1 2943 91 GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES IN GASTRIC CANCER. BOTH GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES INVOLVED IN THE PATHOGENESIS OF GASTRIC CANCER ARE REVIEWED HERE, AND MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS ARE PROPOSED. GASTRIC CARCINOMAS ARE BELIEVED TO EVOLVE FROM NATIVE GASTRIC MUCOSA OR INTESTINAL METAPLASTIC MUCOSA THAT UNDERGOES GENETIC AND EPIGENETIC ALTERATIONS INVOLVING EITHER THE SUPPRESSOR PATHWAY (DEFECTS IN TUMOR SUPPRESSOR GENES) OR MUTATOR PATHWAY (DEFECTS IN DNA MISMATCH REPAIR GENES). METHYLATION OF E-CADHERIN IN NATIVE GASTRIC MUCOSA RESULTS IN UNDIFFERENTIATED CARCINOMAS (SUPPRESSOR PATHWAY), WHILE METHYLATION OF HMLHI RESULTS IN DIFFERENTIATED FOVEOLAR-TYPE CARCINOMAS (MUTATOR PATHWAY). THE MAJORITY OF DIFFERENTIATED GASTRIC CARCINOMAS HOWEVER, ARISE FROM INTESTINAL METAPLASTIC MUCOSA AND EXHIBIT STRUCTURAL ALTERATIONS OF TUMOR SUPPRESSOR GENES, ESPECIALLY P53. THEY APPEAR TO BE RELATED TO CHRONIC INJURY, PERHAPS DUE TO HELICOBACTER PYLORI INFECTION. APPROXIMATELY 20% OF DIFFERENTIATED CARCINOMAS (ORDINARY-TYPE) HAVE EVIDENCE OF MUTATOR PATHWAY TUMORIGENESIS. MUTATIONS OF E-CADHERIN ARE MAINLY INVOLVED IN THE PROGRESSION OF DIFFERENTIATED CARCINOMAS TO UNDIFFERENTIATED TUMORS. THE MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS DEPEND ON THE HISTOLOGICAL BACKGROUND, AND GASTRIC CARCINOMAS SHOW DISTINCT BIOLOGICAL BEHAVIORS AS A RESULT OF DISCERNIBLE CELLULAR GENETIC AND EPIGENETIC ALTERATIONS. 2002 2 1543 21 DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. AS FOR MANY OTHER TUMORS, DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES, LEADING TO ACTIVATION OF ONCOGENES AND INACTIVATION OR LOSS OF TUMOR SUPPRESSOR GENES (TSG). IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC INACTIVATION OF (TUMOR SUPPRESSOR) GENES BY PROMOTER HYPERMETHYLATION HAS BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMORIGENESIS. IN HCC, ABERRANT METHYLATION OF PROMOTER SEQUENCES OCCURS NOT ONLY IN ADVANCED TUMORS, IT HAS BEEN ALSO OBSERVED IN PREMALIGNANT CONDITIONS JUST AS CHRONIC VIRAL HEPATITIS B OR C AND CIRRHOTIC LIVER. THIS REVIEW DISCUSSES THE EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FOCUSING DNA METHYLATION. 2008 3 4131 25 MECHANISMS OF HBV-INDUCED HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND/OR ALTERED VERSIONS OF THE PRES/S ENVELOPE PROTEINS DYSREGULATES CELL TRANSCRIPTION AND PROLIFERATION CONTROL AND SENSITIZES LIVER CELLS TO CARCINOGENIC FACTORS. ACCUMULATION OF PRES1 LARGE ENVELOPE PROTEINS AND/OR PRES2/S MUTANT PROTEINS ACTIVATES THE UNFOLD PROTEINS RESPONSE, THAT CAN CONTRIBUTE TO HEPATOCYTE TRANSFORMATION. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY THE HBV PROTEIN, HBX, WHICH IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS, P53 INACTIVATION BY MUTATIONS AND OVEREXPRESSION OF FETAL LIVER/HEPATIC PROGENITOR CELLS GENES. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. HBV-RELATED HCCS MAY ARISE ON NON-CIRRHOTIC LIVERS, FURTHER SUPPORTING THE NOTION THAT HBV PLAYS A DIRECT ROLE IN LIVER TRANSFORMATION BY TRIGGERING BOTH COMMON AND ETIOLOGY SPECIFIC ONCOGENIC PATHWAYS IN ADDITION TO STIMULATING THE HOST IMMUNE RESPONSE AND DRIVING LIVER CHRONIC NECRO-INFLAMMATION. 2016 4 4462 27 MOLECULAR MECHANISMS OF HBV-ASSOCIATED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV-DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND THE LARGE ENVELOPE PROTEIN DEREGULATE THE CELLULAR TRANSCRIPTION PROGRAM AND PROLIFERATION CONTROL AND SENSITIZE LIVER CELLS TO CARCINOGENIC FACTORS. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY HBX THAT IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS AND P53 INACTIVATION BY MUTATIONS, OVEREXPRESS FETAL LIVER/HEPATIC PROGENITOR CELLS GENES, AND SHOW A SPECIFIC ACTIVATION OF THE AKT PATHWAY. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED, BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. ALL AVAILABLE EVIDENCE STRONGLY SUPPORTS THE NOTION THAT CHRONIC HBV INFECTION TRIGGERS BOTH COMMON AND ETIOLOGY-SPECIFIC ONCOGENIC PATHWAYS, THUS PLAYING A DIRECT ROLE BEYOND STIMULATION OF HOST IMMUNE RESPONSES AND CHRONIC NECROINFLAMMATORY LIVER DISEASE. 2013 5 6753 21 WILD TYPE HBX AND TRUNCATED HBX: PLEIOTROPIC REGULATORS DRIVING SEQUENTIAL GENETIC AND EPIGENETIC STEPS OF HEPATOCARCINOGENESIS AND PROGRESSION OF HBV-ASSOCIATED NEOPLASMS. HEPATITIS B VIRUS (HBV) IS ONE OF THE CAUSATIVE AGENTS OF HEPATOCELLULAR CARCINOMA. THE MOLECULAR MECHANISMS OF TUMORIGENESIS ARE COMPLEX. ONE OF THE HOST FACTORS INVOLVED IS APPARENTLY THE LONG-LASTING INFLAMMATORY REACTION WHICH ACCOMPANIES CHRONIC HBV INFECTION. ALTHOUGH HBV LACKS A TYPICAL VIRAL ONCOGENE, THE HBX GENE ENCODING A PLEIOTROPIC REGULATORY PROTEIN EMERGED AS A MAJOR PLAYER IN LIVER CARCINOGENESIS. HERE WE REVIEW THE TUMORIGENIC FUNCTIONS OF HBX WITH AN EMPHASIS ON WILD TYPE AND TRUNCATED HBX VARIANTS, AND THEIR ROLE IN THE TRANSCRIPTIONAL DYSREGULATION AND EPIGENETIC REPROGRAMMING OF THE HOST CELL GENOME. WE SUGGEST THAT HBX ACQUIRED BY THE HBV GENOME DURING EVOLUTION ACTS LIKE A CELLULAR PROTO-ONC GENE THAT IS ACTIVATED BY DELETION DURING HEPATOCARCINOGENESIS. THE RESULTING VIRAL ONCOGENE (V-ONC GENE) CODES FOR A TRUNCATED HBX PROTEIN THAT FACILITATES TUMOR PROGRESSION. COPYRIGHT (C) 2015 JOHN WILEY & SONS, LTD. 2016 6 6868 20 [PATHOGENESIS OF HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCER WORLDWIDE. MOST OF THE HCC OCCUR IN DEVELOPING COUNTRIES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HCC DEVELOPMENT. HBV INDUCES IMMUNE-MEDIATED CHRONIC HEPATITIS, LIVER INJURY, REGENERATION AND SCAR FORMING RESPONSES, LEADING TO AN INFLAMMATORY, FIBROTIC AND IMMUNE DEFICIENT MICROENVIRONMENT. HBV MAY INTEGRATE INTO HOST GENOME, INDUCING GENETIC ABNORMALITY AND ALTERING THE EXPRESSION OF HCC-RELATED GENES. HBV ALSO EXPRESSES ACTIVE PROTEINS SUCH AS X (HBX) AND S PROTEINS, WHICH MAY TRANS-ACTIVATE HCC-RELATED PROTEINS EXPRESSION, INTERACT WITH INTRACELLULAR SPECIFIC PROTEINS, ACTIVATE A VARIETY OF SIGNALING PATHWAYS, AND INDUCE ABERRANT EPIGENETIC MODIFICATIONS. HBV MUTATION ALSO HAS IMPACT ON HBV RELATED HCC DEVELOPMENT. 2016 7 1646 20 DOES THE HEPATITIS B ANTIGEN HBX PROMOTE THE APPEARANCE OF LIVER CANCER STEM CELLS? HEPATITIS B VIRUS (HBV) IS A MAJOR ETIOLOGIC AGENT OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV-ENCODED X ANTIGEN, HBX, AND PATHWAYS IMPLICATED IN THE SELF-RENEWAL OF STEM CELLS CONTRIBUTE TO HCC, BUT IT IS NOT CLEAR WHETHER HBX EXPRESSION PROMOTES "STEMNESS." THUS, EXPERIMENTS WERE DESIGNED TO TEST THE HYPOTHESIS THAT HBX TRIGGERS MALIGNANT TRANSFORMATION BY PROMOTING PROPERTIES THAT ARE CHARACTERISTIC OF CANCER STEM CELLS (CSC). TO TEST THIS HYPOTHESIS, HEPG2 CELLS WERE STABLY TRANSDUCED WITH HBX AND THEN ASSAYED FOR PHENOTYPIC AND MOLECULAR CHARACTERISTICS OF "STEMNESS." THE RELATIONSHIP BETWEEN HBX AND "STEMNESS"-ASSOCIATED MARKERS WAS ALSO EVALUATED BY IMMUNOHISTOCHEMICAL STAINING OF LIVER AND TUMOR TISSUE SECTIONS FROM HBV-INFECTED PATIENTS. THE RESULTS SHOWED THAT OCT-4, NANOG, KLF-4, BETA-CATENIN, AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) WERE ACTIVATED BY HBX IN VITRO AND IN VIVO. EPCAM WAS DETECTED IN THE NUCLEI OF HUMAN HCC CELLS FROM INFECTED PATIENTS. HBX PROMOTES "STEMNESS" BY ACTIVATING BETA-CATENIN AND EPIGENETIC UPREGULATION OF MIR-181, BOTH OF WHICH TARGET EPCAM. HBX EXPRESSION WAS ALSO ASSOCIATED WITH DEPRESSED LEVELS OF E-CADHERIN. MOREOVER, HBX STIMULATED CELL MIGRATION, GROWTH IN SOFT AGAR, AND SPHEROID FORMATION. THIS WORK IS THE FIRST TO PROPOSE THAT HBV PROMOTES "STEMNESS" IN THE PATHOGENESIS OF HCC. HBX-ASSOCIATED UPREGULATED EXPRESSION OF MULTIPLE "STEMNESS" MARKERS SUPPORTS THE HYPOTHESIS THAT HBX CONTRIBUTES TO HEPATOCARCINOGENESIS, AT LEAST IN PART, BY PROMOTING CHANGES IN GENE EXPRESSION THAT ARE CHARACTERISTICS OF CSCS. 2011 8 6590 27 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015 9 2939 18 GENETIC AND EPIGENETIC ALTERATIONS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). ITS CHRONIC INFECTION CAN LEAD TO CHRONIC LIVER INFLAMMATION AND THE ACCUMULATION OF GENETIC ALTERATIONS TO RESULT IN THE ONCOGENIC TRANSFORMATION OF HEPATOCYTES. HBV CAN ALSO SENSITIZE HEPATOCYTES TO ONCOGENIC TRANSFORMATION BY CAUSING GENETIC AND EPIGENETIC CHANGES OF THE HOST CHROMOSOMES. HBV DNA CAN INSERT INTO HOST CHROMOSOMES AND RECENT LARGE-SCALE WHOLE-GENOME SEQUENCING STUDIES REVEALED RECURRENT HBV DNA INTEGRATIONS SITES THAT MAY PLAY IMPORTANT ROLES IN THE INITIATION OF HEPATOCELLULAR CARCINOGENESIS. HBV CAN ALSO CAUSE EPIGENETIC CHANGES BY ALTERING THE METHYLATION STATUS OF CELLULAR DNA, THE POST-TRANSLATIONAL MODIFICATION OF HISTONES, AND THE EXPRESSION OF MICRORNAS. THESE CHANGES CAN ALSO LEAD TO THE EVENTUAL HEPATOCELLULAR TRANSFORMATION. THESE RECENT FINDINGS ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THE HOST CHROMOSOMES INDUCED BY HBV OPENED A NEW AVENUE FOR THE DEVELOPMENT OF NOVEL DIAGNOSIS AND TREATMENTS FOR HBV-INDUCED HCC. 2015 10 6271 21 THE ONCOGENIC ROLE OF HEPATITIS B VIRUS. THE HEPATITIS B VIRUS (HBV) IS A SMALL ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A WORLD HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV HAS BEEN CLASSIFIED AMONG HUMAN TUMOR VIRUSES BY VIRTUE OF A ROBUST EPIDEMIOLOGIC ASSOCIATION BETWEEN CHRONIC HBV CARRIAGE AND HCC OCCURRENCE. IN THE ABSENCE OF CYTOPATHIC EFFECT IN INFECTED HEPATOCYTES, THE ONCOGENIC ROLE OF HBV MIGHT INVOLVE A COMBINATION OF DIRECT AND INDIRECT EFFECTS OF THE VIRUS DURING THE MULTISTEP PROCESS OF LIVER CARCINOGENESIS. LIVER INFLAMMATION AND HEPATOCYTE PROLIFERATION DRIVEN BY HOST IMMUNE RESPONSES ARE RECOGNIZED DRIVING FORCES OF LIVER CELL TRANSFORMATION. GENETIC AND EPIGENETIC ALTERATIONS CAN ALSO RESULT FROM VIRAL DNA INTEGRATION INTO HOST CHROMOSOMES AND FROM PROLONGED EXPRESSION OF VIRAL GENE PRODUCTS. NOTABLY, THE TRANSCRIPTIONAL REGULATORY PROTEIN HBX ENCODED BY THE X GENE IS ENDOWED WITH TUMOR PROMOTER ACTIVITY. HBX HAS PLEIOTROPIC ACTIVITIES AND PLAYS A MAJOR ROLE IN HBV PATHOGENESIS AND IN LIVER CARCINOGENESIS. BECAUSE HEPATIC TUMORS CARRY A DISMAL PROGNOSIS, THERE IS URGENT NEED TO DEVELOP EARLY DIAGNOSTIC MARKERS OF HCC AND EFFECTIVE THERAPIES AGAINST CHRONIC HEPATITIS B. DECIPHERING THE ONCOGENIC MECHANISMS THAT UNDERLIE HBV-RELATED TUMORIGENESIS MIGHT HELP DEVELOPING ADAPTED THERAPEUTIC STRATEGIES. 2014 11 4920 26 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 12 2377 25 EPIGENETIC REGULATION OF TUMOR SUPPRESSORS BY HELICOBACTER PYLORI ENHANCES EBV-INDUCED PROLIFERATION OF GASTRIC EPITHELIAL CELLS. HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS (EBV) ARE TWO WELL-KNOWN CONTRIBUTORS TO CANCER AND CAN ESTABLISH LIFELONG PERSISTENT INFECTION IN THE HOST. THIS LEADS TO CHRONIC INFLAMMATION, WHICH ALSO CONTRIBUTES TO DEVELOPMENT OF CANCER. ASSOCIATION WITH H. PYLORI INCREASES THE RISK OF GASTRIC CARCINOMA, AND COEXISTENCE WITH EBV ENHANCES PROLIFERATION OF INFECTED CELLS. FURTHER, H. PYLORI-EBV COINFECTION CAUSES CHRONIC INFLAMMATION IN PEDIATRIC PATIENTS. WE HAVE ESTABLISHED AN H. PYLORI-EBV COINFECTION MODEL SYSTEM USING HUMAN GASTRIC EPITHELIAL CELLS. WE SHOWED THAT H. PYLORI INFECTION CAN INCREASE THE ONCOGENIC PHENOTYPE OF EBV-INFECTED CELLS AND THAT THE CYTOTOXIN-ASSOCIATED GENE (CAGA) PROTEIN ENCODED BY H. PYLORI STIMULATED EBV-MEDIATED CELL PROLIFERATION IN THIS COINFECTION MODEL SYSTEM. THIS LED TO INCREASED EXPRESSION OF DNA METHYL TRANSFERASES (DNMTS), WHICH REPROGRAMMED CELLULAR TRANSCRIPTIONAL PROFILES, INCLUDING THOSE OF TUMOR SUPPRESSOR GENES (TSGS), THROUGH HYPERMETHYLATION. THESE FINDINGS PROVIDE NEW INSIGHTS INTO A MOLECULAR MECHANISM WHEREBY COOPERATIVITY BETWEEN TWO ONCOGENIC AGENTS LEADS TO ENHANCED ONCOGENIC ACTIVITY OF GASTRIC CANCER CELLS.IMPORTANCE WE HAVE STUDIED THE COOPERATIVITY BETWEEN H. PYLORI AND EBV, TWO KNOWN ONCOGENIC AGENTS. THIS LED TO AN ENHANCED ONCOGENIC PHENOTYPE IN GASTRIC EPITHELIAL CELLS. WE NOW DEMONSTRATE THAT EBV-DRIVEN EPIGENETIC MODIFICATIONS ARE ENHANCED IN THE PRESENCE OF H. PYLORI, MORE SPECIFICALLY, IN THE PRESENCE OF ITS CAGA SECRETORY ANTIGEN. THIS RESULTS IN INCREASED PROLIFERATION OF THE INFECTED GASTRIC CELLS. OUR FINDINGS NOW ELUCIDATE A MOLECULAR MECHANISM WHEREBY EXPRESSION OF CELLULAR DNA METHYL TRANSFERASES IS INDUCED INFLUENCING INFECTION BY EBV. HYPERMETHYLATION OF THE REGULATORY GENOMIC REGIONS OF TUMOR SUPPRESSOR GENES RESULTS IN THEIR SILENCING. THIS DRASTICALLY AFFECTS THE EXPRESSION OF CELL CYCLE, APOPTOSIS, AND DNA REPAIR GENES, WHICH DYSREGULATES THEIR ASSOCIATED PROCESSES, AND PROMOTION OF THE ONCOGENIC PHENOTYPE. 2018 13 5969 30 TERT PROMOTER MUTATIONS IN PRIMARY LIVER TUMORS. NEXT-GENERATION SEQUENCING HAS DRAWN THE GENETIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA AND SEVERAL SIGNALING PATHWAYS ARE ALTERED AT THE DNA LEVEL IN TUMORS: WNT/BETA-CATENIN, CELL CYCLE REGULATOR, EPIGENETIC MODIFIER, HISTONE METHYLTRANSFERASE, OXIDATIVE STRESS, RAS/RAF/MAP KINASE AND AKT/MTOR PATHWAYS. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS STARTING WITH THE EXPOSURE TO DIFFERENT RISK FACTORS, FOLLOWED BY THE DEVELOPMENT OF A CHRONIC LIVER DISEASE AND CIRRHOSIS PRECEDE IN THE VAST MAJORITY OF THE CASES THE DEVELOPMENT OF HCC. SEVERAL LINES OF EVIDENCE HAVE UNDERLINED THE PIVOTAL ROLE OF TELOMERE MAINTENANCE IN BOTH CIRRHOSIS AND HCC PATHOGENESIS. TERT PROMOTER MUTATIONS WERE IDENTIFIED AS THE MOST FREQUENT GENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH AN OVERALL FREQUENCY AROUND 60%. MOREOVER, IN CIRRHOSIS, TERT PROMOTER MUTATIONS ARE OBSERVED AT THE EARLY STEPS OF HEPATOCARCINOGENESIS SINCE THEY ARE RECURRENTLY IDENTIFIED IN LOW-GRADE AND HIGH-GRADE DYSPLASTIC NODULES. IN CONTRAST, ACQUISITION OF GENOMIC DIVERSITY THROUGH MUTATIONS OF CLASSICAL ONCOGENES AND TUMOR SUPPRESSOR GENES (TP53, CTNNB1, ARID1A...) OCCURRED ONLY IN PROGRESSED HCC. IN NORMAL LIVER, A SUBSET OF HCC CAN DERIVED FROM THE MALIGNANT TRANSFORMATION OF HEPATOCELLULAR ADENOMA (HCA). IN HCA, CTNNB1 MUTATIONS PREDISPOSE TO TRANSFORMATION OF HCA IN HCC AND TERT PROMOTER MUTATIONS ARE REQUIRED IN MOST OF THE CASES AS A SECOND HIT FOR A FULL MALIGNANT TRANSFORMATION. ALL THESE FINDINGS HAVE REFINED OUR KNOWLEDGE OF HCC PATHOGENESIS AND HAVE POINTED TELOMERASE AS A TARGET FOR TAILORED THERAPY IN THE FUTURE. 2016 14 6369 30 THE ROLE OF MICRORNAS IN HELICOBACTER PYLORI PATHOGENESIS AND GASTRIC CARCINOGENESIS. GASTRIC CARCINOGENESIS IS A MULTISTEP PROCESS ORCHESTRATED BY ABERRANCIES IN THE GENETIC AND EPIGENETIC REGULATION OF ONCOGENES AND TUMOR SUPPRESSOR GENES. CHRONIC INFECTION WITH HELICOBACTER PYLORI IS THE STRONGEST KNOWN RISK FACTOR FOR THE DEVELOPMENT OF GASTRIC CANCER. H. PYLORI EXPRESSES A SPECTRUM OF VIRULENCE FACTORS THAT DYSREGULATE HOST INTRACELLULAR SIGNALING PATHWAYS THAT LOWER THE THRESHOLD FOR NEOPLASTIC TRANSFORMATION. IN ADDITION TO BACTERIAL DETERMINANTS, NUMEROUS HOST AND ENVIRONMENTAL FACTORS INCREASE THE RISK OF GASTRIC CARCINOGENESIS. RECENT DISCOVERIES HAVE SHED NEW LIGHT ON THE INVOLVEMENT OF MICRORNAS (MIRNAS) IN GASTRIC CARCINOGENESIS. MIRNAS REPRESENT AN ABUNDANT CLASS OF SMALL, NON-CODING RNAS INVOLVED IN GLOBAL POST-TRANSCRIPTIONAL REGULATION AND, CONSEQUENTLY, PLAY AN INTEGRAL ROLE AT MULTIPLE STEPS IN CARCINOGENESIS, INCLUDING CELL CYCLE PROGRESSION, PROLIFERATION, APOPTOSIS, INVASION, AND METASTASIS. EXPRESSION LEVELS OF MIRNAS ARE FREQUENTLY ALTERED IN MALIGNANCIES, WHERE THEY FUNCTION AS EITHER ONCOGENIC MIRNAS OR TUMOR SUPPRESSOR MIRNAS. THIS REVIEW FOCUSES ON MIRNAS DYSREGULATED BY H. PYLORI AND POTENTIAL ETIOLOGIC ROLES THEY PLAY IN H. PYLORI-MEDIATED GASTRIC CARCINOGENESIS. 2011 15 6848 34 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 16 2435 21 EPIGENETIC SILENCING OF SFRP1 ACTIVATES THE CANONICAL WNT PATHWAY AND CONTRIBUTES TO INCREASED CELL GROWTH AND PROLIFERATION IN HEPATOCELLULAR CARCINOMA. THE WNT PATHWAY IS A KEY REGULATOR OF EMBRYONIC DEVELOPMENT AND STEM CELLS, AND ITS ABERRANT ACTIVATION IS ASSOCIATED WITH HUMAN MALIGNANCIES, MOST NOTABLY HEPATOCELLULAR CARCINOMA (HCC). EPIGENETIC DEREGULATION OF THE GENES ENCODING THE SECRETED FRIZZLED-RELATED PROTEINS (SFRPS), THE WNT SIGNALLING ANTAGONISTS, HAS BEEN LINKED WITH ABERRANT HYPERACTIVATION OF THE WNT SIGNALLING IN HCC CELLS; HOWEVER, THE PRECISE UNDERLYING MECHANISM REMAINS ELUSIVE. WE INVESTIGATED THE METHYLATION PROFILES OF WNT ANTAGONISTS IN LIVER SAMPLES OF DIFFERENT STAGES OF HCC DEVELOPMENT AND LIVER CANCER CELL LINES AND STUDIED THE FUNCTIONAL IMPACT OF ABERRANT EPIGENETIC SILENCING OF SFRPS ON THE CANONICAL WNT PATHWAY AND CELL VIABILITY. WE FOUND THAT THE SFRP1 GENE ENCODING THE SUBUNIT IS A FREQUENT TARGET OF ABERRANT DNA HYPERMETHYLATION AND SILENCING IN HCC TUMOURS, WHEREAS OTHER EXTRACELLULAR WNT ANTAGONISTS, WIF1 AND DKK3, EXHIBITED NO METHYLATION IN TUMOUR CELLS, CONSISTENT WITH THE NOTION THAT ABERRANT METHYLATION EVENTS IN CANCER CELLS ARE NON-RANDOMLY DISTRIBUTED AMONG THE GENES AND THAT THERE IS A STRONG PREFERENCE FOR HYPERMETHYLATION OF SPECIFIC GENES IN HCC. IN ADDITION, BY COMPARING SFRP1 METHYLATION STATUS IN HCC TUMOURS WITH NORMAL, CIRRHOTIC AND CHRONIC HEPATITIS LIVER TISSUES, WE IDENTIFIED SFRP1 GENE AS A POTENTIAL EARLY MARKER OF HCC. THE RESTORATION OF SFRP1 EXPRESSION IN CANCER CELLS BY ECTOPIC EXPRESSION INHIBITED WNT ACTIVITY ACCOMPANIED WITH DESTABILIZATION OF BETA-CATENIN AND DOWNREGULATION OF C-MYC AND CYCLIN D1, THE KNOWN DOWNSTREAM TARGETS OF WNT PATHWAY. IMPORTANTLY, RESTORING SFRP1 LEVELS IN CANCER CELLS INHIBITED CELL GROWTH AND INDUCED APOPTOTIC CELL DEATH. THIS STUDY SUPPORTS THE CRITICAL ROLE FOR SFRP1 SILENCING IN HEPATOCELLULAR CARCINOMA AND REINFORCES THE IMPORTANCE OF THE WNT ANTAGONISTS IN PREVENTING ONCOGENIC STABILIZATION OF BETA-CATENIN AND CHRONIC ACTIVATION OF THE CANONICAL WNT PATHWAY, SUGGESTING THAT SFRP1 MAY BE AN ATTRACTIVE TARGET FOR EARLY CANCER DETECTION AND THERAPEUTIC INTERVENTION. 2012 17 3232 22 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 18 3226 29 HELICOBACTER PYLORI INFECTION, ONCOGENIC PATHWAYS AND EPIGENETIC MECHANISMS IN GASTRIC CARCINOGENESIS. CHRONIC COLONIZATION OF THE HUMAN STOMACH BY HELICOBACTER PYLORI, A GRAM-NEGATIVE BACTERIUM, IS THE MAJOR CAUSE OF CHRONIC GASTRITIS, PEPTIC ULCERS AND GASTRIC CANCER. RECENT PROGRESS HAS ELUCIDATED IMPORTANT BACTERIAL AND HOST FACTORS THAT ARE RESPONSIBLE FOR H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC MALIGNANCY. H. PYLORI CYTOTOXIN-ASSOCIATED ANTIGEN A IS THE MAJOR ONCOGENIC FACTOR INJECTED INTO HOST CELLS FROM BACTERIA AND IT DISRUPTS EPITHELIAL CELL FUNCTIONS. TOGETHER WITH H. PYLORI CAG PATHOGENICITY ISLAND, IT CAUSES GENERAL INFLAMMATORY STRESS WITHIN GASTRIC MUCOSA AND ACTIVATES MULTIPLE ONCOGENIC PATHWAYS IN EPITHELIAL CELLS. A GROWING LIST OF THESE PATHWAYS INCLUDES NF-KAPPAB, ACTIVATOR PROTEIN-1, PI3K, SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3, WNT/BETA-CATENIN AND CYCLOOXYGENASE 2. H. PYLORI INDUCES EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, WHICH PLAY CRITICAL ROLES IN ONCOGENIC TRANSFORMATION. IN ADDITION, INVESTIGATIONS INTO GASTRIC STEM CELL OR PROGENITOR CELL BIOLOGY HAVE SHED LIGHT ON THE MECHANISMS THROUGH WHICH GASTRIC CANCER MAY ORIGINATE. CONTINUED INVESTIGATION IN THESE AREAS WILL YIELD NOVEL INSIGHTS AND HELP TO ELUCIDATE THE MECHANISMS OF BACTERIA-INDUCED CARCINOGENESIS. 2010 19 2656 26 EPIMUTATION AND CANCER: A NEW CARCINOGENIC MECHANISM OF LYNCH SYNDROME (REVIEW). EPIMUTATION IS DEFINED AS ABNORMAL TRANSCRIPTIONAL REPRESSION OF ACTIVE GENES AND/OR ABNORMAL ACTIVATION OF USUALLY REPRESSED GENES CAUSED BY ERRORS IN EPIGENETIC GENE REPRESSION. EPIMUTATION ARISES IN SOMATIC CELLS AND THE GERMLINE, AND CONSTITUTIONAL EPIMUTATION MAY ALSO OCCUR. EPIMUTATION IS THE FIRST STEP OF TUMORIGENESIS AND CAN BE A DIRECT CAUSE OF CARCINOGENESIS. CANCERS ASSOCIATED WITH EPIMUTATION INCLUDE LYNCH SYNDROME (HEREDITARY NON-POLYPOSIS COLORECTAL CANCER, HNPCC), CHRONIC LYMPHOCYTIC LEUKEMIA, BREAST CANCER AND OVARIAN CANCER. EPIMUTATION HAS BEEN SHOWN FOR MANY TUMOR SUPPRESSOR GENES, INCLUDING RB, VHL, HMLH1, APC AND BRCA1, IN SPORADIC CANCERS. METHYLATION HAS RECENTLY BEEN SHOWN IN DNA FROM NORMAL TISSUES AND PERIPHERAL BLOOD IN CASES OF SPORADIC COLORECTAL CANCER AND MANY STUDIES SHOW CONSTITUTIVE EPIMUTATION IN CANCERS. EPIMUTATION OF DNA MISMATCH REPAIR (MMR) GENES (BRCA1, HMLH1 AND HMSH2) INVOLVED IN DEVELOPMENT FAMILIAL CANCERS HAS ALSO BEEN FOUND. THESE RESULTS HAVE LED TO A FOCUS ON EPIMUTATION AS A NOVEL ONCOGENIC MECHANISM. 2012 20 4134 37 MECHANISMS OF HUMAN HEPATOCARCINOGENESIS. THE MAJOR RISK FACTORS AND ETIOLOGICAL AGENTS RESPONSIBLE FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN HUMANS HAVE BEEN IDENTIFIED AND CHARACTERIZED. AMONG THESE ARE CHRONIC INFECTION WITH HEPATITIS B VIRUS OR HEPATITIS C VIRUS, EXPOSURE TO AFLATOXIN B1, AND CIRRHOSIS OF ANY ETIOLOGY (INCLUDING ALCOHOLIC CIRRHOSIS AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES). BOTH CHRONIC HEPATITIS AND CIRRHOSIS REPRESENT MAJOR PRENEOPLASTIC CONDITIONS OF THE LIVER AS THE MAJORITY OF HEPATOCELLULAR CARCINOMAS ARISE IN THESE PATHOLOGICAL SETTINGS. HEPATOCARCINOGENESIS REPRESENTS A LINEAR AND PROGRESSIVE PROCESS IN WHICH SUCCESSIVELY MORE ABERRANT MONOCLONAL POPULATIONS OF HEPATOCYTES EVOLVE. REGENERATIVE HEPATOCYTES IN FOCAL LESIONS IN THE INFLAMED LIVER (CHRONIC HEPATITIS OR CIRRHOSIS) GIVE RISE TO HYPERPLASTIC HEPATOCYTE NODULES, AND THESE PROGRESS TO DYSPLASTIC NODULES, WHICH ARE THOUGHT TO BE THE DIRECT PRECURSOR OF HEPATOCELLULAR CARCINOMA. IN MOST CASES, THE NEOPLASTIC TRANSFORMATION OF HEPATOCYTES RESULTS FROM ACCUMULATION OF GENETIC DAMAGE DURING THE REPETITIVE CELLULAR PROLIFERATION THAT OCCURS IN THE INJURED LIVER IN RESPONSE TO PARACRINE GROWTH FACTOR AND CYTOKINE STIMULATION. HEPATOCELLULAR CARCINOMAS EXHIBIT NUMEROUS GENETIC ABNORMALITIES (INCLUDING CHROMOSOMAL DELETIONS, REARRANGEMENTS, ANEUPLOIDY, GENE AMPLIFICATIONS, AND MUTATIONS), AS WELL AS EPIGENETIC ALTERATIONS (INCLUDING MODULATION OF DNA METHYLATION). THESE GENETIC AND EPIGENETIC ALTERATIONS COMBINE TO ACTIVATE POSITIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING CELLULAR PROTO-ONCOGENES AND THEIR MITOGENIC SIGNALING PATHWAYS) AND INACTIVATE NEGATIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING TUMOR SUPPRESSOR GENES), RESULTING IN CELLS WITH AUTONOMOUS GROWTH POTENTIAL. HOWEVER, HEPATOCELLULAR CARCINOMAS EXHIBIT A HIGH DEGREE OF GENETIC HETEROGENEITY, SUGGESTING THAT MULTIPLE MOLECULAR PATHWAYS MAY BE INVOLVED IN THE GENESIS OF SUBSETS OF HEPATOCELLULAR NEOPLASMS. CONTINUED INVESTIGATION OF THE MECHANISMS OF HEPATOCARCINOGENESIS WILL REFINE OUR CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR BASIS FOR NEOPLASTIC TRANSFORMATION IN LIVER, ENABLING THE DEVELOPMENT OF EFFECTIVE STRATEGIES FOR PREVENTION AND/OR MORE EFFECTIVE TREATMENT OF HEPATOCELLULAR CARCINOMA. 2003