1 6908 38 [THYROID AND HEPATITIS C]. AUTOIMMUNE THYROID DISEASES ARE COMPLEX DISEASES THAT DEVELOP AS A RESULT OF INTERACTIONS BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. IFNA THERAPY OF CHRONIC HCV INFECTION IS ASSOCIATED WITH SUBCLINICAL OR CLINICAL THYROIDITIS, WHILE THE RELATIONSHIP BETWEEN THYROIDITIS AND VIRUS C INFECTION IS STILL DEBATED. 2012 2 3258 36 HEPATITIS C AND INTERFERON INDUCED THYROIDITIS. AUTOIMMUNE THYROID DISEASES (AITDS) ARE COMPLEX DISEASES THAT DEVELOP AS A RESULT OF INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. SIGNIFICANT PROGRESS HAS BEEN MADE IN OUR UNDERSTANDING OF THE GENETIC AND ENVIRONMENTAL TRIGGERS CONTRIBUTING TO AITD. THE MAJOR ENVIRONMENTAL TRIGGERS OF AITD INCLUDE IODINE, SMOKING, MEDICATIONS, PREGNANCY, AND POSSIBLY STRESS. IN THIS REVIEW WE WILL FOCUS ON TWO WELL-DOCUMENTED ENVIRONMENTAL TRIGGERS OF AITD, HEPATITIS C VIRUS (HCV) INFECTION AND INTERFERON ALPHA (IFNA) THERAPY. CHRONIC HCV INFECTION HAS BEEN SHOWN TO BE ASSOCIATED WITH INCREASED INCIDENCE OF CLINICAL AND SUBCLINICAL AUTOIMMUNE THYROIDITIS (I.E. THE PRESENCE OF THYROID ANTIBODIES IN EUTHYROID SUBJECTS). MOREOVER, IFNA THERAPY OF CHRONIC HCV INFECTION IS ASSOCIATED WITH SUBCLINICAL OR CLINICAL THYROIDITIS IN UP TO 40% OF CASES WHICH CAN BE AUTOIMMUNE, OR NON-AUTOIMMUNE THYROIDITIS. IN SOME CASES INTERFERON INDUCED THYROIDITIS (IIT) IN CHRONIC HCV PATIENTS MAY RESULT IN SEVERE SYMPTOMATOLOGY NECESSITATING DISCONTINUATION OF THERAPY. WHILE THE EPIDEMIOLOGY AND CLINICAL PRESENTATION OF HCV AND INTERFERON INDUCED THYROIDITIS HAVE BEEN WELL CHARACTERIZED, THE MECHANISMS CAUSING THESE CONDITIONS ARE STILL POORLY UNDERSTOOD. 2010 3 6356 13 THE ROLE OF HOST IN THE SPECTRUM OF OUTCOMES IN FAMILY CLUSTERS OF HEPATITIS INFECTION: FROM ASYMPTOMATIC TO HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS INFECTIONS ARE PREVALENT WORLDWIDE, BUT THE OUTCOMES OF INFECTION VARY GREATLY FROM HOST TO HOST. IN MANY ENDEMIC REGIONS, VERTICAL TRANSMISSION FROM MOTHER TO CHILD IS MOST COMMON. IN THIS TRANSMISSION SETTING, VIRUS GENOTYPE AND SHARED PATIENT GENETICS MAKE FOR AN INTERESTING COMPARISON OF OUTCOME OF CHRONIC HEPATITIS B INFECTION. THIS CASE SERIES DEMONSTRATES FOUR FAMILY CLUSTERS WHICH DISPLAY DISPARATE OUTCOMES AMONG FAMILY MEMBERS WITH HEPATITIS B VIRUS INFECTIONS, FURTHER STRESSING THE ROLE OF HOST AND NON-GENETIC FACTORS IN THE NATURAL HISTORY OF THE DISEASE. MANY HOST FACTORS HAVE BEEN THEORIZED, FROM EPIGENETIC MECHANISMS TO THE ROLE OF CHRONIC STRESS, BUT MORE RESEARCH IS NEEDED TO BETTER UNDERSTAND THOSE AT HIGHER RISK OF FEARED COMPLICATIONS SUCH AS HEPATOCELLULAR CARCINOMA AND CIRRHOSIS. 2023 4 915 20 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 5 5830 19 STRESS, THYROID DYSREGULATION, AND THYROID CANCER IN CHILDREN AND ADOLESCENTS: PROPOSED IMPENDING MECHANISMS. STRESS IS A POTENTIAL CATALYST FOR THYROID DYSREGULATION THROUGH CROSS-COMMUNICATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-THYROID (HPT) AXES. STRESS AND STRESSORS EXPOSURE MOTIVATES MOLECULAR MECHANISMS AFFECTING COMPOUND FEEDBACK LOOPS OF THE HPT AXIS. WHILE THERE IS EVIDENCE OF CONNECTION BETWEEN STRESS AND THYROID DYSREGULATION, THE QUESTION WHETHER THIS CONNECTION IS IMPLICATED IN THE DEVELOPMENT OF THYROID CANCER (TC) REMAINS UNANSWERED. IN VIEW OF THE RISING INCIDENCE OF TC IN BOTH ADULTS AND CHILDREN ALONGSIDE THE INCREASING STRESS IN OUR MODERN SOCIETY, THERE IS A NEED TO UNDERSTAND POSSIBLE INTERRELATIONS BETWEEN STRESS, THYROID DYSREGULATION, AND TC. PROLONGED GLUCOCORTICOID SECRETION DUE TO STRESS INTERFERES WITH IMMUNE SYSTEM RESPONSE BY ALTERING THE CYTOKINES, INDUCING LOW-GRADE CHRONIC INFLAMMATION, AND SUPPRESSING FUNCTION OF IMMUNE-PROTECTIVE CELLS. CHRONIC INFLAMMATION IS A RISK FACTOR LINKED TO TC. THE ROLE OF AUTOIMMUNITY HAS BEEN A MATTER OF CONTROVERSY. HOWEVER, THERE IS EPIDEMIOLOGICAL CONNECTION BETWEEN AUTOIMMUNE THYROID DISEASE (AITD) AND TC; PATIENTS WITH AITD SHOW INCREASED INCIDENCE IN PAPILLARY THYROID CARCINOMA (PTC), AND THOSE WITH TC SHOW A HIGH PREVALENCE OF INTRATHYROIDAL LYMPHOCYTE INFILTRATION AND THYROID AUTOANTIBODIES. TIMING AND DURATION-DEPENDENT EXPOSURE TO SPECIFIC ENDOCRINE DISRUPTING CHEMICALS (EDCS) HAS AN IMPACT ON THYROID DEVELOPMENT, FUNCTION, AND PROLIFERATION, LEADING TO THYROID DISEASE AND POTENTIALLY CANCER. THYROID HORMONE IMBALANCE, CHRONIC INFLAMMATION, AND EDCS ARE POTENTIAL RISK FACTORS FOR OXIDATIVE STRESS. OXYGEN FREE RADICALS ARE CAPABLE OF CAUSING DNA DAMAGE VIA STIMULATION OF THE MITOGEN-ACTIVATING PROTEIN KINASE OR PHOSPHATIDYLINOSITOL-3-KINASE AND/OR NUCLEAR FACTOR KB PATHWAYS, RESULTING IN TC-ASSOCIATED GENE MUTATIONS SUCH AS RET/PTC, AKAP9-BRAF, NTRK1, RAASF, PIK3CA, AND PTEN. STRESSFUL EVENTS DURING THE CRITICAL PERIODS OF PRENATAL AND EARLY LIFE CAN INFLUENCE NEUROENDOCRINE REGULATION AND INDUCE EPIGENETIC CHANGES. ABERRANT METHYLATION OF TUMOR SUPPRESSOR GENES SUCH AS P16INK4A, RASSF, AND PTEN IS ASSOCIATED WITH PTC; HISTONE H3 ACETYLATION IS SHOWN TO BE HIGHER IN TC, AND THYROID-SPECIFIC NONCODING RNAS ARE DOWNREGULATED IN PTC. THIS REVIEW FOCUSES ON THE ABOVE PROPOSED MECHANISMS THAT POTENTIALLY LEAD TO THYROID TUMORIGENESIS WITH THE AIM TO HELP IN THE DEVELOPMENT OF NOVEL PROGNOSTIC AND THERAPEUTIC STRATEGIES FOR TC. 2023 6 4475 21 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 7 3250 17 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 8 3263 18 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 9 6797 19 [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 10 6707 17 VIRAL HEPATITIS AND HEPATOCELLULAR CARCINOMA: STATE OF THE ART. VIRAL HEPATITIS IS ONE OF THE MAIN CAUSES LEADING TO HEPATOCELLULAR CARCINOMA (HCC). THE CONTINUED RISE IN INCIDENCE OF HCC SUGGESTS ADDITIONAL FACTORS FOLLOWING INFECTION MAY BE INVOLVED. THIS REVIEW EXAMINES RECENT STUDIES INVESTIGATING THE MOLECULAR MECHANISMS OF CHRONIC HEPATITIS AND ITS ASSOCIATION WITH HEPATOCARCINOGENESIS. HEPATITIS B VIRUS PATIENTS WITH GENOTYPE C DISPLAY AN AGGRESSIVE DISEASE COURSE LEADING TO HCC MORE THAN OTHER GENOTYPES. FURTHERMORE, HEPATITIS B EXCRETORY ANTIGEN (HBEAG) SEEMS TO BE A MORE SENSITIVE PREDICTIVE TUMOR MARKER EXHIBITING A SIX-FOLD HIGHER RELATIVE RISK IN PATIENTS WITH POSITIVE HBSAG AND HBEAG THAN THOSE WITH HBSAG ONLY. SINGLE OR COMBINED MUTATIONS OF VIRAL GENOME CAN PREDICT HCC DEVELOPMENT IN UP TO 80% OF PATIENTS. SEVERAL MUTATIONS IN HBX-GENE ARE RELATED WITH HIGHER HCC INCIDENCE. OVEREXPRESSION OF THE CORE PROTEIN IN HCV LEADS TO HEPATOCELLULAR LIPID ACCUMULATION ASSOCIATED WITH ONCOGENESIS. REDUCED NUMBER AND DECREASED FUNCTIONALITY OF NATURAL KILLER CELLS IN CHRONIC HCV INDIVIDUALS DYSREGULATE THEIR SURVEILLANCE FUNCTION IN TUMOR AND VIRAL CELLS RESULTING IN HCC. FURTHERMORE, HIGH T-CELL IMMUNOGLOBULIN AND MUCIN 3 LEVELS SUPRESS CD8+ T-CELLS, WHICH LEAD TO IMMUNOLOGICAL DYSREGULATION. HEPATITIS D PROMOTES HCC DEVELOPMENT INDIRECTLY VIA MODIFICATIONS TO INNATE IMMUNITY, EPIGENETIC ALTERATIONS AND PRODUCTION OF REACTIVE OXYGEN SPECIES WITH THE LHDAG BEING THE MOST HIGHLY ASSOCIATED WITH HCC DEVELOPMENT. SUMMARIZING THE RESULTS, HBV AND HCV INFECTION REPRESENT THE MOST ASSOCIATED FORMS OF VIRAL HEPATITIS CAUSING HCC. FURTHER STUDIES ARE WARRANTED TO FURTHER IMPROVE THE PREDICTION OF HIGH-RISK PATIENTS AND DEVELOPMENT OF TARGETED THERAPEUTICS PREVENTING THE TRANSITION FROM HEPATIC INFLAMMATION-FIBROSIS TO CANCER. 2021 11 4461 15 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 12 5622 16 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 13 2970 17 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 14 3928 11 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 15 309 14 ALCOHOL AND HEPATOCELLULAR CARCINOMA: ADDING FUEL TO THE FLAME. PRIMARY TUMORS OF THE LIVER REPRESENT THE FIFTH MOST COMMON TYPE OF CANCER IN THE WORLD AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH. CASE-CONTROL STUDIES FROM DIFFERENT COUNTRIES REPORT THAT CHRONIC ETHANOL CONSUMPTION IS ASSOCIATED WITH AN APPROXIMATELY 2-FOLD INCREASED ODDS RATIO FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE THE SUBSTANTIAL EPIDEMIOLOGIC DATA IN HUMANS DEMONSTRATING THAT CHRONIC ALCOHOL CONSUMPTION IS A MAJOR RISK FACTOR FOR HCC DEVELOPMENT, THE PATHWAYS CAUSING ALCOHOL-INDUCED LIVER CANCER ARE POORLY UNDERSTOOD. IN THIS OVERVIEW, WE SUMMARIZE THE EPIDEMIOLOGICAL EVIDENCE FOR THE ASSOCIATION BETWEEN ALCOHOL AND LIVER CANCER, REVIEW THE GENETIC, ONCOGENIC, AND EPIGENETIC FACTORS THAT DRIVE HCC DEVELOPMENT SYNERGISTICALLY WITH ETHANOL INTAKE AND DISCUSS THE ESSENTIAL MOLECULAR AND METABOLIC PATHWAYS INVOLVED IN ALCOHOL-INDUCED LIVER TUMORIGENESIS. 2017 16 3266 17 HEPATOCELLULAR CANCER AND GUT MICROBIOME: TIME TO UNTIE GORDIAN'S KNOT. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE LEADING CAUSES OF CANCER DEATH WORLDWIDE AND THE INCIDENCE IS GROWING ON A GLOBAL SCALE. ABOUT 90% OF CASES DEVELOP ON THE CIRRHOTIC LIVER AND THE ETIOLOGY IS MULTIFACTORIAL. INCREASING NUMBER OF STUDIES SUGGEST THAT GUT MICROBIOTA INFLUENCES THE DEVELOPMENT AND PROGRESSION OF LIVER DISEASES, INCLUDING CHRONIC HEPATIC INFLAMMATION, FIBROSIS, CIRRHOSIS, AND HCC. THE KEY ROLE OF GUT MICROBIOTA IN CARCINOGENESIS SEEMS TO BE ASSOCIATED WITH GENOMIC INSTABILITY OF HOST CELLS AND IMMUNE DYSREGULATION. RECENT CLINICAL STUDIES SHOWED THAT A STABLE AND HEALTHY MICROBIOTA INITIALLY COULD HAVE THE ABILITY TO RESIST THE EMERGENCE OF CHRONIC INFLAMMATION AND, THEREFORE, PREVENT THE INDUCTION OF CARCINOGENIC CELLS IN VARIOUS ORGANS SUCH AS THE ESOPHAGUS, STOMACH, COLON, AND LIVER. THE PROGRESSION FROM INFLAMMATION TO CANCER IS A STEPWISE PROCESS OCCURRING BY THE CONCERTED ACTION OF SEVERAL FACTORS SUCH AS DYSBIOSIS, INCREASED GUT PERMEABILITY, DIET, METABOLOMIC, GENETIC, AND EPIGENETIC CHANGES. IN THIS ARTICLE, WE AIMED TO REVIEW THE POSSIBLE ROLE OF GUT MICROBIOTA IN THE DEVELOPMENT, PROGRESSION, AND TREATMENT OF HCC. 2021 17 3265 16 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018 18 551 21 AUTOIMMUNITY AS AN ETIOLOGICAL FACTOR OF CANCER: THE TRANSFORMATIVE POTENTIAL OF CHRONIC TYPE 2 INFLAMMATION. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND AN ALARMING TREND OF INCREASED CANCER INCIDENCE IN ADULTS YOUNGER THAN 50 YEARS OF AGE AND PROJECTED A SUBSTANTIAL RISE IN CANCER INCIDENCE OVER THE NEXT 10 YEARS IN THIS AGE GROUP. THIS TREND WAS EXEMPLIFIED IN THE INCIDENCE OF NON-CARDIA GASTRIC CANCER AND ITS DISPROPORTIONATE IMPACT ON NON-HISPANIC WHITE FEMALES UNDER THE AGE OF 50. THE TREND IS CONCURRENT WITH THE INCREASING INCIDENCE OF AUTOIMMUNE DISEASES IN INDUSTRIALIZED COUNTRIES, SUGGESTING A CAUSAL LINK BETWEEN THE TWO. WHILE AUTOIMMUNITY HAS BEEN SUSPECTED TO BE A RISK FACTOR FOR SOME CANCERS, THE EXACT MECHANISMS UNDERLYING THE CONNECTION BETWEEN AUTOIMMUNITY AND CANCER REMAIN UNCLEAR AND ARE OFTEN CONTROVERSIAL. THE LINK HAS BEEN ATTRIBUTED TO SEVERAL MEDIATORS SUCH AS IMMUNE SUPPRESSION, INFECTION, DIET, ENVIRONMENT, OR, PERHAPS MOST PLAUSIBLY, CHRONIC INFLAMMATION BECAUSE OF ITS WELL-RECOGNIZED ROLE IN TUMORIGENESIS. IN THAT REGARD, AUTOIMMUNE CONDITIONS ARE COMMON CAUSES OF CHRONIC INFLAMMATION AND MAY TRIGGER REPETITIVE CYCLES OF ANTIGEN-SPECIFIC CELL DAMAGE, TISSUE REGENERATION, AND WOUND HEALING. ILLUSTRATING THE CONNECTION BETWEEN AUTOIMMUNE DISEASES AND CANCER ARE PATIENTS WHO HAVE AN INCREASED RISK OF CANCER DEVELOPMENT ASSOCIATED WITH GENETICALLY PREDISPOSED INSUFFICIENCY OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED PROTEIN 4 (CTLA4), A PROTOTYPICAL IMMUNE CHECKPOINT AGAINST AUTOIMMUNITY AND ONE OF THE MAIN TARGETS OF CANCER IMMUNE THERAPY. THE TUMORIGENIC PROCESS TRIGGERED BY CTLA4 INSUFFICIENCY HAS BEEN SHOWN IN A MOUSE MODEL TO BE DEPENDENT ON THE TYPE 2 CYTOKINES INTERLEUKIN-4 (IL4) AND INTERLEUKIN-13 (IL13). IN THIS TYPE 2 INFLAMMATORY MILIEU, CROSSTALK WITH TYPE 2 IMMUNE CELLS MAY INITIATE EPIGENETIC REPROGRAMMING OF EPITHELIAL CELLS, LEADING TO A METAPLASTIC DIFFERENTIATION AND EVENTUALLY MALIGNANT TRANSFORMATION EVEN IN THE ABSENCE OF CLASSICAL ONCOGENIC MUTATIONS. THOSE FINDINGS COMPLEMENT A LARGE BODY OF EVIDENCE FOR TYPE 1, TYPE 3, OR OTHER INFLAMMATORY MEDIATORS IN INFLAMMATORY TUMORIGENESIS. THIS REVIEW ADDRESSES THE POTENTIAL OF AUTOIMMUNITY AS A CAUSAL FACTOR FOR TUMORIGENESIS, THE UNDERLYING INFLAMMATORY MECHANISMS THAT MAY VARY DEPENDING ON HOST-ENVIRONMENT VARIATIONS, AND IMPLICATIONS TO CANCER PREVENTION AND IMMUNOTHERAPY. 2021 19 2166 19 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 20 5233 17 PROFIBROTIC SIGNALING AND HCC RISK DURING CHRONIC VIRAL HEPATITIS: BIOMARKER DEVELOPMENT. DESPITE BREAKTHROUGHS IN ANTIVIRAL THERAPIES, CHRONIC VIRAL HEPATITIS B AND C ARE STILL THE MAJOR CAUSES OF LIVER FIBROSIS AND HEPATOCELLULAR CARCINOMA (HCC). IMPORTANTLY, EVEN IN PATIENTS WITH CONTROLLED INFECTION OR VIRAL CURE, THE CANCER RISK CANNOT BE FULLY ELIMINATED, HIGHLIGHTING A PERSISTING ONCOGENIC PRESSURE IMPOSED BY EPIGENETIC IMPRINTING AND ADVANCED LIVER DISEASE. RELIABLE AND MINIMALLY INVASIVE BIOMARKERS FOR EARLY FIBROSIS AND FOR RESIDUAL HCC RISK IN HCV-CURED PATIENTS ARE URGENTLY NEEDED. CHRONIC INFECTION WITH HBV AND/OR HCV DYSREGULATES ONCOGENIC AND PROFIBROGENIC SIGNALING WITHIN THE HOST, ALSO DISPLAYED IN THE SECRETION OF SOLUBLE FACTORS TO THE BLOOD. THE STUDY OF VIRUS-DYSREGULATED SIGNALING PATHWAYS MAY, THEREFORE, CONTRIBUTE TO THE IDENTIFICATION OF RELIABLE MINIMALLY INVASIVE BIOMARKERS FOR THE DETECTION OF PATIENTS AT EARLY-STAGE LIVER DISEASE POTENTIALLY COMPLEMENTING EXISTING NONINVASIVE METHODS IN CLINICS. WITH A FOCUS ON VIRUS-INDUCED SIGNALING EVENTS, THIS REVIEW PROVIDES AN OVERVIEW OF CANDIDATE BLOOD BIOMARKERS FOR LIVER DISEASE AND HCC RISK ASSOCIATED WITH CHRONIC VIRAL HEPATITIS AND EPIGENETIC VIRAL FOOTPRINTS. 2021