1 1799 136 EFFECT OF HELICOBACTER PYLORI INFECTION ON THE COMPOSITION OF GASTRIC MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. BACKGROUND: GASTRIC CANCER IS ONE OF THE MOST COMMON CANCER TYPES WORLDWIDE. IN CHINA, GASTRIC CANCER HAS BECOME ONE OF THE MAJOR THREATS FOR PUBLIC HEALTH, RANKING SECOND ON INCIDENCE AND THIRD ON CAUSE OF CANCER DEATH. DESPITE THE COMMON RISK FACTORS THAT PROMOTE THE DEVELOPMENT OF GASTRIC CANCER, THE HUGE QUANTITY OF MICROORGANISM COLONIES WITHIN THE GASTROINTESTINAL TRACT, PARTICULARLY HELICOBACTER PYLORI INFECTION, DEMONSTRATES A CORRELATION WITH CHRONIC INFLAMMATION AND GASTRIC CARCINOGENESIS, AS EPIDEMIOLOGICAL STUDIES HAVE DETERMINED THAT H. PYLORI INFECTION CONFERS APPROXIMATELY 75% OF THE ATTRIBUTABLE RISK FOR GASTRIC CANCER. SUMMARY: THE CURRENT ARTICLE DRAWS AN OVERVIEW ON THE CORRELATION BETWEEN THE MICROBIOTA, INFLAMMATION AND GASTRIC TUMORIGENESIS. H. PYLORI INFECTION HAS BEEN IDENTIFIED AS THE MAIN RISK FACTOR AS IT TRIGGERS EPITHELIAL BARRIER DISRUPTION, SURVIVAL SIGNALING AS WELL AS GENETIC/EPIGENETIC MODULATION. APART FROM H. PYLORI, THE EXISTENCE OF A DIVERSE AND COMPLEX COMPOSITION OF MICROBIOTA IN THE STOMACH HAS BEEN IDENTIFIED, WHICH SUPPORTS A ROLE OF MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. MOREOVER, METAGENOMICS STUDIES FOCUSED ON THE COMPOSITION AND FUNCTION OF THE MICROBIOTA HAVE ASSOCIATED MICROBIOTA WITH GASTRIC METABOLIC DISEASES AND EVEN TUMORIGENESIS. APART FROM THE GASTRIC MICROBIOTA, INFLAMMATION IS ANOTHER IDENTIFIED CONTRIBUTOR TO CANCER DEVELOPMENT AS WELL. KEY MESSAGE: THOUGH H. PYLORI INFECTION AND THE NON-H. PYLORI MICROBIOTA PLAY A ROLE IN GASTRIC CANCER, THE PROPERTIES OF GASTRIC MICROBIOTA AND MECHANISMS BY WHICH THEY PARTICIPATE IN THE GENESIS OF GASTRIC CANCER ARE STILL NOT CLEARLY DEPICTED. MOREOVER, IT REMAINS TO BE UNDERSTOOD HOW THE PRESENCE OF MICROBIOTA ALONG WITH H. PYLORI INFECTION AFFECTS THE PROGRESS FROM GASTRIC DISEASE TO CANCER. PRACTICAL IMPLICATIONS: THIS ARTICLE SUMMARIZED A CLUE OF THE CURRENT STUDIES ON MICROBIOTA, H. PYLORI INFECTION AND THE PROGRESSION FROM GASTRIC DISEASE TO CANCER. 2015 2 2852 33 FROM GASTRIC INFLAMMATION TO GASTRIC CANCER. THE MAJORITY OF GASTRIC ADENOCARCINOMAS ARE RELATED TO CHRONIC INFLAMMATION INDUCED BY HELICOBACTER PYLORI INFECTION. FOR INTESTINAL-TYPE GASTRIC CANCER, A MULTISTEP PROCESS OF MUCOSAL ALTERATIONS LEADING FROM GASTRITIS VIA GLANDULAR ATROPHY, INTESTINAL METAPLASIA AND DYSPLASIA TO INVASIVE CARCINOMA IS WELL RECOGNIZED. ONGOING CLINICAL STUDIES FOCUS ON A 'POINT OF NO RETURN'. IT IS DEFINED AS A SITUATION WHEN CERTAIN ALTERATIONS ARE NO LONGER REVERSIBLE BY H. PYLORI ERADICATION AND PROGRESSION TO GASTRIC CANCER MAY CONTINUE. H. PYLORI AFFECTS THE MUCOSAL AS WELL AS THE SYSTEMIC IMMUNE RESPONSE BY SECRETION OF CYTOKINES AND THE RECRUITMENT OF DISTINCT INFLAMMATORY CELLS. THE IMMUNE RESPONSE IS CHARACTERIZED BY A BALANCE BETWEEN A TH1-DOMINATED RESPONSE AND THE RECRUITMENT OF ANTIGEN-SPECIFIC REGULATORY T CELLS THAT ALLOW THE BACTERIA TO PERSIST IN HUMAN GASTRIC MUCOSA. BESIDES IMMUNE-MEDIATED EFFECTS, H. PYLORI INDUCES CELLULAR ALTERATIONS AS WELL AS GENETIC ALTERATIONS IN GENES THAT ARE ESSENTIAL FOR THE EPIGENETIC INTEGRITY AND MUCOSAL HOMEOSTASIS. THESE GENETIC ALTERATIONS DURING GASTRIC CANCER DEVELOPMENT ARE IN FOCUS OF INTENSIVE RESEARCH AND SHOULD ULTIMATELY ALLOW THE IDENTIFICATION OF RISK FACTORS INVOLVED IN GASTRIC CARCINOGENESIS. THE DETECTION OF INDIVIDUALS AT HIGH RISK FOR GASTRIC CANCER WOULD HELP TO DESIGN APPROPRIATE STRATEGIES FOR PREVENTION AND SURVEILLANCE. 2010 3 2853 27 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 4 762 34 CAUSAL ROLE OF HELICOBACTER PYLORI INFECTION AND ERADICATION THERAPY IN GASTRIC CARCINOGENESIS. MANY EPIDEMIOLOGICAL REPORTS INDICATE THAT HELICOBACTER PYLORI (H PYLORI) INFECTION PLAYS AN IMPORTANT ROLE IN GASTRIC CARCINOGENESIS. SEVERAL GENETIC AND EPIGENETIC ALTERATIONS CONTRIBUTE TO THE INITIATION, PROMOTION, AND PROGRESSION OF THE CANCER CELLS IN A MULTI-STEP MANNER. H PYLORI IS KNOWN TO INDUCE CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA. ITS PRODUCTS, INCLUDING SUPEROXIDES, PARTICIPATE IN THE DNA DAMAGE FOLLOWED BY INITIATION, AND THE INFLAMMATION-DERIVED CYTOKINES AND GROWTH FACTORS CONTRIBUTE TO THE PROMOTION OF GASTRIC CARCINOGENESIS. BY ERADICATING H PYLORI, GASTRIC INFLAMMATION CAN BE CURED; THE THERAPY DIMINISHES THE LEVELS NOT ONLY OF INFLAMMATORY CELL INFILTRATION, BUT ALSO ATROPHY/INTESTINAL METAPLASIA IN PART. A RANDOMIZED CONTROLLED TRIAL REVEALED THAT THE ERADICATION THERAPY DIMINISHED THE GASTRIC CANCER PREVALENCE IN CASES WITHOUT PRE-CANCEROUS CONDITIONS. IN ADDITION, RECENT EPIDEMIOLOGICAL STUDIES FROM JAPANESE GROUPS DEMONSTRATED THAT THE DEVELOPMENT OF GASTRIC CANCER, ESPECIALLY OF THE INTESTINAL TYPE, WAS DECREASED BY SUCCESSFUL ERADICATION THERAPY, ALTHOUGH THESE WERE DESIGNED IN A NON-RANDOMIZED MANNER. HOWEVER, IT SHOULD BE MENTIONED THAT ENDOSCOPIC DETECTION IS THE ONLY WAY TO EVALUATE THE DEGREE OF GASTRIC CARCINOGENESIS. WE HAVE REPORTED THAT THE ENDOSCOPIC AND HISTOLOGICAL MORPHOLOGIES COULD BE MODIFIED BY ERADICATION THERAPY AND IT MIGHT CONTRIBUTE TO THE PREVALENCE OF GASTRIC CANCER DEVELOPMENT. CONSIDERING THE BIOLOGICAL NATURE OF CANCER CELL PROLIFERATION, IT IS CONSIDERED THAT A SUFFICIENTLY LONG-TERM FOLLOW-UP WOULD BE ESSENTIAL TO DISCUSS THE ANTICANCER EFFECT OF ERADICATION THERAPY. 2006 5 3220 41 HELICOBACTER PYLORI AND MICRORNAS: RELATION WITH INNATE IMMUNITY AND PROGRESSION OF PRENEOPLASTIC CONDITIONS. THE ACCEPTED PARADIGM FOR INTESTINAL-TYPE GASTRIC CANCER PATHOGENESIS IS A MULTISTEP PROGRESSION FROM CHRONIC GASTRITIS INDUCED BY HELICOBACTER PYLORI (H. PYLORI) TO GASTRIC ATROPHY, INTESTINAL METAPLASIA, DYSPLASIA AND ULTIMATELY GASTRIC CANCER. THE GENETIC AND MOLECULAR MECHANISMS UNDERLYING DISEASE PROGRESSION ARE STILL NOT COMPLETELY UNDERSTOOD AS ONLY A FRACTION OF COLONIZED INDIVIDUALS EVER DEVELOP NEOPLASIA SUGGESTING THAT BACTERIAL, HOST AND ENVIRONMENTAL FACTORS ARE INVOLVED. MICRORNAS ARE NONCODING RNAS THAT MAY INFLUENCE H. PYLORI-RELATED PATHOLOGY THROUGH THE REGULATION OF THE TRANSCRIPTION AND EXPRESSION OF VARIOUS GENES, PLAYING AN IMPORTANT ROLE IN INFLAMMATION, CELL PROLIFERATION, APOPTOSIS AND DIFFERENTIATION. INDEED, H. PYLORI HAVE BEEN SHOWN TO MODIFY MICRORNA EXPRESSION IN THE GASTRIC MUCOSA AND MICRORNAS ARE INVOLVED IN THE IMMUNE HOST RESPONSE TO THE BACTERIA AND IN THE REGULATION OF THE INFLAMMATORY RESPONSE. MICRORNAS HAVE A KEY ROLE IN THE REGULATION OF INFLAMMATORY PATHWAYS AND H. PYLORI MAY INFLUENCE INFLAMMATION-MEDIATED GASTRIC CARCINOGENESIS POSSIBLY THROUGH DNA METHYLATION AND EPIGENETIC SILENCING OF TUMOR SUPPRESSOR MICRORNAS. FURTHERMORE, MICRORNAS INFLUENCED BY H. PYLORI ALSO HAVE BEEN FOUND TO BE INVOLVED IN CELL CYCLE REGULATION, APOPTOSIS AND EPITHELIAL-MESENCHYMAL TRANSITION. ALTOGETHER, MICRORNAS SEEM TO HAVE AN IMPORTANT ROLE IN THE PROGRESSION FROM GASTRITIS TO PRENEOPLASTIC CONDITIONS AND NEOPLASTIC LESIONS AND SINCE EACH MICRORNA CAN CONTROL THE EXPRESSION OF HUNDREDS TO THOUSANDS OF GENES, KNOWLEDGE OF MICRORNAS TARGET GENES AND THEIR FUNCTIONS ARE OF PARAMOUNT IMPORTANCE. IN THIS ARTICLE WE PRESENT A COMPREHENSIVE REVIEW ABOUT THE ROLE OF MICRORNAS IN H. PYLORI GASTRIC CARCINOGENESIS, IDENTIFYING THE MICRORNAS DOWNREGULATED AND UPREGULATED IN THE INFECTION AND CLARIFYING THEIR BIOLOGICAL ROLE IN THE LINK BETWEEN IMMUNE HOST RESPONSE, INFLAMMATION, DNA METHYLATION AND GASTRIC CARCINOGENESIS. 2015 6 3230 43 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 7 3849 39 IS ERADICATION OF HELICOBACTER PYLORI THE FEASIBLE WAY TO PREVENT GASTRIC CANCER? NEW EVIDENCE AND PROGRESS, BUT STILL A LONG WAY TO GO. EPIDEMIOLOGICAL, ANIMAL AND BIOLOGICAL STUDIES PROVIDE COMPELLING EVIDENCE FOR THE ROLE OF HELICOBACTER PYLORI INFECTION IN GASTRIC CARCINOGENESIS. THE FINDING THAT H. PYLORI-INDUCED CHRONIC ATROPHIC GASTRITIS IS THE MAJOR CAUSE OF GASTRIC CANCER SUGGESTS THAT ERADICATION OF THE BACTERIUM MAY PREVENT THIS MALIGNANCY. COMPUTER-SIMULATION STUDIES HAVE CONFIRMED THE COST-EFFECTIVENESS OF ERADICATION IN HIGH-RISK SUBJECTS; HOWEVER, UNRESOLVED ISSUES COMPLICATE ACTIVE TESTING FOR AND TREATMENT OF H. PYLORI INFECTION AMONG ASYMPTOMATIC CARRIERS. CONCERNS INCLUDE THE ENORMOUS COSTS FOR DEVELOPING COUNTRIES TO IMPLEMENT STRATEGIES, THE INCONCLUSIVENESS OF DATA FROM RANDOMIZED CONTROLLED STUDIES, THE POTENTIAL INDUCTION OF ANTIMICROBIAL RESISTANCE, AND THE UNCERTAIN EFFECT OF ELIMINATING THIS ORGANISM ON THE SPECTRUM OF MODERN DISEASE. ALTHOUGH CURRENT EVIDENCE IS INSUFFICIENT TO RECOMMEND UNIVERSAL TESTING AND TREATMENT, IT IS POSSIBLE TO IDENTIFY HIGHLY SUSCEPTIBLE INDIVIDUALS WHO ARE MOST LIKELY TO BENEFIT FROM TREATMENT. NOVEL BIOMARKERS FOR PREDICTING RISK ARE UNDER EXTENSIVE INVESTIGATION, INCLUDING GENETIC, EPIGENETIC AND PROTEINOMIC FACTORS. THE EMERGING EVIDENCE SUGGESTS THAT TREATMENT OF H. PYLORI INFECTION IN ASYMPTOMATIC CARRIERS MAY DECREASE THE BURDEN OF GASTRIC CANCER. HOWEVER, CONFIRMATION OF LONG-TERM BENEFITS REMAINS A LONG WAY OFF. 2008 8 3233 36 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 9 6841 38 [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 10 3219 38 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 11 3223 39 HELICOBACTER PYLORI INFECTION AND AUTOIMMUNE DISEASES; IS THERE AN ASSOCIATION WITH SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS AND AUTOIMMUNE PANCREATITIS? A SYSTEMATIC REVIEW AND META-ANALYSIS STUDY. AUTOIMMUNE DISEASES ARE CONSIDERED AS ONE OF THE MOST IMPORTANT DISORDERS OF THE IMMUNE SYSTEM, IN WHICH THE PROLONGED AND CHRONIC PROCESSES ELIMINATE SELF-TOLERANCE TO THE AUTO-ANTIGENS. THE PREVALENCE OF AUTOIMMUNE DISEASES HAS BEEN INCREASING WORLDWIDE IN THE RECENT YEARS. ACCORDING TO THE LITERATURE, BIOLOGICAL PROCESSES SUCH AS THE HOST GENOME, EPIGENETIC EVENTS, ENVIRONMENTAL CONDITION, DRUG CONSUMPTION, AND INFECTIOUS AGENTS ARE THE MOST IMPORTANT RISK FACTORS THAT MAKE THE HOST SUSCEPTIBLE TO THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THE RECENT YEARS, THE ROLE OF HELICOBACTER PYLORI IN THE INDUCTION OF AUTOIMMUNE DISEASES HAS ATTRACTED EXTENSIVE ATTENTION. VIA MOLECULAR MIMICRY, EPITOPE SPREADING, BYSTANDER ACTIVATION, POLYCLONAL ACTIVATION, DYSREGULATION IN IMMUNE RESPONSE, AND HIGHLY IMMUNE-DOMINANT VIRULENCE, SUCH AS CAGA, H. PYLORI CAUSES TISSUE DAMAGE, POLARITY, AND PROLIFERATION OF THE HOST CELLS LEADING TO THE MODULATION OF HOST IMMUNE RESPONSES. MOREOVER, GIVEN THE LARGE POPULATION WORLDWIDE INFECTED WITH H. PYLORI, IT SEEMS LIKELY THAT THE BACTERIUM MAY DEVELOP INTO AUTOIMMUNE DISEASES THROUGH DYSREGULATION OF THE IMMUNE RESPONSE. THE FREQUENCY AND RELATIONSHIP BETWEEN H. PYLORI INFECTION AND SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS, AND AUTOIMMUNE PANCREATITIS WERE EVALUATED USING THE DATA FROM 43 STUDIES INVOLVING 5052 PATIENTS. ACCORDING TO STATISTICAL ANALYSIS IT IS PROBABLE THAT INFECTION WITH MORE VIRULENT STRAINS OF H. PYLORI (SUCH AS H. PYLORI CAGA POSITIVE) CAN INCREASE THE RISK OF AUTOIMMUNE DISEASES. IN ADDITION, IT WAS SHOWN THAT INFECTION WITH H. PYLORI CAN PREVENT THE DEVELOPMENT OF ATROPHIC GASTRITIS BY STIMULATING INFLAMMATION IN THE GASTRIC ANTRUM. HOWEVER, FUTURE STUDIES SHOULD CONFIRM THE VALIDITY OF THIS STUDY. 2021 12 1180 38 CONVERGENCE OF GENETIC, NUTRITIONAL AND INFLAMMATORY FACTORS IN GASTROINTESTINAL CANCERS. GASTROINTESTINAL CANCERS ACCOUNT FOR 20% OF ALL CANCER INCIDENCES WORLDWIDE. COLORECTAL CANCER IS THE SECOND MOST COMMON CAUSE OF ALL CANCER-RELATED MORTALITY AND IS INCREASING IN WESTERN SOCIETIES. INFECTION AND INFLAMMATION CONTRIBUTE TO 15-20% OF ALL MALIGNANCIES, AND ARE PREDISPOSING RISK FACTORS FOR GASTROINTESTINAL CANCERS. HELICOBACTER PYLORI INFECTION IS COMMONLY ASSOCIATED WITH GASTRIC CANCERS, AND CHRONIC INFLAMMATION INCREASES THE RISK OF COLORECTAL CANCER BY 1% PER YEAR. MICRONUTRIENT STATUS AND COMMON GENETIC VARIATIONS IN HUMAN POPULATIONS MODIFY RISK FOR GASTROINTESTINAL CANCER. CHRONIC INFLAMMATION PROMOTES CARCINOGENESIS BY INDUCING GENE MUTATIONS, INHIBITING APOPTOSIS, AND STIMULATING ANGIOGENESIS AND CELL PROLIFERATION. INFLAMMATION ALSO INDUCES EPIGENETIC ALTERATIONS THAT ARE ASSOCIATED WITH CANCER DEVELOPMENT. TWO KEY GENES IN THE INFLAMMATORY PROCESS, CYCLOOXYGENASE-2 (COX-2) AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB), PROVIDE A MECHANISTIC LINK BETWEEN INFLAMMATION AND CANCER AND ARE TARGETS FOR CHEMOPREVENTION. DIETARY COMPONENTS, AND HUMAN GENETIC VARIATION THAT AFFECTS NUTRIENT UTILIZATION, CAN DIRECTLY MODIFY INFLAMMATORY PROCESSES AND/OR SUPPRESS GENOMIC ALTERATIONS THAT ARE THE MOLECULAR ANTECEDENTS OF CANCERS. THE PRESENT REPORT FOCUSES ON THE CONVERGENCE OF GENETIC, NUTRITIONAL, AND INFLAMMATORY FACTORS IN THE INITIATION AND PROGRESSION OF GASTROINTESTINAL CANCERS, AND THE EMERGING DIETARY STRATEGIES FOR CANCER PREVENTION. 2007 13 4994 39 PERFORMANCE OF DNA METHYLATION ON THE MOLECULAR PATHOGENESIS OF HELICOBACTER PYLORI IN GASTRIC CANCER; TARGETED THERAPY APPROACH. GASTRIC CANCER (GC) IS A SIGNIFICANT CAUSE OF CANCER MORTALITY WHICH HAS LED TO FOCUSED EXPLORATION OF THE PATHOLOGY OF GC. THE ADVENT OF GENOME-WIDE ANALYSIS METHODS HAS MADE IT POSSIBLE TO UNCOVER GENETIC AND EPIGENETIC FLUCTUATION SUCH AS ABNORMAL DNA METHYLATION IN GENE PROMOTER REGIONS THAT IS EXPECTED TO PLAY A KEY ROLE IN GC. THE STUDY OF GASTRIC MALIGNANCIES REQUIRES AN ETIOLOGICAL PERSPECTIVE, AND HELICOBACTER PYLORI (H. PYLORI) WAS IDENTIFIED TO PLAY A ROLE IN GC. H. PYLORI INFECTION CAUSES CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM CAUSING ABNORMAL POLYCLONAL METHYLATION, WHICH MIGHT RAISE THE RISK OF GC. IN THE LAST TWO DECADES, VARIOUS PATHOGENIC FACTORS BY WHICH H. PYLORI INFECTION CAUSES GC HAVE BEEN DISCOVERED. ABNORMAL DNA METHYLATION IS TRIGGERED IN SEVERAL GENES, RENDERING THEM INACTIVE. IN GC, METHYLATION PATTERNS ARE LINKED TO CERTAIN SUBTYPES INCLUDING MICROSATELLITE INSTABILITY. MULTIPLE CANCER-RELATED PROCESSES ARE MORE USUALLY CHANGED BY ABNORMAL DNA METHYLATION THAN THROUGH MUTATIONS, ACCORDING TO CURRENT GENERAL AND COMBINED INVESTIGATIONS. FURTHERMORE, THE AMOUNT OF ACQUIRED ABNORMAL DNA METHYLATION IS HEAVILY LINKED TO THE CHANCES OF DEVELOPING GC. THEREFORE, WE INVESTIGATED ABNORMAL DNA METHYLATION IN GC AND THE LINK BETWEEN METHYLATION AND H. PYLORI INFECTION. 2022 14 4316 32 MICRORNAS AS NON-INVASIVE DIAGNOSTIC BIOMARKERS FOR GASTRIC CANCER: CURRENT INSIGHTS AND FUTURE PERSPECTIVES. NON-INVASIVE DIAGNOSTIC BIOMARKERS MAY CONTRIBUTE TO AN EARLY IDENTIFICATION OF GASTRIC CANCER (GC) AND IMPROVE THE CLINICAL MANAGEMENT. UNFORTUNATELY, NO SENSITIVE AND SPECIFIC SCREENING BIOMARKERS ARE AVAILABLE YET AND THE CURRENTLY AVAILABLE APPROACHES ARE LIMITED BY THE NATURE OF THE DISEASE. GC IS A HETEROGENIC DISEASE WITH VARIOUS DISTINCT GENETIC AND EPIGENETIC EVENTS THAT OCCUR DURING THE MULTIFACTORIAL CASCADE OF CARCINOGENESIS. MICRORNAS (MIRNAS) ARE COMMONLY DEREGULATED IN GASTRIC MUCOSA DURING THE HELICOBACTER PYLORI INFECTION AND IN STEPWISE MANNER FROM CHRONIC GASTRITIS, THROUGH PRENEOPLASTIC CONDITIONS SUCH AS ATROPHIC GASTRITIS AND INTESTINAL METAPLASIA, TO EARLY DYSPLASIA AND INVASIVE CANCER. IDENTIFICATION OF MIRNAS IN BLOOD IN 2008 LED TO A GREAT INTEREST ON MIRNA-BASED DIAGNOSTIC, PROGNOSTIC BIOMARKERS IN GC. IN THIS REVIEW, WE PROVIDE THE MOST RECENT SYSTEMATIC REVIEW ON THE EXISTING STUDIES RELATED TO MIRNAS AS DIAGNOSTIC BIOMARKERS FOR GC. HERE, WE SYSTEMATICALLY EVALUATE 75 STUDIES RELATED TO DIFFERENTIAL EXPRESSION OF CIRCULATING MIRNAS IN GC PATIENTS AND PROVIDE NOVEL VIEW ON VARIOUS HETEROGENIC ASPECTS OF THE EXISTING DATA AND SUMMARIZE THE METHODOLOGICAL DIFFERENCES. FINALLY, WE HIGHLIGHT SEVERAL IMPORTANT ASPECTS CRUCIAL TO IMPROVE THE FUTURE TRANSLATIONAL AND CLINICAL RESEARCH IN THE FIELD. 2018 15 4733 26 NOVEL BIOMARKERS FOR THE IDENTIFICATION AND TARGETED THERAPY OF GASTRIC CANCER. GASTRIC CANCER DEVELOPMENT FOLLOWS THE PATHOLOGIC PATTERN SUCH THAT CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA PROGRESSIVELY TRANSFORMS NORMAL MUCOSA INTO ATROPHY, INTESTINAL METAPLASIA, ADENOMA/DYSPLASIA AND EVENTUALLY INVASIVE AND METASTATIC TUMORS. THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS LEADS TO THE DYSREGULATION OF ONCOGENES AND TUMOR SUPPRESSORS, WHICH WAS CONSIDERED AS THE DRIVER BEHIND EVENTS DURING THE TUMORIGENESIS. ALMOST ALL GASTRIC CANCERS ARE ADENOCARCINOMAS, WHICH SHARE CONSIDERABLE HETEROGENEITY WITH DISTINCT MORPHOLOGY, PATHOGENESIS AND CLINICAL BEHAVIOR. THEREFORE, IDENTIFYING SUBTYPES OF GASTRIC CANCERS WITH MOLECULAR AND GENETIC FEATURES WILL BE BENEFICIAL FOR THE EARLY IDENTIFICATION AND SELECTION OF NEW EFFECTIVE AGENTS FOR TARGETED TREATMENT. HIGH-THROUGHPUT SEQUENCING TECHNIQUES SUCH AS WHOLE GENOMIC, EPIGENOME AND TRANSCRIPTOME SEQUENCING AND PROTEOMICS PLATFORMS HAVE IDENTIFIED MAJOR GENOMIC CHARACTERISTICS THAT EXHIBIT IDENTIFICATION AND PROGNOSTIC IMPACTS AND DISTINCT RESPONSE PATTERNS. IN THIS ARTICLE, THE AUTHORS AIM TO SUMMARIZE THE INFORMATION REGARDING THE MOST PROMISING MOLECULES THAT MAY HAVE CLINICAL APPLICATION AS NON-INVASIVE BIOMARKERS AND THERAPY TARGETS. 2015 16 3229 40 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 17 5180 26 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 18 6369 36 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 19 3221 30 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 20 2894 36 GASTRIC CANCER AS A STEM-CELL DISEASE: DATA AND HYPOTHESES. THE MAIN FUNCTION OF GASTRIC STEM CELLS IS TO MAINTAIN THE INTEGRITY OF THE GASTROINTESTINAL EPITHELIUM AND REPLENISH ALL THE MATURE CELL LINEAGES. IN ORDER TO ACCOMPLISH THIS, GASTRIC STEM CELLS PROLIFERATE AND SELF-RENEW, GIVING RISE TO TRANSIENT AMPLIFYING CELLS WHICH REPLACE THE CONSTANTLY RENEWING EPITHELIUM, ESPECIALLY AFTER INJURY INDUCED BY LONG-TERM INFLAMMATION. GASTRIC CANCER (GC) REMAINS THE FOURTH MOST COMMON CANCER AND THE SECOND LEADING CAUSE OF DEATH FOR CANCER IN THE WORLD. THE MOST ACCEPTED MODEL OF GASTRIC CARCINOGENESIS PROVIDES A MULTIFACTORIAL AND MULTISTEP PATHOGENESIS, INVOLVING A NUMBER OF INITIATORS AND OTHER CONTINUATOR AGENTS. HELICOBACTER PYLORI INFECTION IS RECOGNIZED AS A NECESSARY BUT INSUFFICIENT CAUSE OF GC. RECENT ADVANCES IN GASTRIC STEM CELL BIOLOGY POINT OUT TO TWO HYPOTHESES. IN THE FIRST, IT IS POSTULATED THAT RESIDENT STEM CELLS MAY, IN A CHRONICALLY INFLAMED ENVIRONMENT, AS IN THE CASE OF HELICOBACTER PYLORI-INDUCED GASTRITIS, ACCUMULATE OVER TIME A SERIES OF GENETIC AND EPIGENETIC CHANGES THAT LEAD TO THE EMERGENCE OF GC STEM CELLS. ALTERNATIVELY, THE SETTING OF CHRONIC INFLAMMATORY STRESS MAY LEAD TO LOSS OF THE INDIGENOUS GASTRIC STEM CELLS FROM THEIR NICHES, FOLLOWED BY RECRUITMENT AND ENGRAFTMENT OF BONE MARROW DERIVED STEM CELLS (BMDCS) INTO THE GASTRIC EPITHELIUM. IN THE MOUSE MODEL, INCREASING EVIDENCE SUPPORTS THE HYPOTHESIS THAT BMDCS ARE IMPORTANT CELLULAR SOURCE OF HELICOBACTER-INDUCED GC. THIS REVIEW HIGHLIGHTS DATA AND HYPOTHESES ABOUT GC AS A MODEL OF STEM-CELL DISEASE. 2014