1   42 128 A COMPREHENSIVE GENOME-WIDE PROFILING COMPARISON BETWEEN HBV AND HCV INFECTED HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS WORLDWIDE, ESPECIALLY IN EAST ASIA. EVEN WITH THE PROGRESS IN THERAPY, 5-YEAR SURVIVAL RATES REMAIN UNSATISFIED. CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) HAS BEEN EPIDEMIOLOGICALLY ASSOCIATED WITH HCC AND IS THE MAJOR ETIOLOGY IN THE EAST ASIAN POPULATION. THE DETAILED MECHANISM, ESPECIALLY THE CHANGES OF DNA METHYLATION AND GENE EXPRESSION BETWEEN THE TWO TYPES OF VIRUS-RELATED HCC, AND THEIR CONTRIBUTIONS TO THE HCC DEVELOPMENT, METASTASIS, AND RECURRENCE REMAIN LARGELY UNKNOWN. METHODS: IN THIS INTEGRATED ANALYSIS, WE CHARACTERIZED GENOME-SCALE PROFILES OF HBV AND HCV INFECTED HCC BY COMPARING THEIR GENE EXPRESSION PATTERN, METHYLATION PROFILES, AND COPY NUMBER VARIATIONS FROM THE PUBLICLY ACCESSIBLE DATA OF THE CANCER GENOME ATLAS PROGRAM (TCGA). RESULTS: THE HLA-A, STAT1, AND OAS2 GENES WERE HIGHLY ENRICHED AND UP-REGULATED DISCOVERED IN THE HCV-INFECTED HCC. HYPOMETHYLATION BUT NOT COPY NUMBER VARIATIONS MIGHT BE THE MAJOR FACTOR FOR THE UP-REGULATION OF THESE IMMUNE-RELATED GENES IN HCV-INFECTED HCC. CONCLUSIONS: THE RESULTS INDICATED THE DIFFERENT EPIGENETIC CHANGES OF HBV/HCV RELATED HEPATOCARCINOGENESIS. THE TOP UP-REGULATED GENES IN HCV GROUP WERE SIGNIFICANTLY CLUSTERED IN THE IMMUNE-RELATED AND DEFENSE RESPONSE PATHWAYS. THESE FINDINGS WILL HELP US TO UNDERSTAND THE PATHOGENESIS OF HBV/HCV ASSOCIATED HEPATOCELLULAR CARCINOMA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 2172  41 EPIGENETIC MECHANISMS INVOLVED IN HCV-INDUCED HEPATOCELLULAR CARCINOMA (HCC). HEPATOCELLULAR CARCINOMA (HCC), IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS, WHICH IS LARGELY CAUSED BY VIRUS INFECTION. ABOUT 80% OF THE VIRUS-INFECTED PEOPLE DEVELOP A CHRONIC INFECTION THAT EVENTUALLY LEADS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). WITH APPROXIMATELY 71 MILLION HCV CHRONIC INFECTED PATIENTS WORLDWIDE, THEY STILL HAVE A HIGH RISK OF HCC IN THE NEAR FUTURE. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES. HEPATITIS C VIRUS (HCV) INFECTION LARGELY CAUSES HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE WITH 3 TO 4 MILLION NEWLY INFECTED CASES DIAGNOSED EACH YEAR. IT IS URGENT TO EXPLORE ITS UNDERLYING MOLECULAR MECHANISMS FOR THERAPEUTIC TREATMENT AND BIOMARKER DISCOVERY. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                             
3 4677  34 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	
                                                                                                                                                                                                                                  
4 3567  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 5360  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  332  42 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 4920  40 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 5761  48 SOMATIC MUTATIONS, VIRAL INTEGRATION AND EPIGENETIC MODIFICATION IN THE EVOLUTION OF HEPATITIS B VIRUS-INDUCED HEPATOCELLULAR CARCINOMA. LIVER CANCER IN MEN IS THE SECOND LEADING CAUSE OF CANCER DEATH AND HEPATOCELLULAR CARCINOMA (HCC) ACCOUNTS FOR 70%-85% OF THE TOTAL LIVER CANCER WORLDWIDE. CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) IS THE MAJOR CAUSE OF HCC. CHRONIC, INTERMITTENTLY ACTIVE INFLAMMATION PROVIDES "FERTILE FIELD" FOR "MUTATION, SELECTION, AND ADAPTATION" OF HBV AND THE INFECTED HEPATOCYTES, A LONG-TERM EVOLUTIONARY PROCESS DURING HBV-INDUCED CARCINOGENESIS. HBV MUTATIONS, WHICH ARE POSITIVELY SELECTED BY INSUFFICIENT IMMUNITY, CAN PROMOTE AND PREDICT THE OCCURRENCE OF HCC. RECENTLY, ADVANCED SEQUENCING TECHNOLOGIES INCLUDING WHOLE GENOME SEQUENCING, EXOME SEQUENCING, AND RNA SEQUENCING PROVIDE OPPORTUNITIES TO BETTER UNDER-STAND THE INSIGHT OF HOW SOMATIC MUTATIONS, STRUCTURE VARIATIONS, HBV INTEGRATIONS, AND EPIGENETIC MODIFICATIONS CONTRIBUTE TO HCC DEVELOPMENT. GENOMIC VARIATIONS OF HCC CAUSED BY VARIOUS ETIOLOGICAL FACTORS MAY BE DIFFERENT, BUT THE COMMON DRIVER MUTATIONS ARE IMPORTANT TO ELUCIDATE THE HCC EVOLUTIONARY PROCESS. GENOME-WIDE ANALYSES OF HBV INTEGRATIONS ARE HELPFUL IN CLARIFYING THE TARGETED GENES OF HBV IN CARCINOGENESIS AND DISEASE PROGRESSION. RNA SEQUENCING CAN IDENTIFY KEY MOLECULES WHOSE EXPRESSIONS ARE EPIGENETICALLY MODIFIED DURING HCC EVOLUTION. IN THIS REVIEW, WE SUMMARIZED THE CURRENT FINDINGS OF NEXT GENERATION SEQUENCINGS FOR HBV-HCC AND PROPOSED A THEORY FRAMEWORK OF CANCER EVOLUTION AND DEVELOPMENT BASED ON THE CURRENT KNOWLEDGE OF HBV-INDUCED HCC TO CHARACTERIZE AND INTERPRET EVOLUTIONARY MECHANISMS OF HCC AND POSSIBLE OTHER CANCERS. UNDERSTANDING THE KEY VIRAL AND GENOMIC VARIATIONS INVOLVED IN HCC EVOLUTION IS ESSENTIAL FOR GENERATING EFFECTIVE DIAGNOSTIC, PROGNOSTIC, AND PREDICTIVE BIOMARKERS AS WELL AS THERAPEUTIC TARGETS FOR THE INTERVENTIONS OF HBV-HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9 4461  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 6707  36 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 3780  40 INTERFERON DRIVES HCV SCARRING OF THE EPIGENOME AND CREATES TARGETABLE VULNERABILITIES FOLLOWING VIRAL CLEARANCE. BACKGROUND AND AIMS: CHRONIC HCV INFECTION IS A LEADING ETIOLOGIC DRIVER OF CIRRHOSIS AND ULTIMATELY HCC. OF THE APPROXIMATELY 71 MILLION INDIVIDUALS CHRONICALLY INFECTED WITH HCV, 10%-20% ARE EXPECTED TO DEVELOP SEVERE LIVER COMPLICATIONS IN THEIR LIFETIME. EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS BECOME PROFOUNDLY DISRUPTED IN DISEASE PROCESSES INCLUDING LIVER DISEASE. APPROACH AND RESULTS: TO UNDERSTAND HOW HCV INFECTION INFLUENCES THE EPIGENOME AND WHETHER THESE EVENTS REMAIN AS "SCARS" FOLLOWING CURE OF CHRONIC HCV INFECTION, WE MAPPED GENOME-WIDE DNA METHYLATION, FOUR KEY REGULATORY HISTONE MODIFICATIONS (H3K4ME3, H3K4ME1, H3K27AC, AND H3K27ME3), AND OPEN CHROMATIN IN PARENTAL AND HCV-INFECTED IMMORTALIZED HEPATOCYTES AND THE HUH7.5 HCC CELL LINE, ALONG WITH DNA METHYLATION AND GENE-EXPRESSION ANALYSES FOLLOWING ELIMINATION OF HCV IN THESE MODELS THROUGH TREATMENT WITH INTERFERON-ALPHA (IFN-ALPHA) OR A DIRECT-ACTING ANTIVIRAL (DAA). OUR DATA DEMONSTRATE THAT HCV INFECTION PROFOUNDLY AFFECTS THE EPIGENOME (PARTICULARLY ENHANCERS); HCV SHARES EPIGENETIC TARGETS WITH INTERFERON-ALPHA TARGETS; AND AN OVERWHELMING MAJORITY OF EPIGENETIC CHANGES INDUCED BY HCV REMAIN AS "SCARS" ON THE EPIGENOME FOLLOWING VIRAL CURE. SIMILAR FINDINGS ARE OBSERVED IN PRIMARY HUMAN PATIENT SAMPLES CURED OF CHRONIC HCV INFECTION. SUPPLEMENTATION OF IFN-ALPHA/DAA ANTIVIRAL REGIMENS WITH DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2'-DEOXYCYTIDINE SYNERGIZES IN REVERTING ABERRANT DNA METHYLATION INDUCED BY HCV. FINALLY, BOTH HCV-INFECTED AND CURED CELLS DISPLAYED A BLUNTED IMMUNE RESPONSE, DEMONSTRATING A FUNCTIONAL EFFECT OF EPIGENETIC SCARRING. CONCLUSIONS: INTEGRATION OF EPIGENETIC AND TRANSCRIPTIONAL DATA ELUCIDATE KEY GENE DEREGULATION EVENTS DRIVEN BY HCV INFECTION AND HOW THIS MAY UNDERPIN THE LONG-TERM ELEVATED RISK FOR HCC IN PATIENTS CURED OF HCV DUE TO EPIGENOME SCARRING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 6016  31 THE ASSOCIATION BETWEEN HEPATOCARCINOGENESIS AND INTRACELLULAR ALTERATIONS DUE TO HEPATITIS B VIRUS INFECTION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM LEADING TO SEVERE LIVER DYSFUNCTION, INCLUDING LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. ALTHOUGH CURRENT ANTIVIRAL THERAPIES FOR CHRONIC HBV INFECTION HAVE BEEN IMPROVED AND CAN LEAD TO A STRONG SUPPRESSION OF VIRAL REPLICATION, IT IS DIFFICULT TO COMPLETELY ELIMINATE THE VIRUS WITH THESE THERAPIES ONCE CHRONIC HBV INFECTION IS ESTABLISHED IN THE HOST. FURTHERMORE, CHRONIC HBV INFECTION ALTERS INTRACELLULAR METABOLISM AND SIGNALLING PATHWAYS, RESULTING IN THE ACTIVATION OF CARCINOGENESIS IN THE LIVER. HBV PRODUCES FOUR VIRAL PROTEINS: HEPATITIS B SURFACE-, HEPATITIS B CORE-, HEPATITIS B X PROTEIN, AND POLYMERASE; EACH PLAYS AN IMPORTANT ROLE IN HBV REPLICATION AND THE INTRACELLULAR SIGNALLING PATHWAYS ASSOCIATED WITH HEPATOCARCINOGENESIS. IN VITRO AND IN VIVO EXPERIMENTAL MODELS FOR ANALYZING HBV INFECTION AND REPLICATION HAVE BEEN ESTABLISHED, AND GENE EXPRESSION ANALYSES USING MICROARRAYS OR NEXT-GENERATION SEQUENCING HAVE ALSO BEEN DEVELOPED. THUS, IT IS POSSIBLE TO CLARIFY THE MOLECULAR MECHANISMS FOR INTRACELLULAR ALTERATIONS, SUCH AS ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, THE IMPACT OF HBV VIRAL PROTEINS AND INTRACELLULAR ALTERATIONS IN HBV-ASSOCIATED HEPATOCARCINOGENESIS ARE DISCUSSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 5622  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 6640  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 2980  43 GENETIC BASIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA: LINKAGE BETWEEN INFECTION, INFLAMMATION, AND TUMORIGENESIS. HEPATITIS VIRUS INFECTION IS A LEADING CAUSE OF CHRONIC LIVER DISEASE, INCLUDING CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH ANTI-VIRAL THERAPIES AGAINST HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) HAVE DRAMATICALLY PROGRESSED DURING THE PAST DECADE, THE ESTIMATED NUMBER OF PEOPLE CHRONICALLY INFECTED WITH HBV AND/OR HCV IS ~370 MILLION, AND HEPATITIS VIRUS-ASSOCIATED HEPATOCARCINOGENESIS IS A SERIOUS HEALTH CONCERN WORLDWIDE. UNDERSTANDING THE MECHANISM OF VIRUS-ASSOCIATED CARCINOGENESIS IS CRUCIAL TOWARD BOTH TREATMENT AND PREVENTION, AND THE RECENTLY DEVELOPED WHOLE GENOME/EXOME SEQUENCING ANALYSIS USING NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS CONTRIBUTED TO UNVEILING THE LANDSCAPE OF GENETIC AND EPIGENETIC ABERRATIONS IN NOT ONLY TUMOR TISSUES BUT ALSO THE BACKGROUND LIVER TISSUES UNDERLYING CHRONIC LIVER DAMAGE CAUSED BY HEPATITIS VIRUS INFECTION. SEVERAL MAJOR MECHANISMS UNDERLIE THE GENETIC AND EPIGENETIC ABERRATIONS IN THE HEPATITIS VIRUS-INFECTED LIVER, SUCH AS THE GENERATION OF REACTIVE OXIDATIVE STRESS, ECTOPIC EXPRESSION OF DNA MUTATOR ENZYMES, AND DYSFUNCTION OF THE DNA REPAIR SYSTEM. IN ADDITION, DIRECT ONCOGENIC EFFECTS OF HEPATITIS VIRUS, REPRESENTED BY THE INTEGRATION OF HBV-DNA, ARE OBSERVED IN INFECTED HEPATOCYTES. ELUCIDATING THE WHOLE PICTURE OF GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS THE MECHANISMS OF TUMORIGENESIS, WILL FACILITATE THE DEVELOPMENT OF EFFICIENT TREATMENT AND PREVENTION STRATEGIES FOR HEPATITIS VIRUS-ASSOCIATED HCC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 3190  49 HCV-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH LIVER CANCER RISK PERSIST AFTER SUSTAINED VIROLOGIC RESPONSE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE EFFECTIVE ANTIVIRAL THERAPIES, THE RISK FOR HCC IS DECREASED BUT NOT ELIMINATED AFTER A SUSTAINED VIROLOGIC RESPONSE (SVR) TO DIRECT-ACTING ANTIVIRAL (DAA) AGENTS, AND THE RISK IS HIGHER IN PATIENTS WITH ADVANCED FIBROSIS. WE INVESTIGATED HCV-INDUCED EPIGENETIC ALTERATIONS THAT MIGHT AFFECT RISK FOR HCC AFTER DAA TREATMENT IN PATIENTS AND MICE WITH HUMANIZED LIVERS. METHODS: WE PERFORMED GENOME-WIDE CHIPMENTATION-BASED CHIP-SEQ AND RNA-SEQ ANALYSES OF LIVER TISSUES FROM 6 PATIENTS WITHOUT HCV INFECTION (CONTROLS), 18 PATIENTS WITH CHRONIC HCV INFECTION, 8 PATIENTS WITH CHRONIC HCV INFECTION CURED BY DAA TREATMENT, 13 PATIENTS WITH CHRONIC HCV INFECTION CURED BY INTERFERON THERAPY, 4 PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION, AND 7 PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS IN EUROPE AND JAPAN. HCV-INDUCED EPIGENETIC MODIFICATIONS WERE MAPPED BY COMPARATIVE ANALYSES WITH MODIFICATIONS ASSOCIATED WITH OTHER LIVER DISEASE ETIOLOGIES. UPA/SCID MICE WERE ENGRAFTED WITH HUMAN HEPATOCYTES TO CREATE MICE WITH HUMANIZED LIVERS AND GIVEN INJECTIONS OF HCV-INFECTED SERUM SAMPLES FROM PATIENTS; MICE WERE GIVEN DAAS TO ERADICATE THE VIRUS. PATHWAYS ASSOCIATED WITH HCC RISK WERE IDENTIFIED BY INTEGRATIVE PATHWAY ANALYSES AND VALIDATED IN ANALYSES OF PAIRED HCC TISSUES FROM 8 PATIENTS WITH AN SVR TO DAA TREATMENT OF HCV INFECTION. RESULTS: WE FOUND CHRONIC HCV INFECTION TO INDUCE SPECIFIC GENOME-WIDE CHANGES IN H3K27AC, WHICH CORRELATED WITH CHANGES IN EXPRESSION OF MRNAS AND PROTEINS. THESE CHANGES PERSISTED AFTER AN SVR TO DAAS OR INTERFERON-BASED THERAPIES. INTEGRATIVE PATHWAY ANALYSES OF LIVER TISSUES FROM PATIENTS AND MICE WITH HUMANIZED LIVERS DEMONSTRATED THAT HCV-INDUCED EPIGENETIC ALTERATIONS WERE ASSOCIATED WITH LIVER CANCER RISK. COMPUTATIONAL ANALYSES ASSOCIATED INCREASED EXPRESSION OF SPHK1 WITH HCC RISK. WE VALIDATED THESE FINDINGS IN AN INDEPENDENT COHORT OF PATIENTS WITH HCV-RELATED CIRRHOSIS (N = 216), A SUBSET OF WHICH (N = 21) ACHIEVED VIRAL CLEARANCE. CONCLUSIONS: IN AN ANALYSIS OF LIVER TISSUES FROM PATIENTS WITH AND WITHOUT AN SVR TO DAA THERAPY, WE IDENTIFIED EPIGENETIC AND GENE EXPRESSION ALTERATIONS ASSOCIATED WITH RISK FOR HCC. THESE ALTERATIONS MIGHT BE TARGETED TO PREVENT LIVER CANCER IN PATIENTS TREATED FOR HCV INFECTION.	2019	

17 2682  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18 3187  41 HBV INDUCED HEPATOCELLULAR CARCINOMA AND RELATED POTENTIAL IMMUNOTHERAPY. CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) HAS LONG BEEN RECOGNIZED AS A MAJOR RISK FACTOR IN THE INITIATION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CONTRIBUTING TO OVER HALF THE CASES OF HCC WORLDWIDE. TRANSFORMATION OF THE LIVER WITH HBV INFECTION TO HCC MAINLY RESULTS FROM LONG-TERM INTERACTION BETWEEN HBV AND THE HOST HEPATOCYTES VIA A VARIETY OF MECHANISMS, INCLUDING HBV DNA INTEGRATION, PROLONGED EXPRESSION OF THE VIRAL HBX REGULATORY PROTEIN AND/OR ABERRANT PRES/S ENVELOPE PROTEINS, AND EPIGENETIC DYSREGULATION OF TUMOR SUPPRESSOR GENES. WHILE THERE HAVE BEEN SEVERAL FAILURES IN THE DEVELOPMENT OF DRUGS FOR HCC, THE IMMUNE-TOLERANT MICROENVIRONMENT OF THIS MALIGNANCY SUGGESTS THAT IMMUNOTHERAPEUTIC AGENTS COULD PROVIDE BENEFITS FOR THESE PATIENTS. THIS IS SUPPORTED BY RECENT DATA SHOWING THAT IMMUNOTHERAPY HAS PROMISING ACTIVITY IN PATIENTS WITH ADVANCED HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF HBV-INDUCED HCC AND RECENT IMMUNE BASED APPROACHES FOR THE TREATMENT OF HCC PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19 4127  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 3260  42 HEPATITIS C VIRUS LEAVES AN EPIGENETIC SIGNATURE POST CURE OF INFECTION BY DIRECT-ACTING ANTIVIRALS. THE INCREASING WORLDWIDE PREVALENCE OF HEPATOCELLULAR CARCINOMA (HCC), CHARACTERIZED BY RESISTANCE TO CONVENTIONAL CHEMOTHERAPY, POOR PROGNOSIS AND EVENTUALLY MORTALITY, PLACE IT AS A PRIME TARGET FOR NEW MODES OF PREVENTION AND TREATMENT. HEPATITIS C VIRUS (HCV) IS THE PREDOMINANT RISK FACTOR FOR HCC IN THE US AND EUROPE. MULTIPLE EPIDEMIOLOGICAL STUDIES SHOWED THAT SUSTAINED VIROLOGICAL RESPONSES (SVR) FOLLOWING TREATMENT WITH THE POWERFUL DIRECT ACTING ANTIVIRALS (DAAS), WHICH HAVE REPLACED INTERFERON-BASED REGIMES, DO NOT ELIMINATE TUMOR DEVELOPMENT. WE AIMED TO IDENTIFY AN HCV-SPECIFIC PATHOGENIC MECHANISM THAT PERSISTS POST SVR FOLLOWING DAAS TREATMENT. WE DEMONSTRATE THAT HCV INFECTION INDUCES GENOME-WIDE EPIGENETIC CHANGES BY PERFORMING CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT-GENERATION SEQUENCING (CHIP-SEQ) FOR HISTONE POST-TRANSLATIONAL MODIFICATIONS THAT ARE EPIGENETIC MARKERS FOR ACTIVE AND REPRESSED CHROMATIN. THE CHANGES IN HISTONE MODIFICATIONS CORRELATE WITH REPROGRAMED HOST GENE EXPRESSION AND ALTER SIGNALING PATHWAYS KNOWN TO BE ASSOCIATED WITH HCV LIFE CYCLE AND HCC. THESE EPIGENETIC ALTERATIONS REQUIRE THE PRESENCE OF HCV RNA OR/AND EXPRESSION OF THE VIRAL PROTEINS IN THE CELLS. IMPORTANTLY, THE EPIGENETIC CHANGES INDUCED FOLLOWING INFECTION PERSIST AS AN "EPIGENETIC SIGNATURE" AFTER VIRUS ERADICATION BY DAAS TREATMENT, AS DETECTED USING IN VITRO HCV INFECTION MODELS. THESE OBSERVATIONS LED TO THE IDENTIFICATION OF AN 8 GENE SIGNATURE THAT IS ASSOCIATED WITH HCC DEVELOPMENT AND DEMONSTRATE PERSISTENT EPIGENETIC ALTERATIONS IN HCV INFECTED AND POST SVR LIVER BIOPSY SAMPLES. THE EPIGENETIC SIGNATURE WAS REVERTED IN VITRO BY DRUGS THAT INHIBIT EPIGENETIC MODIFYING ENZYME AND BY THE EGFR INHIBITOR, ERLOTINIB. THIS EPIGENETIC "SCARRING" OF THE GENOME, PERSISTING FOLLOWING HCV ERADICATION, SUGGEST A NOVEL MECHANISM FOR THE PERSISTENT PATHOGENESIS OF HCV AFTER ITS ERADICATION BY DAAS. OUR STUDY OFFERS NEW AVENUES FOR PREVENTION OF THE PERSISTENT ONCOGENIC EFFECTS OF CHRONIC HEPATITIS INFECTIONS USING SPECIFIC DRUGS TO REVERT THE EPIGENETIC CHANGES TO THE GENOME.	2019