1 3232 66 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 2 5181 26 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 3 3227 27 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 4 3229 30 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 5 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 6 3222 30 HELICOBACTER PYLORI ASSOCIATED CHRONIC GASTRITIS, CLINICAL SYNDROMES, PRECANCEROUS LESIONS, AND PATHOGENESIS OF GASTRIC CANCER DEVELOPMENT. HELICOBACTER PYLORI (H. PYLORI) INFECTION IS WELL KNOWN TO BE ASSOCIATED WITH THE DEVELOPMENT OF PRECANCEROUS LESIONS SUCH AS CHRONIC ATROPHIC GASTRITIS (AG), OR GASTRIC INTESTINAL METAPLASIA (GIM), AND CANCER. VARIOUS MOLECULAR ALTERATIONS ARE IDENTIFIED NOT ONLY IN GASTRIC CANCER (GC) BUT ALSO IN PRECANCEROUS LESIONS. H. PYLORI TREATMENT SEEMS TO IMPROVE AG AND GIM, BUT STILL REMAINS CONTROVERSIAL. IN CONTRAST, MANY STUDIES, INCLUDING META-ANALYSIS, SHOW THAT H. PYLORI ERADICATION REDUCES GC. MOLECULAR MARKERS DETECTED BY GENETIC AND EPIGENETIC ALTERATIONS RELATED TO CARCINOGENESIS REVERSE FOLLOWING H. PYLORI ERADICATION. THIS INDICATES THAT THESE CHANGES MAY BE AN IMPORTANT FACTOR IN THE IDENTIFICATION OF HIGH RISK PATIENTS FOR CANCER DEVELOPMENT. PATIENTS WHO UNDERWENT ENDOSCOPIC TREATMENT OF GC ARE AT HIGH RISK FOR DEVELOPMENT OF METACHRONOUS GC. A RANDOMIZED CONTROLLED TRIAL FROM JAPAN CONCLUDED THAT PROPHYLACTIC ERADICATION OF H. PYLORI AFTER ENDOSCOPIC RESECTION SHOULD BE USED TO PREVENT THE DEVELOPMENT OF METACHRONOUS GC, BUT RECENT RETROSPECTIVE STUDIES DID NOT SHOW THE TENDENCY. PATIENTS WITH PRECANCEROUS LESIONS (MOLECULAR ALTERATIONS) THAT DO NOT REVERSE AFTER H. PYLORI TREATMENT, REPRESENT THE "POINT OF NO RETURN" AND MAY BE AT HIGH RISK FOR THE DEVELOPMENT OF GC. THEREFORE, EARLIER H. PYLORI ERADICATION SHOULD BE CONSIDERED FOR PREVENTING GC DEVELOPMENT PRIOR TO THE APPEARANCE OF PRECANCEROUS LESIONS. 2014 7 3230 33 HELICOBACTER PYLORI-INDUCED INFLAMMATION AND EPIGENETIC CHANGES DURING GASTRIC CARCINOGENESIS. THE SEQUENCE OF EVENTS ASSOCIATED WITH THE DEVELOPMENT OF GASTRIC CANCER HAS BEEN DESCRIBED AS "THE GASTRIC PRECANCEROUS CASCADE". THIS CASCADE IS A DYNAMIC PROCESS THAT INCLUDES LESIONS, SUCH AS ATROPHIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA. ACCORDING TO THIS MODEL, HELICOBACTER PYLORI (H. PYLORI) INFECTION TARGETS THE NORMAL GASTRIC MUCOSA CAUSING NON-ATROPHIC GASTRITIS, AN INITIATING LESION THAT CAN BE CURED BY CLEARING H. PYLORI WITH ANTIBIOTICS OR THAT MAY THEN LINGER IN THE CASE OF CHRONIC INFECTION AND PROGRESS TO ATROPHIC GASTRITIS. THE PRESENCE OF VIRULENCE FACTORS IN THE INFECTING H. PYLORI DRIVES THE CARCINOGENESIS PROCESS. INDEPENDENT EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE CONFIRMED THE SEQUENTIAL PROGRESSION OF THESE PRECANCEROUS LESIONS. PARTICULARLY LONG-TERM FOLLOW-UP STUDIES ESTIMATED A RISK OF 0.1% FOR ATROPHIC GASTRITIS/INTESTINAL METAPLASIA AND 6% IN CASE OF DYSPLASIA FOR THE LONG-TERM DEVELOPMENT OF GASTRIC CANCER. WITH THIS IN MIND, A BETTER UNDERSTANDING OF THE GENETIC AND EPIGENETIC CHANGES ASSOCIATED WITH PROGRESSION OF THE CASCADE IS CRITICAL IN DETERMINING THE RISK OF GASTRIC CANCER ASSOCIATED WITH H. PYLORI INFECTION. IN THIS REVIEW, WE WILL SUMMARIZE SOME OF THE MOST RELEVANT MECHANISMS AND FOCUS PREDOMINANTLY BUT NOT EXCLUSIVELY ON THE DISCUSSION OF GENE PROMOTER METHYLATION AND MIRNAS IN THIS CONTEXT. 2015 8 4984 31 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 9 5180 23 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA. 2013 10 3226 35 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 11 3233 28 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 6841 33 [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 13 2853 22 FROM HELICOBACTER PYLORI INFECTION TO GASTRIC CANCER: CURRENT EVIDENCE ON THE IMMUNE RESPONSE. GASTRIC CANCER (GC) IS THE RESULT OF A MULTIFACTORIAL PROCESS WHOSE MAIN COMPONENTS ARE INFECTION BY HELICOBACTER PYLORI (H. PYLORI), BACTERIAL VIRULENCE FACTORS, HOST IMMUNE RESPONSE AND ENVIRONMENTAL FACTORS. THE DEVELOPMENT OF THE NEOPLASTIC MICROENVIRONMENT ALSO DEPENDS ON GENETIC AND EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH RESULTS IN DEREGULATION OF CELL SIGNALING PATHWAYS AND APOPTOSIS PROCESS. THIS REVIEW SUMMARIZES THE MAIN ASPECTS OF THE PATHOGENESIS OF GC AND THE IMMUNE RESPONSE INVOLVED IN CHRONIC INFLAMMATION GENERATED BY H. PYLORI. 2022 14 1540 29 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 15 4960 27 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 16 3219 31 HELICOBACTER PYLORI AND GASTRIC CANCER. INFECTION WITH HELICOBACTER PYLORI IS ESTABLISHED AS THE MAJOR RISK FACTOR FOR GASTRIC CANCER DEVELOPMENT. DAMAGE OF THE MUCOSAL BARRIER DUE TO H. PYLORI-INDUCED INFLAMMATION ENHANCES THE CARCINOGENIC EFFECT OF OTHER RISK FACTORS SUCH AS SALT INTAKE OR TOBACCO SMOKING. THE GENETIC DISPOSITION OF BOTH THE BACTERIAL STRAIN AND THE HOST CAN INCREASE THE POTENTIAL TOWARDS GASTRIC CANCER FORMATION. GENETIC VARIANCE OF THE BACTERIAL PROTEINS CAGA AND VACA IS ASSOCIATED WITH A HIGHER GASTRIC CANCER RISK, AS ARE POLYMORPHISMS AND EPIGENETIC CHANGES IN HOST GENE CODING FOR INTERLEUKINS (IL1BETA, IL8), TRANSCRIPTION FACTORS (CDX2, RUNX3) AND DNA REPAIR ENZYMES. APPLICATION OF HIGH-THROUGHPUT ASSAYS FOR GENOME-WIDE ASSESSMENT OF EITHER GENETIC STRUCTURAL VARIANCE OR GENE EXPRESSION PATTERNS MAY LEAD TO A BETTER UNDERSTANDING OF THE PATHOBIOLOGICAL BACKGROUND OF THESE PROCESSES, INCLUDING THE UNDERLYING SIGNALING PATHWAYS. UNDERSTANDING OF THE STEPWISE ALTERATIONS THAT TAKE PLACE IN THE TRANSITION FROM CHRONIC ATROPHIC GASTRITIS, VIA METAPLASTIC CHANGES, TO INVASIVE NEOPLASIA IS VITAL TO DEFINE THE 'POINT OF NO RETURN' BEFORE WHICH ERADICATION OF H. PYLORI HAS THE POTENTIAL TO PREVENT GASTRIC CANCER. CURRENTLY, ERADICATION AS PREVENTIVE STRATEGY IS ONLY RECOMMENDED FOR HIGH-INCIDENCE REGIONS IN ASIA; LARGE POPULATION STUDIES WITH AN ADEQUATE FOLLOW-UP ARE REQUIRED TO DEMONSTRATE THE EFFECTIVENESS OF SUCH AN APPROACH IN WESTERN POPULATIONS. 2014 17 4725 24 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 18 4409 24 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 19 6369 25 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 20 2943 22 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