1  5602 114 RORGAMMAT(+) HEMATOPOIETIC CELLS ARE NECESSARY FOR TUMOR CELL PROLIFERATION DURING COLITIS-ASSOCIATED TUMORIGENESIS IN MICE. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMON TUMOR ENTITIES. IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES, THE DEVELOPMENT OF COLITIS-ASSOCIATED COLON CANCER IS CONSIDERED A DANGEROUS LONG-TERM COMPLICATION. IL-17A AND THE TRANSCRIPTION FACTOR RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) PLAY FUNDAMENTAL ROLES IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES; IN HUMAN STUDIES, WE DETECTED A DENSE INFILTRATION OF RORGAMMAT-DEPENDENT CD4(+) IL17A(+) T HELPER (TH)17 CELLS IN SPECIMENS OF CRC, ULCERATIVE COLITIS, AND ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER. HOWEVER, THE MECHANISTIC ROLE OF RORGAMMAT(+) HEMATOPOIETIC CELLS IN COLITIS-ASSOCIATED TUMORIGENESIS REMAINS UNCLEAR. TO INVESTIGATE COLITIS-ASSOCIATED COLON TUMORIGENESIS, WE CONDUCTED STUDIES IN THE AOM+DSS MOUSE MODEL THAT REVEALED THE IMPORTANCE OF RORGAMMAT FOR COLON TUMOR PROGRESSION. IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES, MICE SHOWED SIGNS OF INTENSE CHRONIC COLITIS, BUT DEVELOPED SIGNIFICANTLY FEWER MACROSCOPIC TUMOR NODULES. THE REDUCTION OF TUMOR DEVELOPMENT IN RORGAMMAT(-/-) MICE WAS NOT DUE TO REDUCED COLON TUMOR INITIATION. HOWEVER, THE PROLIFERATION RATE OF TUMOR CELLS WAS REDUCED IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 CELLS AND TUMOR CELLS SHOWED PRONOUNCED SIGNS OF SENESCENCE-ASSOCIATED EPIGENETIC AND LYSOSOMAL CHANGES. THESE RESULTS INDICATE AN IMPORTANT ROLE FOR THE IMMUNOLOGICAL MILIEU IN COLITIS-ASSOCIATED CANCER, WHICH IS SHAPED IN-PART BY RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES THAT SUPPORT CRC GROWTH.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2  5435  34 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  3804  25 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  3232  19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  3218  43 HELICOBACTER INFECTION IS REQUIRED FOR INFLAMMATION AND COLON CANCER IN SMAD3-DEFICIENT MICE. ACCUMULATING EVIDENCE SUGGESTS THAT INTESTINAL MICROBIAL ORGANISMS MAY PLAY AN IMPORTANT ROLE IN TRIGGERING AND SUSTAINING INFLAMMATION IN INDIVIDUALS AFFLICTED WITH INFLAMMATORY BOWEL DISEASE (IBD). MOREOVER, INDIVIDUALS WITH IBD ARE AT INCREASED RISK FOR DEVELOPING COLORECTAL CANCER, SUGGESTING THAT CHRONIC INFLAMMATION MAY INITIATE GENETIC OR EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. WE TESTED THE HYPOTHESIS THAT BACTERIA MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER BY SYNERGIZING WITH DEFECTIVE TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, A PATHWAY COMMONLY MUTATED IN HUMAN COLON CANCER. ALTHOUGH OTHERS HAVE REPORTED THAT MICE DEFICIENT IN THE TGF-BETA SIGNALING MOLECULE SMAD3 DEVELOP COLON CANCER, WE FOUND THAT SMAD3-DEFICIENT MICE MAINTAINED FREE OF THE GRAM-NEGATIVE ENTEROHEPATIC BACTERIA HELICOBACTER SPP. FOR UP TO 9 MONTHS DO NOT DEVELOP COLON CANCER. FURTHERMORE, INFECTION OF SMAD3(-/-) MICE WITH HELICOBACTER TRIGGERS COLON CANCER IN 50% TO 66% OF THE ANIMALS. USING REAL-TIME PCR, WE FOUND THAT HELICOBACTER ORGANISMS CONCENTRATE IN THE CECUM, THE PREFERRED SITE OF TUMOR DEVELOPMENT. MUCINOUS ADENOCARCINOMAS DEVELOP 5 TO 30 WEEKS AFTER INFECTION AND ARE PRECEDED BY AN EARLY INFLAMMATORY PHASE, CONSISTING OF INCREASED PROLIFERATION OF EPITHELIAL CELLS; INCREASED NUMBERS OF CYCLOOXYGENASE-2-POSITIVE CELLS, CD4(+) T CELLS, MACROPHAGES; AND INCREASED MHC CLASS II EXPRESSION. COLONIC TISSUE REVEALED INCREASED TRANSCRIPTS FOR THE ONCOGENE C-MYC AND THE PROINFLAMMATORY CYTOKINES INTERLEUKIN-1ALPHA (IL-1ALPHA), IL-1BETA, IL-6, IFN-GAMMA, AND TUMOR NECROSIS FACTOR-ALPHA, SOME OF WHICH HAVE BEEN IMPLICATED IN COLON CANCER. THESE RESULTS SUGGEST THAT BACTERIA MAY BE IMPORTANT IN TRIGGERING COLORECTAL CANCER, NOTABLY IN THE CONTEXT OF GENE MUTATIONS IN THE TGF-BETA SIGNALING PATHWAY, ONE OF THE MOST COMMONLY AFFECTED CELLULAR PATHWAYS IN COLORECTAL CANCER IN HUMANS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6  4732  37 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION.	2023	

7  3170  27 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  6331  31 THE ROLE OF COX-2 IN INTESTINAL INFLAMMATION AND COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A HETEROGENEOUS DISEASE, INCLUDING AT LEAST THREE MAJOR FORMS: HEREDITARY, SPORADIC AND COLITIS-ASSOCIATED CRC. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET AND LIFESTYLE ARE THE RISK FACTORS FOR CRC. AS ELEVATED CYCLOOXYGENASE-2 (COX-2) EXPRESSION WAS FOUND IN MOST CRC TISSUE AND IS ASSOCIATED WITH WORSE SURVIVAL AMONG CRC PATIENTS, INVESTIGATORS HAVE SOUGHT TO EVALUATE THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND SELECTIVE COX-2 INHIBITORS (COXIBS) ON CRC. THE EPIDEMIOLOGICAL STUDIES, CLINICAL TRIALS AND ANIMAL EXPERIMENTS INDICATE THAT NSAIDS ARE AMONG THE MOST PROMISING CHEMOPREVENTIVE AGENTS FOR THIS DISEASE. NSAIDS EXERT THEIR ANTI-INFLAMMATORY AND ANTITUMOR EFFECTS PRIMARILY BY REDUCING PROSTAGLANDIN PRODUCTION BY INHIBITION OF COX-2 ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT BREAKTHROUGHS IN OUR UNDERSTANDING OF THE ROLES OF COX-2 IN CRC AND INFLAMMATORY BOWEL DISEASE. THESE RECENT DATA PROVIDE A RATIONALE FOR RE-EVALUATING COX-2 AS BOTH THE PROGNOSTIC AND THE PREDICTIVE MARKER IN A WIDE VARIETY OF MALIGNANCIES AND FOR RENEWING THE INTEREST IN EVALUATING RELATIVE BENEFITS AND RISK OF COXIBS IN APPROPRIATELY SELECTED PATIENTS FOR CANCER PREVENTION AND TREATMENT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  3226  30 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  1099  32 COLONIC CARCINOGENESIS IN IBD: MOLECULAR EVENTS. PATIENTS WITH ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD) ARE AT INCREASED RISK OF DEVELOPING INTESTINAL CANCERS VIA MECHANISMS THAT REMAIN INCOMPLETELY UNDERSTOOD. SEVERAL EVIDENCES SUGGEST A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT OF CANCER IN THE GASTROINTESTINAL TRACT. IN FACT, PATIENTS WITH UC ARE EXPOSED TO REPEATED EPISODES OF INFLAMMATION THAT PREDISPOSE TO VARIOUS TUMORIGENIC EVENTS AND THE SEQUENCE OF THESE EVENTS ARE DIFFERENT FROM THOSE THAT CONTRIBUTE TO DEVELOP A SPORADIC COLORECTAL CANCER. IN UC CARCINOGENESIS THE EARLY EVENTS ARE REPRESENTED BY DNA METHYLATION THAT PRODUCE AN INHIBITION OF ONCO-SUPPRESSOR GENES, MUTATION OF P53, ANEUPLOIDY AND MICROSATELLITE INSTABILITY. HYPERMETHYLATION OF TUMOR SUPPRESSORS AND DNA MISMATCH REPAIR GENE PROMOTER REGIONS, IS AN EPIGENETIC MECHANISM OF GENE SILENCING THAT CONTRIBUTES TO TUMORIGENESIS AND MIGHT REPRESENT THE FIRST STEP IN INFLAMMATORY CARCINOGENESIS. P53 IS FREQUENTLY MUTATED IN THE EARLY STAGES OF UC-ASSOCIATED CANCER, IN 33-67% OF PATIENTS WITH DYSPLASIA AND IN 83-95% OF UC RELATED CANCER PATIENTS. MOREOVER, ANEUPLOIDY IS AN INDEPENDENT RISK FACTOR FOR FORTHCOMING CARCINOGENESIS IN UC FINALLY, THE INCONSISTENCY BETWEEN THE HIGH CUMULATIVE RATE OF DYSPLASIA IN UC AND THE RELATIVELY LOWER INCIDENCE OF INVASIVE CANCER RAISES THE QUESTION ABOUT THE MECHANISMS OF IMMUNOSURVEILLANCE THAT MAY PREVENT MALIGNANT PROGRESSION OF NEOPLASM IN THE COLON IN MOST CASES. CO-STIMULATORY MOLECULE CD80 UP-REGULATION IN COLONIC MUCOSA IN UC DYSPLASIA MAY BE ONE OF THESE MECHANISM.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  2607  27 EPIGENETICS/EPIGENOMICS AND PREVENTION BY CURCUMIN OF EARLY STAGES OF INFLAMMATORY-DRIVEN COLON CANCER. COLORECTAL CANCER (CRC) IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY IN THE US AND WORLDWIDE. CRC IS THE SECOND MOST COMMON CANCER-RELATED DEATH IN BOTH MEN AND WOMEN GLOBALLY. CHRONIC INFLAMMATION HAS BEEN IDENTIFIED AS ONE OF THE MAJOR RISK FACTORS OF CRC. IT MAY DRIVE GENETIC AND EPIGENETIC/EPIGENOMIC ALTERATIONS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA REGULATION. CURRENT PREVENTION MODALITIES FOR CRC ARE LIMITED AND SOME TREATMENT REGIMENS SUCH AS USE THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG ASPIRIN MAY HAVE SEVERE SIDE EFFECTS, NAMELY GASTROINTESTINAL ULCERATION AND BLEEDING. THEREFORE, THERE IS AN URGENT NEED OF DEVELOPING ALTERNATIVE STRATEGIES. RECENTLY, INCREASING EVIDENCE SUGGESTS THAT SEVERAL DIETARY CANCER CHEMOPREVENTIVE PHYTOCHEMICALS POSSESS ANTI-INFLAMMATION AND ANTIOXIDATIVE STRESS ACTIVITIES, AND MAY PREVENT CANCERS INCLUDING CRC. CURCUMIN (CUR) IS THE YELLOW PIGMENT THAT IS FOUND IN THE RHIZOMES OF TURMERIC (CURCUMA LONGA). MANY STUDIES HAVE DEMONSTRATED THAT CUR EXHIBIT STRONG ANTICANCER, ANTIOXIDATIVE STRESS, AND ANTI-INFLAMMATORY ACTIVITIES BY REGULATING SIGNALING PATHWAYS, SUCH AS NUCLEAR FACTOR ERYTHROID-2-RELATED FACTOR 2, NUCLEAR FACTOR-KAPPAB, AND EPIGENETICS/EPIGENOMICS PATHWAYS OF HISTONES MODIFICATIONS, AND DNA METHYLATION. IN THIS REVIEW, WE WILL DISCUSS THE LATEST EVIDENCE IN EPIGENETICS/EPIGENOMICS ALTERATIONS BY CUR IN CRC AND THEIR POTENTIAL CONTRIBUTION IN THE PREVENTION OF CRC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  4535  28 MULTIPLE ROLES OF TOLL-LIKE RECEPTOR 4 IN COLORECTAL CANCER. TOLL-LIKE RECEPTOR (TLR) SIGNALING HAS BEEN IMPLICATED IN THE INFLAMMATORY RESPONSES IN INTESTINAL EPITHELIAL CELLS (IECS). SUCH INFLAMMATORY SIGNALS MEDIATE COMPLEX INTERACTIONS BETWEEN COMMENSAL BACTERIA AND TLRS AND ARE REQUIRED FOR IEC PROLIFERATION, IMMUNE RESPONSE, REPAIR, AND HOMEOSTASIS. THE UPREGULATION OF CERTAIN TLRS IN COLORECTAL CANCER (CRC) TISSUES SUGGESTS THAT TLRS MAY PLAY AN ESSENTIAL ROLE IN THE PROGNOSIS OF CHRONIC AND INFLAMMATORY DISEASES THAT ULTIMATELY CULMINATE IN CRC. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE LITERATURE ON THE INVOLVEMENT OF THE TLR PATHWAY IN THE INITIATION, PROGRESSION, AND METASTASIS OF CRC, AS WELL AS INHERITED GENETIC VARIATION AND EPIGENETIC REGULATION. THE DIFFERENTIAL EXPRESSION OF TLRS IN EPITHELIAL CELLS HAS ALSO BEEN DISCUSSED. IN PARTICULAR, WE EMPHASIZE THE PHYSIOLOGICAL ROLE OF TLR4 IN CRC DEVELOPMENT AND PATHOGENESIS, AND PROPOSE NOVEL AND PROMISING APPROACHES FOR CRC THERAPEUTICS WITH THE AID OF TLR LIGANDS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  3221  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  4458  27 MOLECULAR MECHANISMS OF ALCOHOL-INDUCED COLORECTAL CARCINOGENESIS. THE ETIOLOGY OF COLORECTAL CANCER (CRC) IS COMPLEX. APPROXIMATELY, 10% OF INDIVIDUALS WITH CRC HAVE PREDISPOSING GERMLINE MUTATIONS THAT LEAD TO FAMILIAL CANCER SYNDROMES, WHEREAS MOST CRC PATIENTS HAVE SPORADIC CANCER RESULTING FROM A COMBINATION OF ENVIRONMENTAL AND GENETIC RISK FACTORS. IT HAS BECOME INCREASINGLY CLEAR THAT CHRONIC ALCOHOL CONSUMPTION IS ASSOCIATED WITH THE DEVELOPMENT OF SPORADIC CRC; HOWEVER, THE EXACT MECHANISMS BY WHICH ALCOHOL CONTRIBUTES TO COLORECTAL CARCINOGENESIS ARE LARGELY UNKNOWN. SEVERAL PROPOSED MECHANISMS FROM STUDIES IN CRC MODELS SUGGEST THAT ALCOHOL METABOLITES AND/OR ENZYMES ASSOCIATED WITH ALCOHOL METABOLISM ALTER CELLULAR REDOX BALANCE, CAUSE DNA DAMAGE, AND EPIGENETIC DYSREGULATION. IN ADDITION, ALCOHOL METABOLITES CAN CAUSE A DYSBIOTIC COLORECTAL MICROBIOME AND INTESTINAL PERMEABILITY, RESULTING IN BACTERIAL TRANSLOCATION, INFLAMMATION, AND IMMUNOSUPPRESSION. ALL OF THESE EFFECTS CAN INCREASE THE RISK OF DEVELOPING CRC. THIS REVIEW AIMS TO OUTLINE SOME OF THE MOST SIGNIFICANT AND RECENT FINDINGS ON THE MECHANISMS OF ALCOHOL IN COLORECTAL CARCINOGENESIS. WE EXAMINE THE EFFECT OF ALCOHOL ON THE GENERATION OF REACTIVE OXYGEN SPECIES, THE DEVELOPMENT OF GENOTOXIC STRESS, MODULATION OF ONE-CARBON METABOLISM, DISRUPTION OF THE MICROBIOME, AND IMMUNOSUPPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
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  5180  21 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  5566  36 ROLE OF INFLAMMATION IN THE DEVELOPMENT OF COLORECTAL CANCER. CHRONIC INFLAMMATION CAN LEAD TO THE DEVELOPMENT OF MANY DISEASES, INCLUDING CANCER. INFLAMMATORY BOWEL DISEASE (IBD) THAT INCLUDES BOTH ULCERATIVE COLITIS (UC) AND CROHNMP'S DISEASE (CD) ARE RISK FACTORS FOR THE DEVELOPMENT OF COLORECTAL CANCER (CRC). MANY CYTOKINES PRODUCED PRIMARILY BY THE GUT IMMUNE CELLS EITHER DURING OR IN RESPONSE TO LOCALIZED INFLAMMATION IN THE COLON AND RECTUM ARE KNOWN TO STIMULATE THE COMPLEX INTERACTIONS BETWEEN THE DIFFERENT CELL TYPES IN THE GUT ENVIRONMENT RESULTING IN ACUTE INFLAMMATION. SUBSEQUENTLY, CHRONIC INFLAMMATION, TOGETHER WITH GENETIC AND EPIGENETIC CHANGES, HAVE BEEN SHOWN TO LEAD TO THE DEVELOPMENT AND PROGRESSION OF CRC. VARIOUS CELL TYPES PRESENT IN THE COLON, SUCH AS ENTEROCYTES, PANETH CELLS, GOBLET CELLS, AND MACROPHAGES, EXPRESS RECEPTORS FOR INFLAMMATORY CYTOKINES AND RESPOND TO TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-1 BETA (IL-1BETA), IL-6, AND OTHER CYTOKINES. AMONG THE SEVERAL CYTOKINES PRODUCED, TNF-ALPHA AND IL-1BETA ARE THE KEY PRO-INFLAMMATORY MOLECULES THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT OF CRC. THE CURRENT REVIEW IS INTENDED TO CONSOLIDATE THE PUBLISHED FINDINGS TO FOCUS ON THE ROLE OF PRO-INFLAMMATORY CYTOKINES, NAMELY TNF-ALPHA AND IL-1BETA, ON INFLAMMATION (AND THE ALTERED IMMUNE RESPONSE) IN THE GUT, TO BETTER UNDERSTAND THE DEVELOPMENT OF CRC IN IBD, USING VARIOUS EXPERIMENTAL MODEL SYSTEMS, PRECLINICAL AND CLINICAL STUDIES. MOREOVER, THIS REVIEW ALSO HIGHLIGHTS THE CURRENT THERAPEUTIC STRATEGIES AVAILABLE (MONOTHERAPY AND COMBINATION THERAPY) TO ALLEVIATE THE SYMPTOMS OR TREAT INFLAMMATION-ASSOCIATED CRC BY USING MONOCLONAL ANTIBODIES OR APTAMERS TO BLOCK PRO-INFLAMMATORY MOLECULES, INHIBITORS OF TYROSINE KINASES IN THE INFLAMMATORY SIGNALING CASCADE, COMPETITIVE INHIBITORS OF PRO-INFLAMMATORY MOLECULES, AND THE NUCLEIC ACID DRUGS LIKE SMALL ACTIVATING RNAS (SARNAS) OR MICRORNA (MIRNA) MIMICS TO ACTIVATE TUMOR SUPPRESSOR OR REPRESS ONCOGENE/PRO-INFLAMMATORY CYTOKINE GENE EXPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                            
19  3445  35 HYPERMETHYLATION OF ITGA4, TFPI2 AND VIMENTIN PROMOTERS IS INCREASED IN INFLAMED COLON TISSUE: PUTATIVE RISK MARKERS FOR COLITIS-ASSOCIATED CANCER. PURPOSE: EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES IS INVOLVED IN EARLY TRANSFORMING EVENTS AND HAS A HIGH IMPACT ON COLORECTAL CARCINOGENESIS. LIKEWISE, COLON CANCERS THAT DERIVE FROM CHRONICALLY INFLAMED BOWEL DISEASES FREQUENTLY EXHIBIT EPIGENETIC CHANGES. BUT THERE IS LITTLE DATA ABOUT EPIGENETIC ABERRATIONS CAUSING COLORECTAL CANCER IN CHRONICALLY INFLAMED TISSUE. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ABERRANT GAIN OF METHYLATION IN THE GENE PROMOTERS OF VIM, TFPI2 AND ITGA4 AS PUTATIVE EARLY MARKERS IN THE DEVELOPMENT FROM INFLAMED TISSUE VIA PRECANCEROUS LESIONS TOWARD COLORECTAL CANCER. METHODS: INITIAL SCREENING OF DIFFERENT CANCER CELL LINES BY USING METHYLATION-SPECIFIC PCR REVEALED A PUTATIVE COLON CANCER-SPECIFIC METHYLATION PATTERN. ADDITIONALLY, A DEMETHYLATION ASSAY WAS PERFORMED TO INVESTIGATE THE METHYLATION-DEPENDENT GENE SILENCING OF ITGA4. THE CANDIDATE MARKERS WERE ANALYZED IN COLONIC TISSUE SPECIMENS FROM PATIENTS WITH COLORECTAL CANCER (N = 15), ADENOMAS (N = 76), SERRATED LESIONS (N = 13), CHRONIC INFLAMMATION (N = 10) AND NORMAL MUCOSAL SAMPLES (N = 9). RESULTS: A HIGH METHYLATION FREQUENCY OF VIM (55.6 %) WAS OBSERVED IN NORMAL COLON TISSUE, WHEREAS ITGA4 AND TFPI2 WERE COMPLETELY UNMETHYLATED IN CONTROLS. A SIGNIFICANT GAIN OF METHYLATION FREQUENCY WITH PROGRESSION OF DISEASE AS WELL AS AN AGE-DEPENDENT EFFECT WAS DETECTABLE FOR TFPI2. ITGA4 METHYLATION FREQUENCY WAS HIGH IN PRECANCEROUS AND CANCEROUS TISSUES AS WELL AS IN INFLAMMATORY BOWEL DISEASES (IBD). CONCLUSION: THE ALREADY ESTABLISHED METHYLATION MARKER VIM DOES NOT PERMIT A SPECIFIC AND SENSITIVE DISCRIMINATION OF HEALTHY AND NEOPLASTIC TISSUE. THE METHYLATION MARKERS ITGA4 AND TFPI2 SEEM TO BE SUITABLE RISK MARKERS FOR INFLAMMATION-ASSOCIATED COLON CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  6661  39 UPREGULATION OF DNA METHYLTRANSFERASE-MEDIATED GENE SILENCING, ANCHORAGE-INDEPENDENT GROWTH, AND MIGRATION OF COLON CANCER CELLS BY INTERLEUKIN-6. INFLAMMATORY BOWEL DISEASE IS CHARACTERIZED BY CHRONIC INFLAMMATION WHICH PREDISPOSES TO COLORECTAL CANCER. THE MECHANISMS BY WHICH INFLAMMATION PROMOTES TUMORIGENESIS ARE NOT FULLY KNOWN. WE AIMED TO INVESTIGATE THE LINKS BETWEEN COLONIC INFLAMMATION AND TUMORIGENESIS VIA EPIGENETIC GENE SILENCING. COLON CANCER SPECIMENS WERE ASSESSED FOR THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT-1) USING IMMUNOHISTOCHEMISTRY. COLORECTAL CARCINOMA CELL LINES WERE ASSESSED FOR DNMT1 EXPRESSION, METHYLCYTOSINE CONTENT, PROMOTER METHYLATION, GENE EXPRESSION, AND TUMORIGENESIS IN RESPONSE TO INTERLEUKIN (IL)-6. DNMT1 WAS EXPRESSED AT HIGHER LEVELS IN BOTH THE PERITUMORAL STROMA AND TUMOR IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED CANCERS COMPARED WITH SPORADIC COLON CANCERS. IL-6 TREATMENT OF COLON CANCER CELLS RESULTED IN AN INCREASE IN DNMT1 EXPRESSION, INDEPENDENT OF DE NOVO GENE EXPRESSION. IL-6 INCREASED THE METHYLATION OF PROMOTER REGIONS OF GENES ASSOCIATED WITH TUMOR SUPPRESSION, ADHESION, AND APOPTOSIS RESISTANCE. EXPRESSION OF A SUBSET OF THESE GENES WAS DOWNREGULATED BY IL-6, AN EFFECT THAT WAS PREVENTED BY PREINCUBATION WITH 5-AZADEOXYCYTIDINE, A DNMT1 INHIBITOR. ANCHORAGE-INDEPENDENT GROWTH AND MIGRATION OF COLON CANCER CELLS WAS ALSO INCREASED BY IL-6 IN A 5-AZADEOXYCYTIDINE-SENSITIVE MANNER. OUR RESULTS INDICATE THAT DNMT-MEDIATED GENE SILENCING MAY PLAY A ROLE IN INFLAMMATION-ASSOCIATED COLON TUMORIGENESIS.	2010