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 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 3 6871 24 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 4 1730 31 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE. 2007 5 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 6 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 7 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 8 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 9 3216 30 HEDGEHOG SIGNALING PATHWAY AND GASTROINTESTINAL STEM CELL SIGNALING NETWORK (REVIEW). HEDGEHOG, BMP/TGFBETA, FGF, WNT AND NOTCH SIGNALING PATHWAYS CONSTITUTE THE STEM CELL SIGNALING NETWORK, WHICH PLAYS A KEY ROLE IN A VARIETY OF PROCESSES, SUCH AS EMBRYOGENESIS, MAINTENANCE OF ADULT TISSUE HOMEOSTASIS, TISSUE REPAIR DURING CHRONIC PERSISTENT INFLAMMATION, AND CARCINOGENESIS. SONIC HEDGEHOG (SHH), INDIAN HEDGEHOG (IHH) AND DESERT HEDGEHOG (DHH) BIND TO PTCH1/PTCH OR PTCH2 RECEPTOR TO RELEASE SMOOTHENED (SMO) SIGNAL TRANSDUCER FROM PATCHED-DEPENDENT SUPPRESSION. SMO THEN ACTIVATES STK36 SERINE/THREONINE KINASE TO STABILIZE GLI FAMILY MEMBERS AND TO PHOSPHORYLATE SUFU FOR NUCLEAR ACCUMULATION OF GLI. HEDGEHOG SIGNALING ACTIVATION LEADS TO GLI-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF TARGET GENES, SUCH AS GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1. GLI1-DEPENDENT POSITIVE FEEDBACK LOOP COMBINED WITH PTCH1-DEPENDENT NEGATIVE FEEDBACK LOOP GIVES RISE TO TRANSIENT PROLIFERATION OF HEDGEHOG TARGET CELLS. IGUANA HOMOLOGS (DZIP1 AND DZIP1L) AND COSTAL-2 HOMOLOGS (KIF7 AND KIF27) ARE IDENTIFIED BY COMPARATIVE INTEGROMICS. SHH-DEPENDENT PARIETAL CELL PROLIFERATION IS IMPLICATED IN GASTRIC MUCOSAL REPAIR DURING CHRONIC HELICOBACTER PYLORI INFECTION. BMP-RUNX3 SIGNALING INDUCES IHH EXPRESSION IN SURFACE DIFFERENTIATED EPITHELIAL CELLS OF STOMACH AND INTESTINE. HEDGEHOG SIGNALS FROM EPITHELIAL CELLS THEN INDUCES FOXL1-MEDIATED BMP4 UPREGULATION IN MESENCHYMAL CELLS. HEDGEHOG SIGNALING IS FREQUENTLY ACTIVATED IN ESOPHAGEAL CANCER, GASTRIC CANCER AND PANCREATIC CANCER DUE TO TRANSCRIPTIONAL UPREGULATION OF HEDGEHOG LIGANDS AND EPIGENETIC SILENCING OF HHIP1/HHIP GENE, ENCODING THE HEDGEHOG INHIBITOR. HOWEVER, HEDGEHOG SIGNALING IS RARELY ACTIVATED IN COLORECTAL CANCER DUE TO NEGATIVE REGULATION BY THE CANONICAL WNT SIGNALING PATHWAY. HEDGEHOG SIGNALING MOLECULES OR TARGETS, SUCH AS SHH, IHH, HHIP1, PTCH1 AND GLI1, ARE APPLIED AS BIOMARKERS FOR CANCER DIAGNOSTICS, PROGNOSTICS AND THERAPEUTICS. SMALL-MOLECULE INHIBITORS FOR SMO OR STK36 ARE SUITABLE TO BE USED FOR TREATMENT OF HEDGEHOG-DEPENDENT CANCER. 2006 10 3805 32 INTESTINE-SPECIFIC HOMEOBOX (ISX) INDUCES INTESTINAL METAPLASIA AND CELL PROLIFERATION TO CONTRIBUTE TO GASTRIC CARCINOGENESIS. BACKGROUND: HELICOBACTER PYLORI INDUCES CHRONIC INFLAMMATION AND INTESTINAL METAPLASIA (IM) THROUGH GENETIC AND EPIGENETIC CHANGES AND ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS THAT CONTRIBUTE TO GASTRIC CARCINOGENESIS. HOWEVER, THE PRECISE MECHANISM OF IM IN GASTRIC CARCINOGENESIS HAS NOT BEEN FULLY ELUCIDATED. WE PREVIOUSLY FOUND THAT INTESTINE-SPECIFIC HOMEOBOX (ISX) MRNA EXPRESSION INCREASED IN ORGANOIDS CULTURED FROM HELICOBACTER-INFECTED MOUSE MUCOSA. IN THIS STUDY, WE ELUCIDATE THE ROLE OF ISX IN THE DEVELOPMENT OF IM AND GASTRIC CARCINOGENESIS. METHODS: ISX EXPRESSION WAS ASSESSED IN HELICOBACTER-INFECTED MOUSE AND HUMAN GASTRIC MUCOSA. MKN45 GASTRIC CANCER CELLS WERE CO-CULTURED WITH H. PYLORI TO DETERMINE WHETHER HELICOBACTER INFECTION INDUCED ISX EXPRESSION. WE ESTABLISHED STABLE MKN45 TRANSFECTED CELLS EXPRESSING ISX (STABLE-ISX MKN45) AND PERFORMED A SPHEROID COLONY FORMATION ASSAY AND A XENOGRAFT MODEL. WE PERFORMED ISX IMMUNOHISTOCHEMISTRY IN CANCER AND ADJACENT GASTRIC TISSUES. RESULTS: ISX EXPRESSION WAS INCREASED IN MOUSE AND HUMAN GASTRIC MUCOSA INFECTED WITH HELICOBACTER. THE PRESENCE OF IM AND H. PYLORI INFECTION IN HUMAN STOMACH WAS CORRELATED WITH ISX EXPRESSION. H. PYLORI INDUCED ISX MRNA AND PROTEIN EXPRESSION. CDX1/2, CYCLIND1, AND MUC2 WERE UPREGULATED IN STABLE-ISX MKN45, WHEREAS MUC5AC WAS DOWNREGULATED. STABLE-ISX MKN45 CELLS FORMED MORE SPHEROID COLONIES, AND HAD HIGH TUMORIGENIC ABILITY. ISX EXPRESSION IN GASTRIC CANCER AND ADJACENT MUCOSA WERE CORRELATED. CONCLUSIONS: ISX EXPRESSION INDUCED BY H. PYLORI INFECTION MAY LEAD TO IM AND HYPERPROLIFERATION OF GASTRIC MUCOSA THROUGH CDX1/2 AND CYCLIND1 EXPRESSION, CONTRIBUTING TO GASTRIC CARCINOGENESIS. 2016 11 600 31 BETA-DEFENSINS AND ANALOGS IN HELICOBACTER PYLORI INFECTIONS: MRNA EXPRESSION LEVELS, DNA METHYLATION, AND ANTIBACTERIAL ACTIVITY. ANTIMICROBIAL PEPTIDES CAN PROTECT THE GASTRIC MUCOSA FROM BACTERIA, BUT HELICOBACTER PYLORI (H. PYLORI) CAN EQUALLY COLONIZE THE GASTRIC APPARATUS. TO UNDERSTAND BETA-DEFENSIN FUNCTION IN H. PYLORI-ASSOCIATED CHRONIC GASTRITIS, WE INVESTIGATED SUSCEPTIBILITY, HUMAN BETA-DEFENSIN MRNA EXPRESSION, AND DNA METHYLATION CHANGES TO PROMOTERS IN THE GASTRIC MUCOSA WITH OR WITHOUT H. PYLORI INFECTION. WE STUDIED THE EXPRESSION OF HBD2 (GENE NAME DEFB4A), HBD3 (DEFB103A), AND HBD4 (DEFB104) USING REAL-TIME PCR IN 15 CONTROL AND 10 H. PYLORI INFECTION PATIENT GASTRIC SPECIMENS. THIS STUDY DEMONSTRATES THAT H. PYLORI INFECTION IS RELATED TO GASTRIC ENHANCEMENT OF INDUCIBLE HBD2, BUT INDUCIBLE HBD3 AND HBD4 EXPRESSION LEVELS REMAINED UNCHANGED. HBD2 GENE METHYLATION LEVELS WERE OVERALL HIGHER IN H. PYLORI-NEGATIVE SAMPLES THAN IN H. PYLORI-POSITIVE SAMPLES. WE ALSO ASSESSED ANTIMICROBIAL SUSCEPTIBILITY USING GROWTH ON BLOOD AGAR. THE H. PYLORI STRAIN TOX+ WAS SUSCEPTIBLE TO ALL DEFENSINS TESTED AND THEIR ANALOGS (3N, 3NI). THESE RESULTS SHOW THAT HBD2 IS INVOLVED IN GASTRITIS DEVELOPMENT DRIVEN BY H. PYLORI, WHICH FACILITATES THE CREATION OF AN EPIGENETIC FIELD DURING H. PYLORI-ASSOCIATED GASTRIC TUMORIGENESIS. 2019 12 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 13 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 14 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 15 5181 25 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER. 2010 16 4960 30 PATHOGENESIS OF PRE-NEOPLASTIC LESIONS OF THE STOMACH: TARGETS FOR PREVENTION. GASTRIC ATROPHY AND INTESTINAL METAPLASIA ARE GENERALLY CONSIDERED TO BE PRECANCEROUS LESIONS OF THE STOMACH. CHRONIC HELICOBACTER PYLORI INFECTION IS ONE THE MOST IMPORTANT FACTORS IN THE DEVELOPMENT OF THESE PRE-MALIGNANT GASTRIC LESIONS. IN ADDITION TO BACTERIAL FACTORS, POLYMORPHISMS IN THE CYTOKINE GENES OF THE HOST THAT MODULATE INFLAMMATORY RESPONSES ARE FOUND TO HAVE A SYNERGISTIC EFFECT IN THE DEVELOPMENT OF GASTRIC CANCER AS WELL AS PRE-NEOPLASTIC LESIONS. RECENTLY, INAPPROPRIATE ACTIVATION OF THE INTESTINE-SPECIFIC TRANSCRIPTION FACTOR LIKE THE HOMEOBOX GENE COMPLEX CDX1 AND CDX2 ARE FOUND TO BE AN IMPORTANT CONTRIBUTING FACTOR IN THE INDUCTION OF INTESTINAL METAPLASIA IN THE STOMACH. ABERRANT EXPRESSION OF CYCLOOXYGENASE-2 AND EPIGENETIC CHANGES ARE ALSO FREQUENTLY DETECTED IN PRE-NEOPLASTIC GASTRIC LESIONS. ONE OF THE MOST IMPORTANT QUESTIONS RELATING TO THESE PRE-NEOPLASTIC GASTRIC LESIONS IS THAT WHETHER H. PYLORI ERADICATION COULD REVERSE THESE CHANGES. HOWEVER, MOST CONTROLLED STUDIES SHOWED NO OR JUST MODEST IMPROVEMENT IN INTESTINAL METAPLASIA AFTER H. PYLORI ERADICATION. FURTHER STUDIES SHOULD EVALUATE THE ROLE OF OTHER CHEMOPREVENTIVE AGENTS, PARTICULARLY CYCLOOXYGENASE-2 INHIBITOR, ON REGRESSION OF PRE-NEOPLASTIC LESIONS. 2004 17 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 18 6579 25 TREFOIL FACTORS AND HUMAN GASTRIC CANCER (REVIEW). TFF1/PS2, TFF2/SP AND TFF3/ITF ARE SOLUBLE PEPTIDES WITH TREFOIL DOMAIN(S) AND C-TERMINAL DIMERIZATION DOMAIN, WHICH ARE CONSERVED AMONG HUMAN, COW, MOUSE AND RAT. TFF1 MRNA IS EXPRESSED IN STOMACH (MUCOUS CELLS IN FUNDUS AND ANTRUM), TFF2 MRNA IN STOMACH (MUCOUS NECK CELLS IN FUNDUS AND BASAL CELLS IN ANTRAL AND PYLORIC GLANDS) AND DUODENUM (BRUNNER'S GLAND), TFF3 MRNA IN SMALL INTESTINE AND LARGE INTESTINE (GOBLET CELLS). EXPRESSION OF TFF1, TFF2 AND TFF3 MRNAS ARE DIFFERENTIALLY REGULATED BY FGF2/BFGF, FGF7/KGF, ESTROGEN, ASPIRIN, ARACHIDONIC ACID, X-RAY IRRADIATION, AND HYDROGEN PEROXIDE. GASTRIC CANCER IS CLASSIFIED INTO THE INTESTINAL TYPE AND THE DIFFUSE TYPE. TFF MRNAS ARE PREFERENTIALLY EXPRESSED IN DIFFUSE-TYPE GASTRIC CANCER CELLS. CUSTOM-MADE MICROARRAY (TFF MRNAS) AND ELISA (TFF PROTEINS) MIGHT BE APPLICABLE FOR SCREENING METHODS OF PERITONEAL AND BONE MARROW DISSEMINATION FROM DIFFUSE-TYPE GASTRIC CANCER. TFF1 AND TFF2 MRNAS ARE FREQUENTLY DOWN-REGULATED IN INTESTINAL-TYPE GASTRIC CANCER. TFF1 GENE, INACTIVATED BY DELETION, MISSENSE MUTATION AND PROMOTER HYPERMETHYLATION, IS A TUMOR SUPPRESSOR GENE IMPLICATED IN GASTRIC CANCER. TFF2 IS A CANDIDATE TUMOR SUPPRESSOR GENE; HOWEVER, GENETIC AND EPIGENETIC ALTERATIONS OF TFF2 GENE IN HUMAN GASTRIC CANCER REMAIN UNCLEAR. TFF1, TFF2 AND TFF3 PLAY KEY ROLES IN MUCOSAL PROTECTION THROUGH MUCOUS-BARRIER FORMATION, AND ALSO IN MUCOSAL REPAIR THROUGH PROMOTION OF RESTITUTION AFTER INJURY. PATIENTS WITH CHRONIC ATROPHIC GASTRITIS AND THOSE WITH ULCERATIVE COLITIS ARE AT RISK OF GASTRIC CANCER AND COLORECTAL CANCER, RESPECTIVELY. TFF1, TFF2 AND TFF3 PROTEINS MIGHT BE APPLICABLE FOR CHEMOPREVENTION OF GASTROINTESTINAL CANCER ASSOCIATED WITH CHRONIC PERSISTENT INFLAMMATION. 2003 19 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 20 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