAT INFLAMMATION TRIGGERS EPIGENETIC ALTERATIONS IN CANCER CELLS AND COMPONENTS OF THE TUMOR MICROENVIRONMENT. THESE ALTERATIONS CAN AFFECT AND MODULATE NUMEROUS ASPECTS OF CANCER DEVELOPMENT, INCLUDING TUMOR GROWTH, THE METABOLIC STATE, METASTATIC SPREAD, IMMUNE ESCAPE, AND IMMUNOSUPPRESSIVE OR IMMUNOSUPPORTIVE LEUKOCYTE GENERATION. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION IN INITIATING EPIGENETIC ALTERATIONS IN IMMUNE CELLS, CANCER-ASSOCIATED FIBROBLASTS, AND CANCER CELLS AND SUGGEST HOW AND WHEN EPIGENETIC INTERVENTIONS CAN BE COMBINED WITH IMMUNOTHERAPIES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 7 4920 27 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 8 3799 22 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 9 4043 27 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 10 6640 32 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 11 928 24 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 12 3250 32 HEPATITIS B VIRUS INFECTION, MICRORNAS AND LIVER DISEASE. HEPATITIS B VIRUS (HBV) ATTACKS THE LIVER AND CAN CAUSE BOTH ACUTE AS WELL AS CHRONIC LIVER DISEASES WHICH MIGHT LEAD TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. REGARDLESS OF THE AVAILABILITY OF A VACCINE AND NUMEROUS TREATMENT OPTIONS, HBV IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY ACROSS THE WORLD. RECENTLY,MICRORNAS (MIRNAS) HAVE EMERGED AS IMPORTANT MODULATORS OF GENE FUNCTION. STUDIES ON THE ROLE OF MIRNA IN THE REGULATION OF HEPATITIS B VIRUS GENE EXPRESSION HAVE BEEN THE FOCUS OF MODERN ANTIVIRAL RESEARCH. MIRNAS CAN REGULATE VIRAL REPLICATION AND PATHOGENESIS IN A NUMBER OF DIFFERENT WAYS, WHICH INCLUDEFACILITATION, DIRECT OR INDIRECT INHIBITION, ACTIVATION OF IMMUNE RESPONSE, EPIGENETIC MODULATION, ETC. NEVERTHELESS, THESE MECHANISMS CAN APPROPRIATELY BE USED WITH A DIAGNOSTICAND/OR THERAPEUTIC APPROACH. THE PRESENT REVIEW IS AN ATTEMPT TO CLASSIFY SPECIFIC MIRNAS THAT ARE REPORTED TO BE ASSOCIATED WITH VARIOUS ASPECTS OF HEPATITIS B BIOLOGY, IN ORDER TO PRECISELY PRESENT THE PARTICIPATION OF INDIVIDUAL MIRNAS IN MULTIPLE ASPECTS RELATING TO HBV. 2015 13 4475 31 MOLECULAR PATHOGENESIS OF HEPATITIS C VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION WITH HEPATITIS C VIRUS (HCV) IS CAUSALLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HCV IS NOT CYTOLYTIC AND REPLICATES ENTIRELY IN THE CYTOPLASM. VIRAL INTERACTION WITH THE HOST LEADS TO SUBVERSION OF IMMUNE RESPONSE AND OTHER DEFENSE MECHANISMS. THE RECENT DEVELOPMENT OF ROBUST CELL CULTURE SYSTEMS FOR HCV INFECTION PROVIDES NEW OPPORTUNITIES FOR THE STUDY OF VIRUS-CELL INTERACTION AND VIRAL PATHOGENESIS. HCV INFECTION CAUSES ACTIVE INFLAMMATION AND FIBROSIS, WHICH ULTIMATELY PROGRESSES TO CIRRHOSIS. THE ONSET OF CIRRHOSIS USUALLY PRECEDES THE MULTISTAGE PROCESS OF TUMOR DEVELOPMENT, IN WHICH COMMON THEMES OF VIRAL CARCINOGENESIS CAN BE IDENTIFIED. WHILE CHRONIC INFLAMMATION AND CIRRHOSIS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN TUMOR INITIATION, THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. RECENT STUDIES HAVE REVEALED THAT INFECTION WITH HCV INDUCES GENOME INSTABILITY, LEADING TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS WHICH CONTRIBUTE TO THE FULL DEVELOPMENT OF HCC TUMOR. THE EXPRESSION OF VIRAL ONCOPROTEINS SUCH AS C AND NS5A IS CRITICALLY INVOLVED BOTH IN THE INDUCTION OF GENOME INSTABILITY AND IN DYSREGULATING CELLULAR CONTROL OF GROWTH AND SIGNAL TRANSDUCTION. A BETTER UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF HCV WILL REVEAL NOVEL STRATEGIES FOR THE PREVENTION AND TREATMENT OF RELATED DISEASES INCLUDING HCC. 2007 14 2970 29 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 15 4200 33 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 16 2166 30 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 17 4888 31 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 18 4127 31 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 19 915 28 CHRONIC HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS AND CANCER: SYNERGY BETWEEN VIRAL AND HOST FACTORS. HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTIONS REPRESENT MAJOR CAUSES OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. DESPITE INDUCING SHARED PATHOLOGICAL EVENTS LEADING TO ONCOGENIC TRANSFORMATION, THESE TWO VIRUSES PRESENT PROFOUND DIFFERENCES IN THEIR MOLECULAR FEATURES, LIFE CYCLE AND INTERPLAY WITH HOST FACTORS, WHICH SIGNIFICANTLY DIFFERENTIATE THE PROGNOSTIC AND THERAPEUTIC APPROACH TO THE RELATED DISEASES. IN THE PRESENT REVIEW, WE REPORT THE MAIN MECHANISMS INVOLVED IN THE MULTISTEP PROCESS LEADING FROM HCV/HBV INFECTION AND CANCER DEVELOPMENT, DISCUSSING SIDE-BY-SIDE THE ANALOGIES AND DIFFERENCES BETWEEN THE TWO VIRUSES. SUCH EVENTS CAN BE BROADLY CATEGORIZED INTO (A) DIRECT ONCOGENIC EFFECTS, INVOLVING INTEGRATION IN THE HOST GENOME (IN THE CASE OF HBV) AND CHROMOSOMAL INSTABILITY, INTERFERENCE WITH ONCOSUPPRESSOR PATHWAYS, INDUCTION OF OXIDATIVE STRESS, PROMOTION OF ANGIOGENESIS, EPITHELIAL-MESENCHYMAL TRANSITION, ALTERATIONS IN THE EPIGENETIC ASSET AND INTERACTION WITH NON-CODING RNAS; AND (B) INDIRECT ACTIVITIES MOSTLY MEDIATED BY HOST EVENTS, INCLUDING CHRONIC INFLAMMATION SUSTAINED BY PECULIAR CYTOKINE NETWORKS (SUCH AS INTERLEUKIN-6 AND LYMPHOTOXINS), METABOLIC DYSFUNCTIONS PROMOTED BY STEATOHEPATITIS, INTERPLAY WITH GUT MICROBIOTA AND FIBROTIC EVENTS (MAINLY IN HCV INFECTION). THIS SCENARIO SUGGESTS THAT THE INTEGRATED STUDY OF VIRAL AND HOST FACTORS MAY LEAD TO THE SUCCESSFUL DEVELOPMENT OF NOVEL BIOMARKERS AND TARGETS FOR THERAPY. 2015 20 4687 21 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