1 4286 178 MICRORNA EXPRESSION ANALYSIS IN HIGH FAT DIET-INDUCED NAFLD-NASH-HCC PROGRESSION: STUDY ON C57BL/6J MICE. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF THE LIVER. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A FREQUENT CHRONIC LIVER DISORDER IN DEVELOPED COUNTRIES. NAFLD CAN PROGRESS THROUGH THE MORE SEVERE NON ALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS AND, LASTLY, HCC. GENETIC AND EPIGENETIC ALTERATIONS OF CODING GENES AS WELL AS DEREGULATION OF MICRORNAS (MIRNAS) ACTIVITY PLAY A ROLE IN HCC DEVELOPMENT. IN THIS STUDY, THE C57BL/6J MOUSE MODEL WAS LONG TERM HIGH-FAT (HF) OR LOW-FAT (LF) DIET FED, IN ORDER TO ANALYZE MOLECULAR MECHANISMS RESPONSIBLE FOR THE HEPATIC DAMAGE PROGRESSION. METHODS: MICE WERE HF OR LF DIET FED FOR DIFFERENT TIME POINTS, THEN PLASMA AND HEPATIC TISSUES WERE COLLECTED. HISTOLOGICAL AND CLINICAL CHEMISTRY ASSAYS WERE PERFORMED TO ASSESS THE PROGRESSION OF LIVER DISEASE. MICRORNAS' DIFFERENTIAL EXPRESSION WAS EVALUATED ON POOLED RNAS FROM TISSUES, AND SOME MIRNAS SHOWING DYSREGULATION WERE FURTHER ANALYZED AT THE INDIVIDUAL LEVEL. RESULTS: CHOLESTEROL, LOW AND HIGH DENSITY LIPOPROTEINS, TRIGLYCERIDES AND ALANINE AMINOTRANSFERASE INCREASE WAS DETECTED IN HF MICE. GROSS ANATOMICAL EXAMINATION REVEALED HEPATOMEGALY IN HF LIVERS, AND HISTOLOGICAL ANALYSIS HIGHLIGHTED DIFFERENT DEGREES AND LEVELS OF STEATOSIS, INFLAMMATORY INFILTRATE AND FIBROSIS IN HF AND LF ANIMALS, DEMONSTRATING THE PROGRESSION FROM NAFLD THROUGH NASH. MACROSCOPIC NODULES, SHOWING TYPICAL NEOPLASTIC FEATURES, WERE OBSERVED IN 20% OF HF DIET FED MICE. FIFTEEN MIRNAS DIFFERENTIALLY EXPRESSED IN HF WITH RESPECT TO LF HEPATIC TISSUES DURING THE PROGRESSION OF LIVER DAMAGE, AND IN TUMORS WITH RESPECT TO HF NON TUMOR LIVER SPECIMENS WERE IDENTIFIED. AMONG THEM, MIR-340-5P, MIR-484, MIR-574-3P, MIR-720, WHOSE EXPRESSION WAS NEVER DESCRIBED IN NAFLD, NASH AND HCC TISSUES, AND MIR-125A-5P AND MIR-182, WHICH SHOWED EARLY AND SIGNIFICANT DYSREGULATION IN THE SEQUENTIAL HEPATIC DAMAGE PROCESS. CONCLUSIONS: IN THIS STUDY, FIFTEEN MICRORNAS WHICH WERE MODULATED IN HEPATIC TISSUES AND IN TUMORS DURING THE TRANSITION NAFLD-NASH-HCC ARE REPORTED. BESIDES SOME ALREADY DESCRIBED, NEW AND EARLY DYSREGULATED MIRNAS WERE IDENTIFIED. FUNCTIONAL ANALYSES ARE NEEDED TO VALIDATE THE RESULTS HERE OBTAINED, AND TO BETTER DEFINE THE ROLE OF THESE MOLECULES IN THE PROGRESSION OF THE HEPATIC DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                
2 4677  55 NEW LNCRNAS IN CHRONIC HEPATITIS C PROGRESSION: FROM FIBROSIS TO HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH IN THE WORLD, AND ABOUT 80% OF THE CASES ARE ASSOCIATED WITH HEPATITIS B OR C. GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED OVER DECADES OF CHRONIC INJURY AND MAY AFFECT THE FUNCTIONING OF TUMOR SUPPRESSOR GENES AND PROTOONCOGENES. STUDIES HAVE EVIDENCED THE ROLE OF LONG NON-CODING RNAS (LNCRNA) WITH ONCOGENIC OR TUMOR SUPPRESSOR ACTIVITIES, SUGGESTING A GREAT POTENTIAL IN THE TREATMENT, DIAGNOSIS OR INDICATOR OF PROGNOSIS IN CANCER. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO EVALUATE THE GLOBAL EXPRESSION PROFILE LNCRNA IN HEPATIC TISSUE SAMPLES WITH DIFFERENT STAGES OF FIBROSIS ASSOCIATED WITH CHRONIC HEPATITIS C, HCC AND NORMAL LIVER, IN ORDER TO IDENTIFY NEW LNCRNAS THAT COULD CONTRIBUTE TO STUDY THE PROGRESSION OF HEPATIC FIBROSIS TO HCC ASSOCIATED WITH CHRONIC HEPATITIS C. RNA-SEQ WAS PERFORMED ON ILLUMINA NEXTSEQ PLATFORM TO IDENTIFY LNCRNAS EXPRESSED DIFFERENTLY IN 15 PATIENTS WITH CHRONIC HEPATITIS C, THREE PATIENTS WITH HCC AND THREE NORMAL LIVER SPECIMENS. WHEN THE PATHOLOGICAL TISSUES (FIBROSIS AND CARCINOMA) WERE COMPARED TO NORMAL HEPATIC TISSUE, WERE IDENTIFIED 2, 6 E 34 DIFFERENTIALLY EXPRESSED LNCRNAS IN MODERATE FIBROSIS, ADVANCED FIBROSIS AND HCC, RESPECTIVELY. THE CARCINOMA GROUP HAD THE HIGHEST PROPORTION OF DIFFERENTIALLY EXPRESSED LNCRNA (34) AND OF THESE, 29 WERE EXCLUSIVE IN THIS TYPE OF TISSUE. A HEAT MAP OF THE DEREGULATED LNCRNA REVEALED DIFFERENT EXPRESSION PATTERNS ALONG THE PROGRESSION OF FIBROSIS TO HCC. THE RESULTS SHOWED THE DEREGULATION OF SOME LNCRNA ALREADY CLASSIFIED AS TUMOR SUPPRESSORS IN HCC AND OTHER CANCERS, AS WELL AS SOME UNPUBLISHED LNCRNA WHOSE FUNCTION IS UNKNOWN. SOME OF THESE LNCRNAS ARE DYSREGULATED SINCE THE EARLY STAGES OF LIVER INJURY IN PATIENTS WITH HEPATITIS C, OTHERS OVEREXPRESSED ONLY IN TUMOR TISSUE, INDICATING THEMSELVES AS CANDIDATES OF MARKERS OF FIBROSIS PROGRESSION OR TUMOR, WITH POTENTIAL CLINICAL APPLICATIONS IN PROGNOSIS AS WELL AS A THERAPEUTIC TARGET. ALTHOUGH THERE ARE ALREADY STUDIES ON LNCRNA IN HEPATOCELLULAR CARCINOMA, THIS IS THE FIRST STUDY CONDUCTED IN SAMPLES EXCLUSIVELY OF HCV-RELATED LIVER AND HCV HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  413  47 ANALYSIS OF MIRNAS PROFILES IN SERUM OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS EMERGING AS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE, AFFECTING 25% OF THE WORLD POPULATION. IN RECENT YEARS, THERE HAS BEEN INCREASING EVIDENCE FOR THE INVOLVEMENT OF MICRORNAS IN THE EPIGENETIC REGULATION OF GENES TAKING PART IN THE DEVELOPMENT OF STEATOSIS AND STEATOHEPATITIS-TWO MAIN STAGES OF NAFLD PATHOGENESIS. IN THE PRESENT STUDY, MIRNA PROFILES WERE STUDIED IN GROUPS OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS TO COMPARE THE CHARACTERISTICS OF RNA-DEPENDENT EPIGENETIC REGULATION OF THE STAGES OF NAFLD DEVELOPMENT. ACCORDING TO THE RESULTS OF MIRNA SCREENING, 23 MIRNAS WERE DIFFERENTIALLY EXPRESSED SERUM IN A GROUP OF PATIENTS WITH STEATOHEPATITIS AND 2 IN A GROUP OF PATIENTS WITH STEATOSIS. MIR-195-5P AND MIR-16-5P ARE COMMON DIFFERENTIALLY EXPRESSED MIRNAS FOR BOTH STEATOSIS AND STEATOHEPATITIS. WE ANALYZED THE OBTAINED RESULTS: THE SEARCH FOR TARGET GENES FOR THE DIFFERENTIALLY EXPRESSED MIRNAS IN OUR STUDY AND THE SUBSEQUENT GENE SET ENRICHMENT ANALYSIS PERFORMED ON KEGG AND REACTOME DATABASES REVEALED WHICH METABOLIC PATHWAYS UNDERGO CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION IN STEATOSIS AND STEATOHEPATITIS. NEW FINDINGS WITHIN THE FRAMEWORK OF THIS STUDY ARE THE DYSREGULATION OF NEUROHUMORAL PATHWAYS IN THE PATHOGENESIS OF NAFLD AS AN OBJECT OF CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION. THE MIRNAS DIFFERENTIALLY EXPRESSED IN OUR STUDY WERE FOUND TO TARGET 7% OF GENES IN THE CLASSIC PATHOGENESIS OF NAFLD IN THE GROUP OF PATIENTS WITH STEATOSIS AND 50% IN THE GROUP OF PATIENTS WITH STEATOHEPATITIS. THE EFFECTS OF THESE MICRORNAS ON GENES FOR THE PATHOGENESIS OF NAFLD WERE ANALYZED IN DETAIL. MIR-374A-5P, MIR-1-3P AND MIR-23A-3P DO NOT TARGET GENES DIRECTLY INVOLVED IN THE PATHOGENESIS OF NAFLD. THE DIFFERENTIALLY EXPRESSED MIRNAS FOUND IN THIS STUDY TARGET GENES LARGELY RESPONSIBLE FOR MITOCHONDRIAL FUNCTION. THE ROLE OF MIR-423-5P, MIR-143-5P AND MIR-200C-3 IN REGULATING APOPTOTIC PROCESSES IN THE LIVER AND HEPATOCARCINOGENESIS IS OF INTEREST FOR FUTURE EXPERIMENTAL STUDIES. THESE MIR-374A, MIR-143, MIR-1, MIR-23A, AND MIR-423 HAVE POTENTIAL FOR STEATOHEPATITIS DIAGNOSIS AND ARE POORLY STUDIED IN THE CONTEXT OF NAFLD. THUS, THIS WORK OPENS UP PROSPECTS FOR FURTHER STUDIES OF MICRORNAS AS DIAGNOSTIC AND THERAPEUTIC BIOMARKERS FOR NAFLD.	2021	
                                                                                                                                                                                                                                                                                                       
4 1666  57 DOWNREGULATION OF MICRORNA-145A-5P PROMOTES STEATOSIS-TO-NASH PROGRESSION THROUGH UPREGULATION OF NR4A2. BACKGROUND & AIMS: THE MOLECULAR MECHANISMS UNDERLYING THE PROGRESSION OF SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH) REMAIN INCOMPLETELY UNDERSTOOD, THOUGH THE POTENTIAL ROLE OF EPIGENETIC REGULATION BY MICRORNA (MIRNAS) IS AN AREA OF INCREASING INTEREST. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ROLE AND MECHANISM OF MIRNAS DURING STEATOSIS-TO-NASH PROGRESSION. METHODS: MIR-145A-5P WAS IDENTIFIED AS AN IMPORTANT CHECKPOINT IN STEATOSIS-TO-NASH PROGRESSION. IN VIVO LOSS-OF-FUNCTION AND GAIN-OF-FUNCTION STUDIES WERE PERFORMED TO EXPLORE THE ROLE OF MIR-145A-5P AND NR4A2 IN NASH PROGRESSION. RNA-SEQUENCING AND BIOINFORMATIC ANALYSIS WERE USED TO INVESTIGATE THE TARGETS OF MIR-145A-5P. RESULTS: SUPPRESSION OF MIR-145A-5P IN THE LIVER AGGRAVATED LIPID ACCUMULATION AND ACTIVATED HEPATIC INFLAMMATION, LIVER INJURY AND FIBROSIS IN STEATOTIC MICE, WHEREAS ITS RESTORATION MARKEDLY ATTENUATED DIET-INDUCED NASH PATHOGENESIS. MECHANISTICALLY, MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 AND THUS INHIBIT THE EXPRESSION OF NASH-ASSOCIATED GENES. SIMILARLY, NR4A2 OVEREXPRESSION PROMOTED STEATOSIS-TO-NASH PROGRESSION WHILE LIVER-SPECIFIC NR4A2 KNOCKOUT MICE WERE PROTECTED FROM DIET-INDUCED NASH. THIS ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS WAS ALSO CONFIRMED IN PRIMARY HUMAN HEPATOCYTES. FURTHERMORE, THE EXPRESSION OF MIR-145A-5P WAS REDUCED AND THE EXPRESSION OF NR4A2 WAS INCREASED IN THE LIVERS OF PATIENTS WITH NASH, WHILE THEIR EXPRESSION LEVELS SIGNIFICANTLY NEGATIVELY AND POSITIVELY CORRELATED WITH FEATURES OF LIVER PATHOLOGY, RESPECTIVELY. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS IN STEATOSIS-TO-NASH PROGRESSION, SUGGESTING THAT EITHER SUPPLEMENTATION OF MIR-145A-5P OR PHARMACOLOGICAL INHIBITION OF NR4A2 IN HEPATOCYTES MAY PROVIDE A PROMISING THERAPEUTIC APPROACH FOR THE TREATMENT OF NASH. IMPACT AND IMPLICATIONS: NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A DYNAMIC SPECTRUM OF CHRONIC LIVER DISEASES RANGING FROM SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH). UNFORTUNATELY, THERE ARE CURRENTLY NO APPROVED DRUGS FOR NASH. OUR CURRENT STUDY IDENTIFIED MIR-145A-5P AS A NOVEL REGULATOR THAT INHIBITS STEATOSIS-TO-NASH PROGRESSION. WE FOUND THAT MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 TO SUPPRESS THE EXPRESSION OF NASH-ASSOCIATED GENES. THE DIFFERENTIAL EXPRESSION OF MIR-145A-5P AND NR4A2 WAS FURTHER CONFIRMED IN PATIENTS WITH NASH, RAISING THE POSSIBILITY THAT SUPPLEMENTATION OF MIR-145A-5P OR SUPPRESSION OF NR4A2 IN HEPATOCYTES MIGHT PROVIDE NOVEL STRATEGIES FOR TREATING NASH.	2023	

5 5438  35 REMOVAL OF EPIGENETIC REPRESSIVE MARK ON INFLAMMATORY GENES IN FAT LIVER. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE. THE DETAILED EPIGENOMIC CHANGES DURING FAT ACCUMULATION IN LIVER ARE NOT CLEAR YET. HERE, WE PERFORMED CHIP-SEQ ANALYSIS IN THE LIVER TISSUES OF HIGH-FAT DIET AND REGULAR CHOW DIET MICE AND INVESTIGATED THE DYNAMIC LANDSCAPES OF H3K27AC AND H3K9ME3 MARKS ON CHROMATIN. WE FIND THAT THE ACTIVATED TYPICAL ENHANCERS MARKED WITH H3K27AC ARE ENRICHED ON LIPID METABOLIC PATHWAYS IN FAT LIVER; HOWEVER, SUPER ENHANCERS DO NOT CHANGE MUCH. THE REGIONS COVERED WITH H3K9ME3 REPRESSIVE MARK SEEM TO UNDERGO GREAT CHANGES, AND ITS PEAK NUMBER AND INTENSITY BOTH DECREASE IN FAT LIVER. THE ENHANCERS LOCATED IN LOST H3K9ME3 REGIONS ARE ENRICHED IN LIPID METABOLISM AND INFLAMMATORY PATHWAYS; AND MOTIF ANALYSIS SHOWS THAT THEY ARE POTENTIAL TARGETS FOR TRANSCRIPTION FACTORS INVOLVED IN METABOLIC AND INFLAMMATORY PROCESSES. OUR STUDY HAS REVEALED THAT H3K9ME3 MAY PLAY AN IMPORTANT ROLE DURING THE PATHOGENESIS OF NAFLD THROUGH REGULATING THE ACCESSIBILITY OF ENHANCERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  332  44 ALTERATION OF EPIGENETIC PROFILE IN HUMAN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL IMPLICATIONS. HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON CANCER WORLDWIDE AND DEVELOPS AGAINST A BACKGROUND OF CHRONIC LIVER DAMAGE. A VARIETY OF HCC-RELATED GENES ARE KNOWN TO BE ALTERED BY GENETIC AND EPIGENETIC MECHANISMS. THEREFORE, INFORMATION REGARDING ALTERATION OF THE GENETIC AND EPIGENETIC PROFILES IN HCC IS ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF THIS TYPE OF TUMOR. METHYLATION AT CPG SITES IN GENE PROMOTERS IS KNOWN TO AFFECT THE TRANSCRIPTION OF THE CORRESPONDING GENES. ABNORMAL REGIONAL HYPERMETHYLATION IS OBSERVED IN THE 5' REGION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) IN HCC, AND THIS HYPERMETHYLATION MAY PROMOTE CARCINOGENESIS THROUGH THE TRANSCRIPTIONAL INACTIVATION OF DOWNSTREAM TSGS. THE DNA DAMAGE INDUCED BY OXIDATION IS A TRIGGER OF ABNORMAL DNA METHYLATION AND INACTIVATION OF TSGS THROUGH RECRUITMENT OF THE POLYCOMB REPRESSIVE COMPLEX TO THE PROMOTER SEQUENCE. THUS, OXIDATIVE STRESS MAY BE RESPONSIBLE FOR THE EMERGENCE OF HCC FROM CHRONIC HEPATITIS AND LIVER CIRRHOSIS THROUGH THE EPIGENETIC ALTERATION OF TSGS. THERE HAVE BEEN SEVERAL ATTEMPTS TO APPLY EPIGENETIC INFORMATION TO THE DIAGNOSIS AND TREATMENT OF HCC. THE PREDICTIVE VALUE OF SELECTED METHYLATION EVENTS ON SURVIVAL IN HCC PATIENTS HAS BEEN REPORTED, AND THE METHYLATION PROFILE OF BACKGROUND LIVER COULD BE ASSOCIATED WITH RECURRENCE-FREE SURVIVAL OF HCC PATIENTS WHO HAVE UNDERGONE HEPATECTOMY. ANOTHER STUDY DETECTED METHYLATED DNA FROM HCC CELLS IN SERUM, AND THE CIRCULATING TUMOR DNA WAS REGARDED AS A POTENTIAL TUMOR MARKER. IN ADDITION, SEVERAL TRIALS OF HCC THERAPY HAVE TARGETED THE EPIGENETIC MACHINERY AND WERE BASED UPON COMPREHENSIVE ANALYSES OF DNA METHYLATION OF THIS TYPE OF TUMOR. HERE, WE PRESENT AN OVERVIEW OF RESEARCH REGARDING DNA METHYLATION STATUS IN HUMAN HCC AND DESCRIBE THE CLINICAL APPLICATION OF EPIGENETIC INFORMATION TO HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7 1128  41 COMPREHENSIVE ANALYSIS OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION IN HUMAN NAFLD. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A MULTIFACTORIAL CONDITION WITH A COMPLEX ETIOLOGY. ITS INCIDENCE IS INCREASING GLOBALLY IN PARALLEL WITH THE OBESITY EPIDEMIC, AND IT IS NOW CONSIDERED THE MOST COMMON LIVER DISEASE IN WESTERN COUNTRIES. THE PRECISE MECHANISMS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF NAFLD ARE COMPLEX AND STILL POORLY UNDERSTOOD. THE DYSREGULATION OF EPIGENETIC AND EPITRANSCRIPTOMIC MECHANISMS IS INCREASINGLY RECOGNIZED TO PLAY PATHOGENIC ROLES IN MULTIPLE CONDITIONS, INCLUDING CHRONIC LIVER DISEASES. HERE, WE HAVE PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES IN A TOTAL OF 903 LIVER TISSUE SAMPLES CORRESPONDING TO PATIENTS WITH NORMAL LIVER, OBESE PATIENTS, AND PATIENTS WITH NON-ALCOHOLIC FATTY LIVER (NAFL) AND NON-ALCOHOLIC STEATOHEPATITIS (NASH), ADVANCING STAGES IN NAFLD PROGRESSION. WE INTEGRATED TEN TRANSCRIPTOMIC DATASETS IN AN UNBIASED MANNER, ENABLING THEIR ROBUST ANALYSIS AND COMPARISON. WE DESCRIBE THE COMPLETE LANDSCAPE OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION ALONG THE COURSE OF THE DISEASE. WE IDENTIFY SIGNATURES OF GENES SIGNIFICANTLY DYSREGULATED IN ASSOCIATION WITH DISEASE PROGRESSION, PARTICULARLY WITH LIVER FIBROSIS DEVELOPMENT. MOST OF THESE EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS HAVE NOT BEEN PREVIOUSLY DESCRIBED IN HUMAN NAFLD, AND THEIR ALTERED EXPRESSION MAY HAVE PATHOGENIC IMPLICATIONS. WE ALSO PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF ENZYMES INVOLVED IN THE METABOLISM OF THE SUBSTRATES AND COFACTORS OF EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS. THIS STUDY PROVIDES NOVEL INFORMATION ON NAFLD PATHOGENESIS AND MAY ALSO GUIDE THE IDENTIFICATION OF DRUG TARGETS TO TREAT THIS CONDITION AND ITS PROGRESSION TOWARDS HEPATOCELLULAR CARCINOMA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 6092  45 THE EFFECTS OF EPIGENETIC MODIFICATION ON THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES AND THE INVOLVED MECHANISM. INTRODUCTION: EPIGENETIC MODIFICATION IS A TYPE OF GENE EXPRESSION AND REGULATION THAT DOES NOT INVOLVE CHANGES IN DNA SEQUENCES. AN INCREASING NUMBER OF STUDIES HAVE PROVEN THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES THROUGH THE GENE REGULATION AND PROTEIN EXPRESSIONS OF HEPATOCELLULAR LIPID METABOLISM, INFLAMMATORY REACTION, CELL PROLIFERATION, AND ACTIVATION, ETC.AREAS COVERED: IN THIS STUDY, WE ELABORATED AND ANALYZED THE UNDERLYING FUNCTIONAL MECHANISM OF EPIGENETIC MODIFICATION IN ALCOHOLIC LIVER DISEASE (ALD), NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), LIVER FIBROSIS (LF), VIRAL HEPATITIS, HEPATOCELLULAR CARCINOMA (HCC), AND RESEARCH PROGRESS OF RECENT YEARS.EXPERT OPINION: THE FURTHER UNDERSTANDING OF EPIGENETIC MECHANISMS THAT CAN REGULATE GENE EXPRESSION AND CELL PHENOTYPE LEADS TO NEW INSIGHTS IN EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE. CURRENTLY, HEPATOLOGISTS ARE EXPLORING THE ROLE OF DNA METHYLATION, HISTONE/CHROMATIN MODIFICATION, AND NON-CODING RNA IN SPECIFIC LIVER PATHOLOGY. THESE FINDINGS HAVE LED TO ADVANCES IN DIRECT EPIGENETIC BIOMARKER TESTING OF PATIENT TISSUE OR BODY FLUID SPECIMENS, AS WELL AS QUANTITATIVE ANALYSIS. BASED ON THESE FINDINGS, DRUG VALIDATION OF SOME TARGETS INVOLVED IN THE EPIGENETIC MECHANISM OF LIVER DISEASE IS GRADUALLY BEING CARRIED OUT CLINICALLY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 3567  37 IMPACT OF HEPATITIS VIRUS AND AGING ON DNA METHYLATION IN HUMAN HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) USUALLY DEVELOPS ON THE BASIS OF CHRONIC HEPATITIS AND LIVER CIRRHOSIS, WHERE INACTIVATION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) TAKES PLACE VIA METHYLATION OF THE PROMOTER. INTERESTINGLY, THESE METHYLATION EVENTS ARE MORE PREVALENT IN A BACKGROUND LIVER AT HIGH RISK OF HCC THAN ONE AT LOW RISK. ABNORMAL METHYLATION IS ALSO OBSERVED IN PRECANCEROUS NODULES SUCH AS DYSPLASTIC NODULES AND ADENOMAS, SUGGESTING THAT EPIGENETIC ALTERATION IS AN EARLY EVENT FOR HCC CARCINOGENESIS. IT IS POSSIBLE THAT INFECTION WITH THE HEPATITIS VIRUS INDUCES ALTERATION OF METHYLATION AT PROMOTERS OF TSGS. SOME STUDIES SUGGESTED THAT VIRAL PROTEINS INTERFERE WITH DNA METHYLTRANSFERASE IN CHRONIC HEPATITIS B. INDUCTION OF EPIGENETIC ALTERATION IN CHRONIC HEPATITIS C MIGHT, HOWEVER, MIGHT BE A CONSEQUENCE OF OXIDATIVE STRESS. IN ADDITION, WE PROPOSED AGE SHOULD BE TAKEN INTO CONSIDERATION FOR HCC DEVELOPMENT VIA EPIGENETIC PATHWAYS. FURTHER INVESTIGATIONS ARE REQUIRED TO UNDERSTAND THE MECHANISM OF INDUCING EPIGENETIC INSTABILITY DURING HEPATOCARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10 5622  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 5921  41 TARGETING CLINICAL EPIGENETIC REPROGRAMMING FOR CHEMOPREVENTION OF METABOLIC AND VIRAL HEPATOCELLULAR CARCINOMA. OBJECTIVE: HEPATOCELLULAR CARCINOMA (HCC) IS THE FASTEST-GROWING CAUSE OF CANCER-RELATED MORTALITY WITH CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) AS MAJOR AETIOLOGIES. TREATMENT OPTIONS FOR HCC ARE UNSATISFACTORY AND CHEMOPREVENTIVE APPROACHES ARE ABSENT. CHRONIC HEPATITIS C (CHC) RESULTS IN EPIGENETIC ALTERATIONS DRIVING HCC RISK AND PERSISTING FOLLOWING CURE. HERE, WE AIMED TO INVESTIGATE EPIGENETIC MODIFICATIONS AS TARGETS FOR LIVER CANCER CHEMOPREVENTION. DESIGN: LIVER TISSUES FROM PATIENTS WITH NASH AND CHC WERE ANALYSED BY CHIP-SEQ (H3K27AC) AND RNA-SEQ. THE LIVER DISEASE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL REPROGRAMMING IN PATIENTS WAS MODELLED IN A LIVER CELL CULTURE SYSTEM. PERTURBATION STUDIES COMBINED WITH A TARGETED SMALL MOLECULE SCREEN FOLLOWED BY IN VIVO AND EX VIVO VALIDATION WERE USED TO IDENTIFY CHROMATIN MODIFIERS AND READERS FOR HCC CHEMOPREVENTION. RESULTS: IN PATIENTS, CHC AND NASH SHARE SIMILAR EPIGENETIC AND TRANSCRIPTOMIC MODIFICATIONS DRIVING CANCER RISK. USING A CELL-BASED SYSTEM MODELLING EPIGENETIC MODIFICATIONS IN PATIENTS, WE IDENTIFIED CHROMATIN READERS AS TARGETS TO REVERT LIVER GENE TRANSCRIPTION DRIVING CLINICAL HCC RISK. PROOF-OF-CONCEPT STUDIES IN A NASH-HCC MOUSE MODEL SHOWED THAT THE PHARMACOLOGICAL INHIBITION OF CHROMATIN READER BROMODOMAIN 4 INHIBITED LIVER DISEASE PROGRESSION AND HEPATOCARCINOGENESIS BY RESTORING TRANSCRIPTIONAL REPROGRAMMING OF THE GENES THAT WERE EPIGENETICALLY ALTERED IN PATIENTS. CONCLUSION: OUR RESULTS UNRAVEL THE FUNCTIONAL RELEVANCE OF METABOLIC AND VIRUS-INDUCED EPIGENETIC ALTERATIONS FOR PATHOGENESIS OF HCC DEVELOPMENT AND IDENTIFY CHROMATIN READERS AS TARGETS FOR CHEMOPREVENTION IN PATIENTS WITH CHRONIC LIVER DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 6723  38 VITAMIN D RECEPTOR GENE METHYLATION IN HEPATOCELLULAR CARCINOMA. WORLDWIDE, HEPATOCELLULAR CARCINOMA (HCC) IS THE MAJOR SUBTYPE OF PRIMARY LIVER CANCERS. HCC IS TYPICALLY DIAGNOSED LATE IN ITS COURSE. WITH RESPECT TO CANCER, THE GENOMIC ACTIONS OF VITAMIN D ARE MEDIATED THROUGH BINDING TO THE VITAMIN D RECEPTOR (VDR), WHICH ALLOWS IT TO MODULATE THE EXPRESSION OF GENES IN A CELL-AND TISSUE-SPECIFIC MANNER. EPIGENETICS IS A RAPIDLY EVOLVING FIELD OF GENETIC STUDY APPLICABLE TO HCC. CHANGES IN DNA METHYLATION PATTERNS ARE THOUGHT TO BE EARLY EVENTS IN HEPATOCARCINOGENESIS. CURCUMIN HAS GREAT POTENTIAL AS AN EPIGENETIC AGENT. ACCORDINGLY, THE CURRENT STUDY HAS BEEN DESIGNED TO STUDY THE METHYLATION STATUS OF VDR GENE PROMOTER FOR THE FIRST TIME IN HCC AIMING TO FIND ITS CLINICAL SIGNIFICANCE AND POTENTIAL SCREENING ROLE IN CHRONIC LIVER DISEASE (CLD). ADDITIONALLY, WE AIMED TO INVESTIGATE, THE EFFECT OF CURCUMIN ON HCC CELL LINE, AIMING TO DISCOVER NEW THERAPEUTIC TARGETS THROUGH EPIGENETICS. THIS STUDY WAS CONDUCTED ON 45 FORMALIN-FIXED, PARAFFIN-EMBEDDED LIVER TISSUE BLOCKS INCLUDING 15 HCC SAMPLES (GROUP A), 15 CLD SAMPLES (GROUP B) AND 15 APPARENTLY NORMAL TISSUE TAKEN FROM AROUND BENIGN LESIONS (GROUP C). METHYLATION SPECIFIC RESTRICTION DIGESTION AND QPCR WERE DONE ON ALL SAMPLES AFTER DNA EXTRACTION. THE PERCENTAGE OF VDR GENE PROMOTER METHYLATION WAS SIGNIFICANTLY HIGHER IN THE HCC GROUP COMPARED TO BOTH CLD AND CONTROL GROUPS (P < 0.01). VDR PROMOTER METHYLATION BY (MS-QPCR) WAS DECREASED AND THE RELATIVE EXPRESSION OF VDR BY (QRT-PCR) WAS MARKEDLY INCREASED IN A DOSE-DEPENDENT FASHION IN CELLS GROWN IN CURCUMIN-ADEQUATE MEDIUM. IN CONCLUSION, THIS STUDY MAY OPEN A NEW GATE FOR THE USE OF VDR PROMOTER METHYLATION AS A POTENTIAL BIOMARKER IN HCC.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 3292  44 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14 2780  40 EZH2 DOWN-REGULATION EXACERBATES LIPID ACCUMULATION AND INFLAMMATION IN IN VITRO AND IN VIVO NAFLD. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST PREVALENT, CHRONIC LIVER DISEASES, WORLDWIDE. IT IS A MULTIFACTORIAL DISEASE CAUSED BY COMPLEX INTERACTIONS BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. RECENTLY, SEVERAL MICRORNAS, SOME OF WHICH EPIGENETICALLY REGULATED, HAVE BEEN FOUND TO BE UP- AND/OR DOWN-REGULATED DURING NAFLD DEVELOPMENT. HOWEVER, IN NAFLD, THE ESSENTIAL ROLE OF THE POLYCOMB GROUP PROTEIN ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CONTROLS THE EPIGENETIC SILENCING OF SPECIFIC GENES AND/OR MICRORNAS BY TRIMETHYLATING LYS27 ON HISTONE H3, STILL REMAINS UNKNOWN. IN THIS STUDY, WE DEMONSTRATE THAT THE NUCLEAR EXPRESSION/ACTIVITY OF THE EZH2 PROTEIN IS DOWN-REGULATED BOTH IN LIVERS FROM NAFLD RATS AND IN THE FREE FATTY ACID-TREATED HEPG2. THE DROP IN EZH2 IS INVERSELY CORRELATED WITH: (I) LIPID ACCUMULATION; (II) THE EXPRESSION OF PRO-INFLAMMATORY MARKERS INCLUDING TNF-ALPHA AND TGF-BETA; AND (III) THE EXPRESSION OF MIR-200B AND MIR-155. CONSISTENTLY, THE PHARMACOLOGICAL INHIBITION OF EZH2 BY 3-DEAZANEPLANOCIN A (DZNEP) SIGNIFICANTLY REDUCES EZH2 EXPRESSION/ACTIVITY, WHILE IT INCREASES LIPID ACCUMULATION, INFLAMMATORY MOLECULES AND MICRORNAS. IN CONCLUSION, THE RESULTS OF THIS STUDY SUGGEST THAT THE DEFECTIVE ACTIVITY OF EZH2 CAN ENHANCE THE NAFLD DEVELOPMENT BY FAVOURING STEATOSIS AND THE DE-REPRESSION OF THE INFLAMMATORY GENES AND THAT OF SPECIFIC MICRORNAS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 2104  38 EPIGENETIC EVENTS IN LIVER CANCER RESULTING FROM ALCOHOLIC LIVER DISEASE. EPIGENETIC MECHANISMS PLAY AN EXTENSIVE ROLE IN THE DEVELOPMENT OF LIVER CANCER (I.E., HEPATOCELLULAR CARCINOMA [HCC]) ASSOCIATED WITH ALCOHOLIC LIVER DISEASE (ALD) AS WELL AS IN LIVER DISEASE ASSOCIATED WITH OTHER CONDITIONS. FOR EXAMPLE, EPIGENETIC MECHANISMS, SUCH AS CHANGES IN THE METHYLATION AND/OR ACETYLATION PATTERN OF CERTAIN DNA REGIONS OR OF THE HISTONE PROTEINS AROUND WHICH THE DNA IS WRAPPED, CONTRIBUTE TO THE REVERSION OF NORMAL LIVER CELLS INTO PROGENITOR AND STEM CELLS THAT CAN DEVELOP INTO HCC. CHRONIC EXPOSURE TO BEVERAGE ALCOHOL (I.E., ETHANOL) CAN INDUCE ALL OF THESE EPIGENETIC CHANGES. THUS, ETHANOL METABOLISM RESULTS IN THE FORMATION OF COMPOUNDS THAT CAN CAUSE CHANGES IN DNA METHYLATION AND INTERFERE WITH OTHER COMPONENTS OF THE NORMAL PROCESSES REGULATING DNA METHYLATION. ALCOHOL EXPOSURE ALSO CAN ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION PATTERNS THROUGH A VARIETY OF MECHANISMS AND SIGNALING PATHWAYS. ALCOHOL ALSO ACTS INDIRECTLY ON ANOTHER MOLECULE CALLED TOLL-LIKE RECEPTOR 4 (TLR4) THAT IS A KEY COMPONENT IN A CRUCIAL REGULATORY PATHWAY IN THE CELLS AND WHOSE DYSREGULATION IS INVOLVED IN THE DEVELOPMENT OF HCC. FINALLY, ALCOHOL USE REGULATES AN EPIGENETIC MECHANISM INVOLVING SMALL MOLECULES CALLED MIRNAS THAT CONTROL TRANSCRIPTIONAL EVENTS AND THE EXPRESSION OF GENES IMPORTANT TO ALD.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 3241  44 HEPATIC MICRORNA MODULATION MIGHT BE AN EARLY EVENT TO NON-ALCOHOLIC FATTY LIVER DISEASE DEVELOPMENT DRIVEN BY HIGH-FAT DIET IN MALE MICE. INTRODUCTION: METABOLIC ALTERATIONS CAUSED BY AN IMBALANCE OF MACRONUTRIENT CONSUMPTION ARE OFTEN RELATED TO THE MODULATION OF MICRORNAS (MIRNAS), WHICH COULD ALTER MRNAS EXPRESSION PROFILE AND ACCELERATE THE DEVELOPMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). AIMS: THIS STUDY AIMED TO INVESTIGATE THE CONTRIBUTION OF MIRNAS IN MODULATING EARLY STAGES OF NAFLD IN MICE SUBMITTED TO A HIGH-FAT DIET (HFD). METHODS AND RESULTS: MALE SWISS MICE, FED EITHER A CONTROL DIET OR AN HFD FOR 1, 3, 7, 15, 30, 56 DAYS, WERE ASSESSED FOR METABOLIC ALTERATIONS, GENE EXPRESSION AND NAFLD MARKERS. A HEPATOCYTE CELL LINE WAS USED TO INVESTIGATE THE EFFECTS OF MIR-370 MODULATION ON ENZYMES INVOLVED IN BETA-OXIDATION. BODY WEIGHT AND ADIPOSITY WERE HIGHER AFTER 7 DAYS OF HFD. FASTING GLUCOSE AND INSULIN INCREASED AFTER 3 AND 7 DAYS OF HFD, RESPECTIVELY. WHILE HEPATIC LIPID CONTENT INCREASED FROM THE FIRST DAY ON, HEPATIC GLYCOGEN HAD A DECREASE AFTER 3 DAYS OF HFD CONSUMPTION. MIR-370 AND LET-7 EXPRESSION INCREASED WITH ACUTE AND CHRONIC EXPOSURE TO HFD, ACCOMPANIED BY CARNITINE PALMITOYLTRANSFERASE 1A (CPT1A), ACYL-COA DEHYDROGENASE VERY LONG CHAIN (ACADVL) AND PROTEIN KINASE AMP-ACTIVATED CATALYTIC SUBUNIT 2 (PRKAA2) DOWNREGULATION, WHILE DECREASED MIR-122 EXPRESSION WAS ACCOMPANIED BY 1-ACYLGLYCEROL-3-PHOSPHATE-O-ACYLTRANSFERASE (AGPAT) UPREGULATION AFTER 56 DAYS OF HFD CONSUMPTION, SOME OF THEM CONFIRMED BY IN VITRO EXPERIMENTS. DESPITE FLUCTUATIONS IN TNFA AND IL6 MRNA LEVELS, MOLECULAR MODULATION WAS CONSISTENT WITH HEPATIC TG AND NAFLD DEVELOPMENT. CONCLUSION: HEPATIC MIR-370-122-LET7 MIRNA MODULATION COULD BE THE FIRST INSULT TO NAFLD DEVELOPMENT, PRECEDING CHANGES IN GLYCEMIC HOMEOSTASIS AND ADIPOSITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 1615  37 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18 5770  31 SPECIFIC MOLECULAR SIGNATURES OF NON-TUMOR LIVER TISSUE MAY PREDICT A RISK OF HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON HUMAN CANCERS AND A MAJOR CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE BLEAK OUTCOMES OF HCC PATIENTS EVEN AFTER CURATIVE TREATMENT HAVE BEEN, AT LEAST PARTIALLY, ATTRIBUTED TO ITS MULTICENTRIC ORIGIN. THEREFORE, IT IS NECESSARY TO EXAMINE NOT ONLY TUMOR TISSUE BUT ALSO NON-TUMOR LIVER TISSUE TO INVESTIGATE THE MOLECULAR MECHANISMS OPERATING DURING HEPATOCARCINOGENESIS BASED ON THE CONCEPT OF "FIELD CANCERIZATION". SEVERAL STUDIES PREVIOUSLY INVESTIGATED THE ASSOCIATION OF MOLECULAR ALTERATIONS IN NON-TUMOR LIVER TISSUE WITH CLINICAL FEATURES AND PROGNOSIS IN HCC PATIENTS ON A GENOME-WIDE SCALE. IN PARTICULAR, SPECIFIC ALTERATIONS OF DNA METHYLATION PROFILES HAVE BEEN CONFIRMED IN NON-TUMOR LIVER TISSUE. THIS REVIEW FOCUSES ON THE POSSIBLE CLINICAL VALUE OF ARRAY-BASED COMPREHENSIVE ANALYSES OF MOLECULAR ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IN NON-TUMOR LIVER TISSUE TO CLARIFY THE RISK OF HEPATOCARCINOGENESIS. CARCINOGENETIC RISK ESTIMATION BASED ON SPECIFIC METHYLATION SIGNATURES MAY BE ADVANTAGEOUS FOR CLOSE FOLLOW-UP OF PATIENTS WHO ARE AT HIGH RISK OF HCC DEVELOPMENT. FURTHERMORE, EPIGENETIC THERAPIES FOR PATIENTS WITH CHRONIC LIVER DISEASES MAY BE HELPFUL TO REDUCE THE RISK OF HCC DEVELOPMENT BECAUSE EPIGENETIC ALTERATIONS ARE POTENTIALLY REVERSIBLE, AND THUS PROVIDE PROMISING MOLECULAR TARGETS FOR THERAPEUTIC INTERVENTION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19 2682  40 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 5360  39 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY.	2013