1 3396 115 HOST SHP1 PHOSPHATASE ANTAGONIZES HELICOBACTER PYLORI CAGA AND CAN BE DOWNREGULATED BY EPSTEIN-BARR VIRUS. MOST IF NOT ALL GASTRIC CANCERS ARE ASSOCIATED WITH CHRONIC INFECTION OF THE STOMACH MUCOSA WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS(1-4). APPROXIMATELY 10% OF GASTRIC CANCERS ALSO HARBOUR EPSTEIN-BARR VIRUS (EBV) IN THE CANCER CELLS(5,6). FOLLOWING DELIVERY INTO GASTRIC EPITHELIAL CELLS VIA TYPE IV SECRETION(7,8), THE CAGA-ENCODED CAGA PROTEIN UNDERGOES TYROSINE PHOSPHORYLATION ON THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS INITIALLY BY SRC FAMILY KINASES (SFKS) AND THEN BY C-ABL(9,10). TYROSINE-PHOSPHORYLATED CAGA BINDS TO THE PRO-ONCOGENIC PROTEIN TYROSINE PHOSPHATASE SHP2 AND THEREBY DEREGULATES THE PHOSPHATASE ACTIVITY(11,12), WHICH HAS BEEN CONSIDERED TO PLAY AN IMPORTANT ROLE IN GASTRIC CARCINOGENESIS(13). HERE WE SHOW THAT THE SHP2 HOMOLOGUE SHP1 INTERACTS WITH CAGA INDEPENDENTLY OF THE EPIYA MOTIF. THE INTERACTION POTENTIATES THE PHOSPHATASE ACTIVITY OF SHP1 THAT DAMPENS THE ONCOGENIC ACTION OF CAGA BY DEPHOSPHORYLATING THE CAGA EPIYA MOTIFS. IN VITRO INFECTION OF GASTRIC EPITHELIAL CELLS WITH EBV INDUCES SHP1 PROMOTER HYPERMETHYLATION, WHICH STRENGTHENS PHOSPHORYLATION-DEPENDENT CAGA ACTION VIA EPIGENETIC DOWNREGULATION OF SHP1 EXPRESSION. CLINICAL SPECIMENS OF EBV-POSITIVE GASTRIC CANCERS ALSO EXHIBIT SHP1 HYPERMETHYLATION WITH REDUCED SHP1 EXPRESSION. THE RESULTS REVEAL THAT SHP1 IS THE LONG-SOUGHT PHOSPHATASE THAT CAN ANTAGONIZE CAGA. AUGMENTED H. PYLORI CAGA ACTIVITY, VIA SHP1 INHIBITION, MIGHT ALSO CONTRIBUTE TO THE DEVELOPMENT OF EBV-POSITIVE GASTRIC CANCER. 2016 2 4409 48 MOLECULAR ANATOMY AND PATHOGENIC ACTIONS OF HELICOBACTER PYLORI CAGA THAT UNDERPIN GASTRIC CARCINOGENESIS. CHRONIC INFECTION WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS IS THE STRONGEST RISK FACTOR FOR GASTRIC CANCER. THE CAGA GENE PRODUCT, CAGA, IS DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE BACTERIAL TYPE IV SECRETION SYSTEM. DELIVERED CAGA THEN UNDERGOES TYROSINE PHOSPHORYLATION AT THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS IN ITS C-TERMINAL REGION AND ACTS AS AN ONCOGENIC SCAFFOLD PROTEIN THAT PHYSICALLY INTERACTS WITH MULTIPLE HOST SIGNALING PROTEINS IN BOTH TYROSINE PHOSPHORYLATION-DEPENDENT AND -INDEPENDENT MANNERS. ANALYSIS OF CAGA USING IN VITRO CULTURED GASTRIC EPITHELIAL CELLS HAS INDICATED THAT THE NONPHYSIOLOGICAL SCAFFOLDING ACTIONS OF CAGA CELL-AUTONOMOUSLY PROMOTE THE MALIGNANT TRANSFORMATION OF THE CELLS BY ENDOWING THE CELLS WITH MULTIPLE PHENOTYPIC CANCER HALLMARKS: SUSTAINED PROLIFERATION, EVASION OF GROWTH SUPPRESSORS, INVASIVENESS, RESISTANCE TO CELL DEATH, AND GENOMIC INSTABILITY. TRANSGENIC EXPRESSION OF CAGA IN MICE LEADS TO IN VIVO ONCOGENIC ACTION OF CAGA WITHOUT ANY OVERT INFLAMMATION. THE IN VIVO ONCOGENIC ACTIVITY OF CAGA IS FURTHER POTENTIATED IN THE PRESENCE OF CHRONIC INFLAMMATION. SINCE HELICOBACTER PYLORI INFECTION TRIGGERS A PROINFLAMMATORY RESPONSE IN HOST CELLS, A FEEDFORWARD STIMULATION LOOP THAT AUGMENTS THE ONCOGENIC ACTIONS OF CAGA AND INFLAMMATION IS CREATED IN CAGA-INJECTED GASTRIC MUCOSA. GIVEN THAT HELICOBACTER PYLORI IS NO LONGER COLONIZED IN ESTABLISHED GASTRIC CANCER LESIONS, THE MULTISTEP NATURE OF GASTRIC CANCER DEVELOPMENT SHOULD INCLUDE A "HIT-AND-RUN" PROCESS OF CAGA ACTION. THUS, ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS THAT COMPENSATE FOR CAGA-DIRECTED CANCER HALLMARKS MAY BE REQUIRED FOR COMPLETION OF THE "HIT-AND-RUN" PROCESS OF GASTRIC CARCINOGENESIS. 2020 3 2377 42 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 4 1540 40 DNA METHYLATION IN GASTRIC CANCER, RELATED TO HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS. GASTRIC CANCER IS A LEADING CAUSE OF CANCER DEATH WORLDWIDE, AND SIGNIFICANT EFFORT HAS BEEN FOCUSED ON CLARIFYING THE PATHOLOGY OF GASTRIC CANCER. IN PARTICULAR, THE DEVELOPMENT OF GENOME-WIDE ANALYSIS TOOLS HAS ENABLED THE DETECTION OF GENETIC AND EPIGENETIC ALTERATIONS IN GASTRIC CANCER; FOR EXAMPLE, ABERRANT DNA METHYLATION IN GENE PROMOTER REGIONS IS THOUGHT TO PLAY A CRUCIAL ROLE IN GASTRIC CARCINOGENESIS. THE ETIOLOGICAL VIEWPOINT IS ALSO ESSENTIAL FOR THE STUDY OF GASTRIC CANCERS, AND TWO DISTINCT PATHOGENS, HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV), ARE KNOWN TO PARTICIPATE IN GASTRIC CARCINOGENESIS. CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM DUE TO H. PYLORI INFECTION INDUCES ABERRANT POLYCLONAL METHYLATION THAT MAY LEAD TO AN INCREASED RISK OF GASTRIC CANCER. IN ADDITION, EBV INFECTION IS KNOWN TO CAUSE EXTENSIVE METHYLATION, AND EBV-POSITIVE GASTRIC CANCERS DISPLAY A HIGH METHYLATION EPIGENOTYPE, IN WHICH ABERRANT METHYLATION EXTENDS TO NOT ONLY POLYCOMB REPRESSIVE COMPLEX (PRC)-TARGET GENES IN EMBRYONIC STEM CELLS BUT ALSO NON-PRC-TARGET GENES. HERE, WE REVIEW ABERRANT DNA METHYLATION IN GASTRIC CANCER AND THE ASSOCIATION BETWEEN METHYLATION AND INFECTION WITH H. PYLORI AND EBV. 2014 5 3225 31 HELICOBACTER PYLORI INFECTION INTRODUCES DNA DOUBLE-STRAND BREAKS IN HOST CELLS. GASTRIC CANCER IS AN INFLAMMATION-RELATED MALIGNANCY RELATED TO LONG-STANDING ACUTE AND CHRONIC INFLAMMATION CAUSED BY INFECTION WITH THE HUMAN BACTERIAL PATHOGEN HELICOBACTER PYLORI. INFLAMMATION CAN RESULT IN GENOMIC INSTABILITY. HOWEVER, THERE ARE CONSIDERABLE DATA THAT H. PYLORI ITSELF CAN ALSO PRODUCE GENOMIC INSTABILITY BOTH DIRECTLY AND THROUGH EPIGENETIC PATHWAYS. OVERALL, THE MECHANISMS OF H. PYLORI-INDUCED HOST GENOMIC INSTABILITIES REMAIN POORLY UNDERSTOOD. WE USED MICROARRAY SCREENING OF H. PYLORI-INFECTED HUMAN GASTRIC BIOPSY SPECIMENS TO IDENTIFY CANDIDATE GENES INVOLVED IN H. PYLORI-INDUCED HOST GENOMIC INSTABILITIES. WE FOUND UPREGULATION OF ATM EXPRESSION IN VIVO IN GASTRIC MUCOSAL CELLS INFECTED WITH H. PYLORI. USING GASTRIC CANCER CELL LINES, WE CONFIRMED THAT THE H. PYLORI-RELATED ACTIVATION OF ATM WAS DUE TO THE ACCUMULATION OF DNA DOUBLE-STRAND BREAKS (DSBS). DSBS WERE OBSERVED FOLLOWING INFECTION WITH BOTH CAG PATHOGENICITY ISLAND (PAI)-POSITIVE AND -NEGATIVE STRAINS, BUT THE EFFECT WAS MORE ROBUST WITH CAG PAI-POSITIVE STRAINS. THESE RESULTS ARE CONSISTENT WITH THE FACT THAT INFECTIONS WITH BOTH CAG PAI-POSITIVE AND -NEGATIVE STRAINS ARE ASSOCIATED WITH GASTRIC CARCINOGENESIS, BUT THE RISK IS HIGHER IN INDIVIDUALS INFECTED WITH CAG PAI-POSITIVE STRAINS. 2014 6 6841 36 [MECHANISMS OF H. PYLORI INFECTION-INDUCED GASTRIC CARCINOGENESIS]. MANY EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED A STRONG ASSOCIATION BETWEEN H. PYLORI (HELICOBACTER PYLORI) INFECTION AND HUMAN GASTRIC CANCER DEVELOPMENT. THE PRECISE MECHANISMS ACCOUNTING FOR GASTRIC CANCER DEVELOPMENT INDUCED BY H. PYLORI INFECTION ARE STILL NOT COMPLETELY UNDERSTOOD. HOWEVER, IT SHOULD BE REASONABLE TO ASSUME THAT THERE ARE TWO DISTINCT MOLECULAR PATHWAYS FOR GASTRIC CARCINOGENESIS BY H. PYLORI INFECTION; THE DIRECT ACTION OF THE BACTERIA ITSELF ON GASTRIC EPITHELIAL CELLS, AND THE ACCUMULATION OF GENETIC CHANGES CAUSED BY PROLONGED BACTERIAL INFECTION AND CHRONIC INFLAMMATION. AS A DIRECT ACTION OF H. PYLORI, BACTERIAL PROTEINS SUCH AS CAGA COULD BE DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE TYPE IV SECRETION APPARATUS AND MODIFY THE HOST CELL FUNCTIONS RELATED TO CELL PROLIFERATION. IN ADDITION TO THE DIRECT BACTERIAL ACTION, H. PYLORI INFECTION AND THE RESULTANT INFLAMMATORY RESPONSE CAUSE VARIOUS GENETIC AND EPIGENETIC CHANGES IN TUMOR-RELATED GENES OF THE GASTRIC EPITHELIAL CELLS. NOTABLY, EXPRESSION OF AID (ACTIVATION-INDUCED CYTIDINE DEAMINASE), A DNA EDITING ENZYME THAT UNDERGOES SOMATIC HYPERMUTATION ON HUMAN GENES, IS INDUCED IN RESPONSE TO H. PYLORI INFECTION AND PROINFLAMMATORY CYTOKINE STIMULATION IN HUMAN GASTRIC EPITHELIAL CELLS. AS A RESULT, THE ACCUMULATION OF GENETIC ALTERATIONS WOULD PERSIST UNTIL THE CLINICAL STAGE OF ATROPHIC GASTRITIS AND EVENTUALLY TRIGGER THE MALIGNANT TRANSFORMATION OF GASTRIC CELLS. 2010 7 4727 27 NOTABLE ROLES OF EZH2 AND DNMT1 IN EPIGENETIC DORMANCY OF THE SHP1 GENE DURING THE PROGRESSION OF CHRONIC MYELOID LEUKAEMIA. TUMOR DEVELOPMENT IS ASSOCIATED WITH THE METHYLATION OF CYTOSINE-GUANINE (CPG) ISLANDS. THE OCCURRENCE OF METHYLATION REQUIRES SEVERAL FACTORS, SUCH AS DNA METHYLATION SYSTEMS AND POLYCOMB GROUP (PCG) PROTEINS. AT PRESENT, NOVEL DRUGS ARE NEEDED FOR THE TREATMENT OF CHRONIC MYELOID LEUKAEMIA (CML), PARTICULARLY CONSIDERING THE CURRENT PROGNOSIS OF CML. THE METHYLATION STATUS OF THE SRC HOMOLOGY 2 DOMAIN-CONTAINING TYROSINE PHOSPHATASE 1 (SHP1) GENE, A NEGATIVE REGULATOR OF SIGNAL TRANSDUCTION, HAS BEEN IDENTIFIED AS BEING ALTERED IN NUMEROUS HAEMATOLOGICAL MALIGNANCIES. DNA METHYLTRANSFERASE 1 (DNMT1) AND THE PCG PROTEIN COMPLEX MEMBER ENHANCER OF ZESTE HOMOLOG 2 (EZH2) PARTICIPATE IN A NUMBER OF GENE METHYLATION PROCESSES. THE PRESENT STUDY INVESTIGATED THE METHYLATION STATUS OF THE SHP1 GENE IN CML, AND EXAMINED THE ASSOCIATION BETWEEN DNMT1 AND EZH2 ACTIVITY AND THE SHP1 GENE METHYLATION STATUS TO DEVELOP NOVEL STRATEGIES FOR THE TREATMENT OF CML. THE RESULTS REVEALED THAT SHP1 GENE METHYLATION STATUS WAS ALTERED DURING THE PROGRESSION OF CML. THESE DATA INDICATED THAT SHP1 GENE METHYLATION IS ASSOCIATED WITH THE PROGRESSION OF THIS DISEASE. THE ASSOCIATIONS OF DNMT1 AND EZH2 ACTIVITIES WITH THE METHYLATION STATUS OF THE SHP1 GENE WERE ADDITIONALLY INVESTIGATED VIA CHROMATIN IMMUNOPRECIPITATION. DNMT1 AND EZH2 WERE REVEALED TO BE BOUND TO THE PROMOTER REGION OF THE SHP1 GENE, AND WERE INVOLVED IN THE PROCESS OF SHP1 METHYLATION. FURTHERMORE, DNMT1 AND EZH2 WERE ASSOCIATED WITH DISEASE PROGRESSION. THUS, THE FINDINGS OF THE PRESENT STUDY SUGGEST A NEW TARGET FOR THE TREATMENT OF CML, PARTICULARLY FOR FUTURE DRUG DEVELOPMENT. 2017 8 4725 30 NORMAL GASTRIC TISSUE HELICOBACTER PYLORI INFECTION IS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION, INCREASED MITOTIC TICK RATE, TISSUE CELL COMPOSITION, AND NATURAL KILLER CELL METHYLATION ALTERATIONS. BACKGROUND: GASTRIC ADENOCARCINOMAS ARE A LEADING CAUSE OF GLOBAL MORTALITY, ASSOCIATED WITH CHRONIC INFECTION WITH HELICOBACTER PYLORI . THE MECHANISMS BY WHICH INFECTION WITH H. PYLORI CONTRIBUTES TO CARCINOGENESIS ARE NOT WELL UNDERSTOOD. RECENT STUDIES FROM SUBJECTS WITH AND WITHOUT GASTRIC CANCER HAVE IDENTIFIED SIGNIFICANT DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA ASSOCIATED WITH H. PYLORI INFECTION AND GASTRIC CANCER RISK. HERE WE FURTHER INVESTIGATED DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA IN GASTRIC CANCER CASES (N = 42) AND CONTROL SUBJECTS (N = 42) WITH H. PYLORI INFECTION DATA. WE ASSESSED TISSUE CELL TYPE COMPOSITION, DNA METHYLATION ALTERATIONS WITHIN CELL POPULATIONS, EPIGENETIC AGING, AND REPETITIVE ELEMENT METHYLATION. RESULTS: IN NORMAL GASTRIC MUCOSA OF BOTH GASTRIC CANCER CASES AND CONTROL SUBJECTS, WE OBSERVED INCREASED EPIGENETIC AGE ACCELERATION ASSOCIATED WITH H. PYLORI INFECTION. WE ALSO OBSERVED AN INCREASED MITOTIC TICK RATE ASSOCIATED WITH H. PYLORI INFECTION IN BOTH GASTRIC CANCER CASES AND CONTROLS. SIGNIFICANT DIFFERENCES IN IMMUNE CELL POPULATIONS ASSOCIATED WITH H. PYLORI INFECTION IN NORMAL TISSUE FROM CANCER CASES AND CONTROLS WERE IDENTIFIED USING DNA METHYLATION CELL TYPE DECONVOLUTION. WE ALSO FOUND NATURAL KILLER CELL-SPECIFIC METHYLATION ALTERATIONS IN NORMAL MUCOSA FROM GASTRIC CANCER PATIENTS WITH H. PYLORI INFECTION. CONCLUSIONS: OUR FINDINGS FROM NORMAL GASTRIC MUCOSA PROVIDE INSIGHT INTO UNDERLYING CELLULAR COMPOSITION AND EPIGENETIC ASPECTS OF H. PYLORI ASSOCIATED GASTRIC CANCER ETIOLOGY. 2023 9 3226 32 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 10 4984 36 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 11 3233 30 HELICOBACTER, INFLAMMATION, AND GASTRIC CANCER. HELICOBACTER PYLORI INFECTION LEADS TO LONG-LASTING CHRONIC INFLAMMATION AND REPRESENTS THE MOST COMMON RISK FACTOR UNDERLYING GASTRIC CANCER. RECENTLY, NEW INSIGHTS INTO THE MECHANISMS THROUGH WHICH H. PYLORI AND MUCOSAL INFLAMMATION LEAD TO CANCER DEVELOPMENT HAVE EMERGED. H. PYLORI VIRULENCE FACTORS, IN PARTICULAR SPECIFIC CAGA GENOTYPES, REPRESENT MAIN FACTORS IN GASTRIC CANCER, INDUCING ALTERED INTRACELLULAR SIGNALING IN EPITHELIAL CELLS. THE CHRONIC NATURE OF H. PYLORI INFECTION APPEARS TO RELATE TO THE VACA VIRULENCE FACTOR AND TH17/TREG MECHANISMS. A ROLE OF H. PYLORI INFECTION IN EPIGENETIC AND MICRORNA DEREGULATION HAS BEEN SHOWN. MUTATION OF THE EPITHELIAL CELL GENOME, A HALLMARK OF CANCER, WAS DEMONSTRATED TO ACCUMULATE IN H. PYLORI INFECTED STOMACH PARTLY DUE TO INADEQUATE DNA REPAIR. GASTRIC STEM CELLS WERE SHOWN TO BE TARGETS OF OXIDATIVE INJURY IN THE HELICOBACTER-INFLAMMATORY MILIEU. RECENT ADVANCES EMPHASIZING THE CONTRIBUTION OF BACTERIAL FACTORS, INFLAMMATORY MEDIATORS, AND THE HOST EPITHELIAL RESPONSE IN GASTRIC CARCINOGENESIS ARE REVIEWED. 2013 12 3221 28 HELICOBACTER PYLORI AND THE MOLECULAR PATHOGENESIS OF INTESTINAL-TYPE GASTRIC CARCINOMA. GASTRIC CARCINOMA IS AN INFLAMMATION-RELATED CANCER CAUSED BY LONG-TERM INFECTION WITH THE HUMAN BACTERIAL PATHOGEN, HELICOBACTER PYLORI. THE PATTERN OF ACUTE-ON-CHRONIC INFLAMMATION CAUSES PROGRESSIVE MUCOSAL DAMAGE WHICH MAY RESULT IN ATROPHY WITH METAPLASTIC EPITHELIA AND EVENTUALLY GASTRIC CANCER. RECENTLY, IT HAS BEEN RECOGNIZED THAT H. PYLORI CAN ALSO CAUSE GENETIC INSTABILITY SUCH AS DOUBLE-STRANDED DNA BREAKS AND CAN PRODUCE GENE ACTIVATION AND SILENCING VIA EPIGENETIC PATHWAYS. AS GENETIC INSTABILITY IS THE HALLMARK OF CANCER, WE HIGHLIGHT RECENT PROGRESS IN UNDERSTANDING THE GASTRIC CARCINOGENESIS IN RELATION TO H. PYLORI-RELATED INFLAMMATION, H. PYLORI-INDUCED DOUBLE-STRANDED DNA BREAKAGE AND ABERRANT GENE EXPRESSION AS WELL AS THE MECHANISMS AND ROLE OF H. PYLORI-ASSOCIATED EPIGENETIC CHANGE IN GENE EXPRESSION. 2014 13 3227 32 HELICOBACTER PYLORI INFECTION-INDUCED H3SER10 PHOSPHORYLATION IN STEPWISE GASTRIC CARCINOGENESIS AND ITS CLINICAL IMPLICATIONS. BACKGROUND: OUR PREVIOUS WORKS HAVE DEMONSTRATED THAT HELICOBACTER PYLORI (HP) INFECTION CAN ALTER HISTONE H3 SERINE 10 PHOSPHORYLATION STATUS IN GASTRIC EPITHELIAL CELLS. HOWEVER, WHETHER HELICOBACTER PYLORI-INDUCED HISTONE H3 SERINE 10 PHOSPHORYLATION PARTICIPATES IN GASTRIC CARCINOGENESIS IS UNKNOWN. WE INVESTIGATE THE EXPRESSION OF HISTONE H3 SERINE 10 PHOSPHORYLATION IN VARIOUS STAGES OF GASTRIC DISEASE AND EXPLORE ITS CLINICAL IMPLICATION. MATERIALS AND METHODS: STOMACH BIOPSY SAMPLES FROM 129 PATIENTS WERE COLLECTED AND STAINED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION, KI67, AND HELICOBACTER PYLORI BY IMMUNOHISTOCHEMISTRY STAINING, EXPRESSED AS LABELING INDEX. THEY WERE CATEGORIZED INTO NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, LOW-GRADE INTRAEPITHELIAL NEOPLASIA, HIGH-GRADE INTRAEPITHELIAL NEOPLASIA, AND INTESTINAL-TYPE GASTRIC CANCER GROUPS. HELICOBACTER PYLORI INFECTION WAS DETERMINED BY EITHER (13) C-UREA BREATH TEST OR IMMUNOHISTOCHEMISTRY STAINING. RESULTS: IN HELICOBACTER PYLORI-NEGATIVE PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION WAS GRADUALLY INCREASED IN NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA GROUPS, PEAKED AT LOW-GRADE INTRAEPITHELIAL NEOPLASIA, AND DECLINED IN HIGH-GRADE INTRAEPITHELIAL NEOPLASIA AND GASTRIC CANCER GROUPS. IN HELICOBACTER PYLORI-INFECTED PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION FOLLOWED THE SIMILAR PATTERN AS ABOVE, WITH INCREASED EXPRESSION OVER THE CORRESPONDING HELICOBACTER PYLORI-NEGATIVE CONTROLS EXCEPT IN NONATROPHIC GASTRITIS PATIENT WHOSE LABELING INDEX WAS DECREASED WHEN COMPARED WITH HELICOBACTER PYLORI-NEGATIVE CONTROL. LABELING INDEX OF KI67 IN HELICOBACTER PYLORI-NEGATIVE GROUPS WAS HIGHER IN GASTRIC CANCER THAN CHRONIC ATROPHIC GASTRITIS AND LOW-GRADE INTRAEPITHELIAL NEOPLASIA GROUPS, AND HIGHER IN INTESTINAL METAPLASIA GROUP COMPARED WITH CHRONIC ATROPHIC GASTRITIS GROUP. IN HELICOBACTER PYLORI-POSITIVE GROUPS, KI67 LABELING INDEX WAS INCREASED STEPWISE FROM NONATROPHIC GASTRITIS TO GASTRIC CANCER EXCEPT SLIGHTLY DECREASE IN CHRONIC ATROPHIC GASTRITIS GROUP. IN ADDITION, WE NOTED THAT HISTONE H3 SERINE 10 PHOSPHORYLATION STAINING IS ACCOMPANIED WITH ITS LOCATION CHANGES FROM GASTRIC GLAND BOTTOM EXPANDED TO WHOLE GLAND AS DISEASE STAGE PROGRESS. CONCLUSIONS: THESE RESULTS INDICATE THAT STEPWISE GASTRIC CARCINOGENESIS IS ASSOCIATED WITH ALTERED HISTONE H3 SERINE 10 PHOSPHORYLATION, HELICOBACTER PYLORI INFECTION ENHANCES HISTONE H3 SERINE 10 PHOSPHORYLATION EXPRESSION IN THESE PROCESSES; IT IS ALSO ACCOMPANIED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION LOCATION CHANGE FROM GLAND BOTTOM STAINING EXPAND TO WHOLE GLAND EXPRESSION. THE RESULTS SUGGEST THAT EPIGENETIC DYSREGULATION MAY PLAY IMPORTANT ROLES IN HELICOBACTER PYLORI-INDUCED GASTRIC CANCER. 2018 14 2943 24 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 15 3232 25 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 16 1321 33 DEMONSTRATION AND CHARACTERIZATION OF MUTATIONS INDUCED BY HELICOBACTER PYLORI ORGANISMS IN GASTRIC EPITHELIAL CELLS. BACKGROUND: HELICOBACTER PYLORI GASTRITIS INCREASES GASTRIC CANCER RISK. MICROSATELLITE INSTABILITY-TYPE MUTATIONS ARE SECONDARY TO DEFICIENT DNA MISMATCH REPAIR. H. PYLORI GASTRITIS IS MORE FREQUENT IN PATIENTS WITH MICROSATELLITE INSTABILITY-POSITIVE GASTRIC CANCERS, AND H. PYLORI ORGANISMS INDEPENDENTLY OF INFLAMMATION CAN REDUCE DNA MISMATCH REPAIR PROTEIN LEVELS, RAISING THE HYPOTHESIS THAT H. PYLORI ORGANISMS MIGHT LEAD TO MUTAGENESIS DURING INFECTION. MATERIALS AND METHODS: MUTATIONS WERE DETECTED USING A GREEN FLUORESCENT PROTEIN REPORTER VECTOR (PEGFP-CA13). GASTRIC CANCER AGS CELLS TRANSFECTED WITH PEGFP-CA13 WERE COCULTURED WITH H. PYLORI OR ESCHERICHIA COLI. THE NUMBERS OF GREEN FLUORESCENT PROTEIN (GFP)-POSITIVE CELLS WERE DETERMINED, AND GFP, HMSH2, AND HMLH1 PROTEIN LEVELS WERE MEASURED BY WESTERN BLOT. THE EFFECT OF H. PYLORI ON CPG METHYLATION STATUS OF HMLH1 WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: GFP LEVELS AND GFP-POSITIVE CELL NUMBERS IN AGS CELLS COCULTURED WITH H. PYLORI SIGNIFICANTLY INCREASED, AS THE LEVELS OF HMLH1 AND HMSH2 DROPPED. H. PYLORI COCULTURES INDUCED LOW-LEVEL CPG METHYLATION OF THE HMLH1 PROMOTER. SEQUENCE ANALYSIS OF CELLS COCULTURED WITH H. PYLORI SHOWED AN INCREASED NUMBER OF FRAMESHIFT MUTATIONS AND POINT MUTATIONS AS COMPARED TO CELLS NOT COCULTURED WITH H. PYLORI (P = .03 AND P = .001, RESPECTIVELY). CONCLUSIONS: THIS IS THE FIRST REPORT SHOWING THAT H. PYLORI BACTERIA MAY LEAD TO ACCUMULATION OF GENOMIC MUTATIONS, INDEPENDENTLY OF UNDERLYING INFLAMMATION. THIS IS ASSOCIATED WITH REDUCED DNA MISMATCH REPAIR, AND IS AT LEAST IN PART ASSOCIATED WITH CPG METHYLATION OF THE HMLH1 PROMOTER. THESE DATA SUPPORT THE NOTION THAT H. PYLORI-INDUCED MUTATIONS AND EPIGENETIC ALTERATIONS IN GASTRIC EPITHELIAL CELLS DURING CHRONIC GASTRITIS MAY CONTRIBUTE TO AN INCREASED RISK OF GASTRIC CANCER ASSOCIATED WITH H. PYLORI INFECTION. 2006 17 4114 30 MECHANISMS FOR THE INDUCTION OF GASTRIC CANCER BY HELICOBACTER PYLORI INFECTION: ABERRANT DNA METHYLATION PATHWAY. MULTIPLE PATHOGENIC MECHANISMS BY WHICH HELICOBACTER PYLORI INFECTION INDUCES GASTRIC CANCER HAVE BEEN ESTABLISHED IN THE LAST TWO DECADES. IN PARTICULAR, ABERRANT DNA METHYLATION IS INDUCED IN MULTIPLE DRIVER GENES, WHICH INACTIVATES THEM. METHYLATION PROFILES IN GASTRIC CANCER ARE ASSOCIATED WITH SPECIFIC SUBTYPES, SUCH AS MICROSATELLITE INSTABILITY. RECENT COMPREHENSIVE AND INTEGRATED ANALYSES SHOWED THAT MANY CANCER-RELATED PATHWAYS ARE MORE FREQUENTLY ALTERED BY ABERRANT DNA METHYLATION THAN BY MUTATIONS. ABERRANT DNA METHYLATION CAN EVEN BE PRESENT IN NONCANCEROUS GASTRIC MUCOSAE, PRODUCING AN "EPIGENETIC FIELD FOR CANCERIZATION." MECHANISTICALLY, H. PYLORI-INDUCED CHRONIC INFLAMMATION, BUT NOT H. PYLORI ITSELF, PLAYS A DIRECT ROLE IN THE INDUCTION OF ABERRANT DNA METHYLATION. THE EXPRESSION OF THREE INFLAMMATION-RELATED GENES, IL1B, NOS2, AND TNF, IS HIGHLY ASSOCIATED WITH THE INDUCTION OF ABERRANT DNA METHYLATION. IMPORTANTLY, THE DEGREE OF ACCUMULATED ABERRANT DNA METHYLATION IS STRONGLY CORRELATED WITH GASTRIC CANCER RISK. A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THE UTILITY OF EPIGENETIC CANCER RISK DIAGNOSIS FOR METACHRONOUS GASTRIC CANCER. SUPPRESSION OF ABERRANT DNA METHYLATION BY A DEMETHYLATING AGENT WAS SHOWN TO INHIBIT GASTRIC CANCER DEVELOPMENT IN AN ANIMAL MODEL. INDUCTION OF ABERRANT DNA METHYLATION IS THE MAJOR PATHWAY BY WHICH H. PYLORI INFECTION INDUCES GASTRIC CANCER, AND THIS CAN BE UTILIZED FOR TRANSLATIONAL OPPORTUNITIES. 2017 18 2661 31 EPSTEIN-BARR VIRUS AND GASTRIC CARCINOMA--VIRAL CARCINOGENESIS THROUGH EPIGENETIC MECHANISMS. EPSTEIN-BARR VIRUS (EBV)-ASSOCIATED GASTRIC CARCINOMA (GC) IS THE MONOCLONAL GROWTH OF EBV-INFECTED EPITHELIAL CELLS, AND THE ENTITY WAS RECOGNIZED ONLY RECENTLY. EBV-ASSOCIATED GC IS DISTRIBUTED WORLDWIDE AND MORE THAN 90,000 PATIENTS ARE ESTIMATED TO DEVELOP GC ANNUALLY IN ASSOCIATION WITH EBV (10% OF TOTAL GC). EBV-ASSOCIATED GC OCCURS IN TWO FORMS IN TERMS OF THE HISTOLOGICAL FEATURES, I.E., LYMPHOEPITHELIOMA-LIKE GC AND ORDINARY TYPE OF GC. BOTH SHARE CHARACTERISTIC CLINICOPATHOLOGICAL FEATURES, SUCH AS THE PREFERENTIAL OCCURRENCE AS MULTIPLE CANCER AND REMNANT STOMACH CANCER. WHILE THE EXPRESSION OF EBV-LATENT GENES IS RESTRICTED TO SEVERAL IN THE INFECTED CELLS (LATENCY I), EBV-ASSOCIATED GC SHOWS GASTRIC CELL PHENOTYPE, RESISTANCE TO APOPTOSIS, AND THE PRODUCTION OF IMMUNOMODULATOR MOLECULES. RECENTLY, GLOBAL AND NON-RANDOM CPG ISLAND METHYLATION OF THE PROMOTER REGION OF MANY CANCER-RELATED GENES HAS BEEN DEMONSTRATED WITH THEIR DECREASED EXPRESSION, SUCH AS P16 INK4A, P73 AND E-CADHERIN. THIS ABNORMALITY IS ACCOMPANIED BY METHYLATION OF THE EBV GENOME ITSELF, SUGGESTING A PROCESS OF VIRUS-DRIVEN HYPERMETHYLATION IN THE DEVELOPMENT OF NEOPLASTIC CELLS. FURTHER STUDIES ARE NECESSARY TO DETERMINE THE PRECISE SEQUENCE OF EBV INFECTION, METHYLATION, TRANSFORMATION AND SELECTION OF THE PREDOMINANT CLONE WITHIN THE STOMACH MUCOSA. FUTURE STUDIES ARE ALSO DESIRABLE FOR THE TARGET AND STRATEGY OF THERAPY, SUCH AS INITIATING VIRAL REPLICATION OR REVERSING THE DNA METHYLATION OF CELLULAR GENES. 2008 19 2430 27 EPIGENETIC SILENCING OF MIR-210 INCREASES THE PROLIFERATION OF GASTRIC EPITHELIUM DURING CHRONIC HELICOBACTER PYLORI INFECTION. PERSISTENT COLONIZATION OF THE GASTRIC MUCOSA BY HELICOBACTER PYLORI (HP) ELICITS CHRONIC INFLAMMATION AND ABERRANT EPITHELIAL CELL PROLIFERATION, WHICH INCREASES THE RISK OF GASTRIC CANCER. HERE WE EXAMINE THE ABILITY OF MICRORNAS TO MODULATE GASTRIC CELL PROLIFERATION IN RESPONSE TO PERSISTENT HP INFECTION AND FIND THAT EPIGENETIC SILENCING OF MIR-210 PLAYS A KEY ROLE IN GASTRIC DISEASE PROGRESSION. IMPORTANTLY, DNA METHYLATION OF THE MIR-210 GENE IS INCREASED IN HP-POSITIVE HUMAN GASTRIC BIOPSIES AS COMPARED WITH HP-NEGATIVE CONTROLS. MOREOVER, SILENCING OF MIR-210 IN GASTRIC EPITHELIAL CELLS PROMOTES PROLIFERATION. WE IDENTIFY STMN1 AND DIMT1 AS MIR-210 TARGET GENES AND DEMONSTRATE THAT INHIBITION OF MIR-210 EXPRESSION AUGMENTS CELL PROLIFERATION BY ACTIVATING STMN1 AND DIMT1. TOGETHER, OUR RESULTS HIGHLIGHT INFLAMMATION-INDUCED EPIGENETIC SILENCING OF MIR-210 AS A MECHANISM OF INDUCTION OF CHRONIC GASTRIC DISEASES, INCLUDING CANCER, DURING HP INFECTION. 2014 20 3229 31 HELICOBACTER PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. HELICOBACTER PYLORI (H. PYLORI) INFECT OVER HALF OF THE WORLD'S POPULATION. THE PREVALENCE OF H. PYLORI INFECTION AND THE PREDOMINANT GENOTYPE OF H. PYLORI VIRULENCE FACTORS VARY CONSIDERABLY ACROSS DIFFERENT GEOGRAPHICAL REGIONS. H. PYLORI COULD UNIQUELY PERSIST FOR DECADES IN THE HARSH STOMACH ENVIRONMENT, WHERE IT DAMAGES THE GASTRIC MUCOSA AND CHANGES THE PATTERN OF GASTRIC HORMONE RELEASE, THEREBY AFFECTS GASTRIC PHYSIOLOGY. BY UTILIZING VARIOUS VIRULENCE FACTORS, H. PYLORI TARGETS DIFFERENT CELLULAR PROTEINS TO MODULATE THE HOST INFLAMMATORY RESPONSE AND INITIATE MULTIPLE "HITS" ON THE GASTRIC MUCOSA, RESULTING IN CHRONIC GASTRITIS AND PEPTIC ULCERATION. AMONG THE LONG-TERM CONSEQUENCES OF H. PYLORI INFECTION IS GASTRIC MALIGNANCIES, PARTICULARLY GASTRIC CANCER (GC) AND GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA. AS SUCH, H. PYLORI HAS BEEN RECOGNIZED AS A CLASS I CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. DESPITE A CLOSE CAUSAL LINK BETWEEN H. PYLORI INFECTION AND THE DEVELOPMENT OF GASTRIC MALIGNANCIES, THE PRECISE MECHANISMS INVOLVED IN THIS PROCESS ARE STILL OBSCURE. STUDIES OVER THE PAST TWO DECADES HAVE REVEALED THAT H. PYLORI EXERT ONCOGENIC EFFECTS ON GASTRIC MUCOSA THROUGH A COMPLEX INTERACTION BETWEEN BACTERIAL FACTORS, HOST FACTORS, AND ENVIRONMENTAL FACTORS. NUMEROUS SIGNALING PATHWAYS CAN BE ACTIVATED BY H. PYLORI. IN THIS REVIEW, WE AIM TO ELABORATE ON THE RECENT DEVELOPMENTS IN THE PATHOPHYSIOLOGICAL MECHANISMS OF H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. 2014