1 3289 117 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 2 2800 42 FEEDBACK REGULATORS OF HYPOXIA-INDUCIBLE FACTORS AND THEIR ROLE IN CANCER BIOLOGY. MALIGNANT TUMORS ARE CHARACTERIZED BY REGIONS OF LOW OXYGEN CONCENTRATION (HYPOXIA). THE HYPOXIC TUMOR MICROENVIRONMENT CONTRIBUTES TO TUMOR PROGRESSION BY ACTIVATING A SET OF ADAPTIVE RESPONSES VIA THE KEY TRANSCRIPTIONAL REGULATORS HIF-1ALPHA AND HIF-2ALPHA. THESE FACTORS HAVE BEEN TRADITIONALLY LINKED TO AN AGGRESSIVE TUMOR PHENOTYPE BY PROMOTING PROCESSES ESSENTIAL FOR TUMOR GROWTH, SUCH AS ANGIOGENESIS, GLYCOLYSIS, METASTASIS AND INVASION, AS WELL AS DIFFERENTIATION AND SELF RENEWAL. NOTABLY, THE COMPLEX HIF PATHWAY ALSO INITIATES ANTI-TUMORIGENIC MECHANISMS THAT LEAD TO CELL CYCLE ARREST OR CELL DEATH, INDICATING THE NEED FOR A STRINGENT CONTROL OF THE EXTENT AND THE DIRECTION OF THE HYPOXIA RESPONSE. THE IMPORTANCE OF THIS CONTROL FOR TUMOR CELL SURVIVAL IS ILLUSTRATED BY THE INTRICATE REGULATION OF HIF ACTIVITY AT THE MRNA, PROTEIN AND EPIGENETIC LEVEL BY A COMPLEX NETWORK OF POSITIVE AND NEGATIVE FEEDBACK REGULATORS. WE PROPOSE THAT THESE FEEDBACK REGULATORS HELP TO FLEXIBLY ADJUST AND ADAPT HIF ACTIVATED RESPONSES TO THE FLUCTUATING OXYGEN CONCENTRATIONS WITHIN TUMORS DURING ACUTE AND CHRONIC HYPOXIA AND TO CURTAIL THE TUMOR-SUPPRESSING COMPONENTS OF THE HIF PATHWAY. MOREOVER, FEEDBACK REGULATION OF HIF INDUCES A SWITCH FROM HIF-1ALPHA TO HIF-2ALPHA DRIVEN RESPONSES UNDER CHRONIC HYPOXIA WHICH MAY HAVE ESSENTIAL FUNCTIONS IN THE REGULATION OF TUMOR CELL DIFFERENTIATION AND TUMOR STEM CELL MAINTENANCE. GIVEN THEIR CENTRAL ROLE IN CANCER BIOLOGY, HIF FEEDBACK REGULATORS MAY REPRESENT AN ATTRACTIVE AND NOVEL ANTI-TUMOR THERAPY TARGET TO OVERCOME CELL DEATH RESISTANCE IN TUMORS. 2010 3 6428 31 THE TUMOR MICROENVIRONMENT AND METASTATIC DISEASE. THE MICROENVIRONMENT OF SOLID TUMORS IS A HETEROGENEOUS, COMPLEX MILIEU FOR TUMOR GROWTH AND SURVIVAL THAT INCLUDES FEATURES SUCH AS ACIDIC PH, LOW NUTRIENT LEVELS, ELEVATED INTERSTITIAL FLUID PRESSURE (IFP) AND CHRONIC AND FLUCTUATING LEVELS OF OXYGENATION THAT RELATE TO THE ABNORMAL VASCULAR NETWORK THAT EXISTS IN TUMORS. THE METASTATIC POTENTIAL OF TUMOR CELLS IS BELIEVED TO BE REGULATED BY INTERACTIONS BETWEEN THE TUMOR CELLS AND THEIR EXTRACELLULAR ENVIRONMENT (EXTRACELLULAR MATRIX (ECM)). THESE INTERACTIONS CAN BE MODIFIED BY THE ACCUMULATION OF GENETIC CHANGES AND BY THE TRANSIENT ALTERATIONS IN GENE EXPRESSION INDUCED BY THE LOCAL TUMOR MICROENVIRONMENT. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT ALTERED GENE EXPRESSION IN RESPONSE TO THE HYPOXIC MICROENVIRONMENT IS A CONTRIBUTING FACTOR TO INCREASED METASTATIC EFFICIENCY. A NUMBER OF GENES THAT HAVE BEEN IMPLICATED IN THE METASTATIC PROCESS, INVOLVING ANGIOGENESIS, INTRA/EXTRAVASATION, SURVIVAL AND GROWTH, HAVE BEEN FOUND TO BE HYPOXIA-RESPONSIVE. THE VARIOUS METASTATIC DETERMINANTS, GENETIC AND EPIGENETIC, SOMATIC AND INHERITED MAY SERVE AS PRECEDENTS FOR THE FUTURE IDENTIFICATION OF MORE GENES THAT ARE INVOLVED IN METASTASIS. MUCH RESEARCH HAS FOCUSED ON GENETIC AND MOLECULAR PROPERTIES OF THE TUMOR CELLS THEMSELVES. IN THE PRESENT REVIEW WE DISCUSS THE EPIGENETIC AND PHYSIOLOGICAL REGULATION OF METASTASIS AND EMPHASIZE THE NEED FOR FURTHER STUDIES ON THE INTERACTIONS BETWEEN THE PATHOPHYSIOLOGIC TUMOR MICROENVIRONMENT AND THE TUMOR EXTRACELLULAR MATRIX. 2009 4 6151 27 THE FIRE WITHIN: CELL-AUTONOMOUS MECHANISMS IN INFLAMMATION-DRIVEN CANCER. INFLAMMATORY CELLS ARE IMPORTANT FOR TUMOR INITIATION AND PROMOTION, PROVIDING CANCER CELLS WITH CYTOKINES THAT ENHANCE CELL PROLIFERATION AND SURVIVAL. ALTHOUGH MALIGNANT EPITHELIAL CELLS WERE TRADITIONALLY CONSIDERED TO BE ON THE RECEIVING END OF THESE MICROENVIRONMENTAL INTERACTIONS, RECENT STUDIES SHOW THAT EPITHELIAL CELLS CAN UNDERGO INFLAMMATORY REPROGRAMMING ON THEIR OWN. SUCH EPIGENETIC SWITCHES ARE OFTEN TRIGGERED BY CHRONIC TISSUE INJURY AND PLAY IMPORTANT ROLES IN TISSUE REPAIR. BY CONVERTING TERMINALLY DIFFERENTIATED CELLS THAT HARBOR EVEN A SINGLE ONCOGENIC MUTATION TO A LESS DIFFERENTIATED STATE WITH A HIGHER PROLIFERATIVE POTENTIAL, CELL-AUTONOMOUS INFLAMMATION IS AN IMPORTANT CONTRIBUTOR TO TUMOR INITIATION. 2019 5 4284 34 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 6 3659 30 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 7 1232 36 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 8 1150 38 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 9 6710 34 VIRAL-INDUCED HUMAN CARCINOGENESIS: AN OXIDATIVE STRESS PERSPECTIVE. ONCOGENIC TRANSFORMATION OCCURS VIA MANY DIFFERENT MECHANISMS. ALTERATIONS IN THE EXPRESSION OF CERTAIN KEY GENES (ONCOGENES AND/OR TUMOR SUPPRESSOR GENES) CONTRIBUTE TO THE DEVELOPMENT OF THE TUMORIGENIC STATE OF UNCONTROLLED CELL PROLIFERATION. TUMOR VIRUSES' STUDIES HAVE CONTRIBUTED OVER THE LAST 2 DECADES SIGNIFICANTLY IN CANCER ETIOLOGY, FIRST BY PROVIDING VALUABLE INFORMATION ON THE MECHANISMS AND DISSECTION OF CELL SIGNALING AND GROWTH CONTROL PATHWAYS AND SECOND BY BEING CAUSATIVE AGENTS OF HUMAN NEOPLASIA. VIRUSES CONTRIBUTE TO THE DEVELOPMENT OF THE NEOPLASTIC STATE THROUGH MANY MECHANISMS: INACTIVATION OF TUMOR SUPPRESSOR GENES, HYPERSTIMULATION OF CELLULAR PROTO-ONCOGENE TRANSCRIPTION, OR BY VIRAL PROTEIN INTERFERENCE WITH THE CELLULAR TRANSCRIPTION, SIGNAL TRANSDUCTION, DNA REPAIR AND APOPTOSIS PATHWAYS AND INDUCTION OF CHRONIC OXIDATIVE STRESS. ON THE OTHER HAND, ONLY RECENTLY RESEARCH HAS PROVIDED EVIDENCE OF THE EPIGENETIC PATHWAY INVOLVEMENT AND ESPECIALLY THE DNA METHYLATION MACHINERY. TO THIS END, BOTH HYPOMETHYLATION-INDUCED ONCOGENIC ACTIVATION AND/OR HYPERMETHYLATION-INDUCED TUMOR SUPPRESSOR GENE SILENCING ARE LINKED WITH VIRAL-INDUCED CARCINOGENESIS. IN THIS REVIEW, WE DISCUSS THE CURRENT STATUS OF KNOWLEDGE ON VIRAL-ASSOCIATED CARCINOGENESIS WITH EMPHASIS ON THE MECHANISMS OF OXIDATIVE STRESS AND DNA DAMAGE INDUCTION IN HUMANS BY VIRUSES AS WELL AS IMPLICATIONS IN CANCER TREATMENT. 2010 10 3799 27 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 11 2036 22 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 12 1864 31 EMERGING AVENUES LINKING INFLAMMATION AND CANCER. THE ROLE OF INFLAMMATION IN CARCINOGENESIS HAS BEEN EXTENSIVELY INVESTIGATED AND WELL DOCUMENTED. MANY BIOCHEMICAL PROCESSES THAT ARE ALTERED DURING CHRONIC INFLAMMATION HAVE BEEN IMPLICATED IN TUMORIGENESIS. THESE INCLUDE SHIFTING CELLULAR REDOX BALANCE TOWARD OXIDATIVE STRESS; INDUCTION OF GENOMIC INSTABILITY; INCREASED DNA DAMAGE; STIMULATION OF CELL PROLIFERATION, METASTASIS, AND ANGIOGENESIS; DEREGULATION OF CELLULAR EPIGENETIC CONTROL OF GENE EXPRESSION; AND INAPPROPRIATE EPITHELIAL-TO-MESENCHYMAL TRANSITION. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT CONVERSION OF CELLS IN A BACKGROUND OF CHRONIC INFLAMMATION. INAPPROPRIATE TRANSCRIPTION OF GENES ENCODING INFLAMMATORY MEDIATORS, SURVIVAL FACTORS, AND ANGIOGENIC AND METASTATIC PROTEINS IS THE KEY MOLECULAR EVENT IN LINKING INFLAMMATION AND CANCER. ABERRANT CELL SIGNALING PATHWAYS COMPRISING VARIOUS KINASES AND THEIR DOWNSTREAM TRANSCRIPTION FACTORS HAVE BEEN IDENTIFIED AS THE MAJOR CONTRIBUTORS IN ABNORMAL GENE EXPRESSION ASSOCIATED WITH INFLAMMATION-DRIVEN CARCINOGENESIS. THE POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS ALSO PROVIDES THE MOLECULAR BASIS FOR LINKING INFLAMMATION TO CANCER. THIS REVIEW HIGHLIGHTS THE MULTIFACETED ROLE OF INFLAMMATION IN CARCINOGENESIS IN THE CONTEXT OF ALTERED CELLULAR REDOX SIGNALING. 2012 13 4111 35 MECHANISMS CONTRIBUTING TO PERSISTENTLY ACTIVATED CELL PHENOTYPES IN PULMONARY HYPERTENSION. CHRONIC PULMONARY HYPERTENSION (PH) IS CHARACTERIZED BY THE ACCUMULATION OF PERSISTENTLY ACTIVATED CELL TYPES IN THE PULMONARY VESSEL EXHIBITING ABERRANT EXPRESSION OF GENES INVOLVED IN APOPTOSIS RESISTANCE, PROLIFERATION, INFLAMMATION AND EXTRACELLULAR MATRIX (ECM) REMODELLING. CURRENT THERAPIES FOR PH, FOCUSING ON VASODILATATION, DO NOT NORMALIZE THESE ACTIVATED PHENOTYPES. FURTHERMORE, CURRENT APPROACHES TO DEFINE ADDITIONAL THERAPEUTIC TARGETS HAVE FOCUSED ON DETERMINING THE INITIATING SIGNALS AND THEIR DOWNSTREAM EFFECTORS THAT ARE IMPORTANT IN PH ONSET AND DEVELOPMENT. ALTHOUGH THESE APPROACHES HAVE PRODUCED A LARGE NUMBER OF COMPELLING PH TREATMENT TARGETS, MANY PROMISING HUMAN DRUGS HAVE FAILED IN PH CLINICAL TRIALS. HEREIN, WE PROPOSE THAT ONE CONTRIBUTING FACTOR TO THESE FAILURES IS THAT PROCESSES IMPORTANT IN PH DEVELOPMENT MAY NOT BE GOOD TREATMENT TARGETS IN THE ESTABLISHED PHASE OF CHRONIC PH. WE HYPOTHESIZE THAT THIS IS DUE TO ALTERATIONS OF CHROMATIN STRUCTURE IN PH CELLS, RESULTING IN FUNCTIONAL DIFFERENCES BETWEEN THE SAME FACTOR OR PATHWAY IN NORMAL OR EARLY PH CELLS VERSUS CELLS IN CHRONIC PH. WE PROPOSE THAT THE HIGH EXPRESSION OF GENES INVOLVED IN THE PERSISTENTLY ACTIVATED PHENOTYPE OF PH VASCULAR CELLS IS PERPETUATED BY AN OPEN CHROMATIN STRUCTURE AND MULTIPLE TRANSCRIPTION FACTORS (TFS) VIA THE RECRUITMENT OF HIGH LEVELS OF EPIGENETIC REGULATORS INCLUDING THE HISTONE ACETYLASES P300/CBP, HISTONE ACETYLATION READERS INCLUDING BRDS, THE MEDIATOR COMPLEX AND THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (ABSTRACT FIGURE). THUS, DETERMINING HOW GENE EXPRESSION IS CONTROLLED BY EXAMINING CHROMATIN STRUCTURE, TFS AND EPIGENETIC REGULATORS ASSOCIATED WITH ABERRANTLY EXPRESSED GENES IN PULMONARY VASCULAR CELLS IN CHRONIC PH, MAY UNCOVER NEW PH THERAPEUTIC TARGETS. 2019 14 476 41 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 15 925 35 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 16 2914 38 GENE REGULATORY NETWORK UNDERLYING THE IMMORTALIZATION OF EPITHELIAL CELLS. BACKGROUND: TUMORIGENIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS IN VITRO HAS BEEN DESCRIBED EXPERIMENTALLY AS THE POTENTIAL RESULT OF SPONTANEOUS IMMORTALIZATION. THIS PROCESS IS CHARACTERIZED BY A SERIES OF CELL-STATE TRANSITIONS, IN WHICH NORMAL EPITHELIAL CELLS ACQUIRE FIRST A SENESCENT STATE WHICH IS LATER SURPASSED TO ATTAIN A MESENCHYMAL STEM-LIKE PHENOTYPE WITH A POTENTIALLY TUMORIGENIC BEHAVIOR. IN THIS PAPER WE AIM TO PROVIDE A SYSTEM-LEVEL MECHANISTIC EXPLANATION TO THE EMERGENCE OF THESE CELL TYPES, AND TO THE TIME-ORDERED TRANSITION PATTERNS THAT ARE COMMON TO NEOPLASIAS OF EPITHELIAL ORIGIN. TO THIS END, WE FIRST INTEGRATE PUBLISHED FUNCTIONAL AND WELL-CURATED MOLECULAR DATA OF THE COMPONENTS AND INTERACTIONS THAT HAVE BEEN FOUND TO BE INVOLVED IN SUCH CELL STATES AND TRANSITIONS INTO A NETWORK OF 41 MOLECULAR COMPONENTS. WE THEN REDUCE THIS INITIAL NETWORK BY REMOVING SIMPLE MEDIATORS (I.E., LINEAR PATHWAYS), AND FORMALIZE THE RESULTING REGULATORY CORE INTO LOGICAL RULES THAT GOVERN THE DYNAMICS OF EACH OF THE NETWORK COMPONENTS AS A FUNCTION OF THE STATES OF ITS REGULATORS. RESULTS: COMPUTATIONAL DYNAMIC ANALYSIS SHOWS THAT OUR PROPOSED GENE REGULATORY NETWORK MODEL RECOVERS EXACTLY THREE ATTRACTORS, EACH OF THEM DEFINED BY A SPECIFIC GENE EXPRESSION PROFILE THAT CORRESPONDS TO THE EPITHELIAL, SENESCENT, AND MESENCHYMAL STEM-LIKE CELLULAR PHENOTYPES, RESPECTIVELY. WE SHOW THAT ALTHOUGH A MESENCHYMAL STEM-LIKE STATE CAN BE ATTAINED EVEN UNDER UNPERTURBED PHYSIOLOGICAL CONDITIONS, THE LIKELIHOOD OF CONVERGING TO THIS STATE IS INCREASED WHEN PRO-INFLAMMATORY CONDITIONS ARE SIMULATED, PROVIDING A SYSTEMS-LEVEL MECHANISTIC EXPLANATION FOR THE CARCINOGENIC ROLE OF CHRONIC INFLAMMATORY CONDITIONS OBSERVED IN THE CLINIC. WE ALSO FOUND THAT THE REGULATORY CORE YIELDS AN EPIGENETIC LANDSCAPE THAT RESTRICTS TEMPORAL PATTERNS OF PROGRESSION BETWEEN THE STEADY STATES, SUCH THAT RECOVERED PATTERNS RESEMBLE THE TIME-ORDERED TRANSITIONS OBSERVED DURING THE SPONTANEOUS IMMORTALIZATION OF EPITHELIAL CELLS, BOTH IN VIVO AND IN VITRO. CONCLUSION: OUR STUDY STRONGLY SUGGESTS THAT THE IN VITRO TUMORIGENIC TRANSFORMATION OF EPITHELIAL CELLS, WHICH STRONGLY CORRELATES WITH THE PATTERNS OBSERVED DURING THE PATHOLOGICAL PROGRESSION OF EPITHELIAL CARCINOGENESIS IN VIVO, EMERGES FROM UNDERLYING REGULATORY NETWORKS INVOLVED IN EPITHELIAL TRANS-DIFFERENTIATION DURING DEVELOPMENT. 2017 17 6100 32 THE EMERGING ROLE OF EPIGENETIC MODIFIERS IN REPAIR OF DNA DAMAGE ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES (ROS), WHICH CAN CONTRIBUTE TO THE INITIATION AND DEVELOPMENT OF MANY DIFFERENT HUMAN CANCERS. ABERRANT EPIGENETIC ALTERATIONS THAT CAUSE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES ARE ALSO IMPLICATED IN MANY DISEASES ASSOCIATED WITH INFLAMMATION, INCLUDING CANCER. HOWEVER, IT IS NOT CLEAR HOW ALTERED EPIGENETIC GENE SILENCING IS INITIATED DURING CHRONIC INFLAMMATION. THE HIGH LEVEL OF ROS AT SITES OF INFLAMMATION IS KNOWN TO INDUCE OXIDATIVE DNA DAMAGE IN SURROUNDING EPITHELIAL CELLS. FURTHERMORE, DNA DAMAGE IS KNOWN TO TRIGGER SEVERAL RESPONSES, INCLUDING RECRUITMENT OF DNA REPAIR PROTEINS, TRANSCRIPTIONAL REPRESSION, CHROMATIN MODIFICATIONS AND OTHER CELL SIGNALING EVENTS. RECRUITMENT OF EPIGENETIC MODIFIERS TO CHROMATIN IN RESPONSE TO DNA DAMAGE RESULTS IN TRANSIENT COVALENT MODIFICATIONS TO CHROMATIN SUCH AS HISTONE UBIQUITINATION, ACETYLATION AND METHYLATION AND DNA METHYLATION. DNA DAMAGE ALSO ALTERS NON-CODING RNA EXPRESSION. ALL OF THESE ALTERATIONS HAVE THE POTENTIAL TO ALTER GENE EXPRESSION AT SITES OF DAMAGE. TYPICALLY, THESE MODIFICATIONS AND GENE TRANSCRIPTION ARE RESTORED BACK TO NORMAL ONCE THE REPAIR OF THE DNA DAMAGE IS COMPLETED. HOWEVER, CHRONIC INFLAMMATION MAY INDUCE SUSTAINED DNA DAMAGE AND DNA DAMAGE RESPONSES THAT RESULT IN THESE TRANSIENT COVALENT CHROMATIN MODIFICATIONS BECOMING MITOTICALLY STABLE EPIGENETIC ALTERATIONS. UNDERSTANDING HOW EPIGENETIC ALTERATIONS ARE INITIATED DURING CHRONIC INFLAMMATION WILL ALLOW US TO DEVELOP PHARMACEUTICAL STRATEGIES TO PREVENT OR TREAT CHRONIC INFLAMMATION-INDUCED CANCER. THIS REVIEW WILL FOCUS ON TYPES OF DNA DAMAGE AND EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES, THE TYPES OF DNA DAMAGE AND TRANSIENT COVALENT CHROMATIN MODIFICATIONS INDUCED BY INFLAMMATION AND OXIDATIVE DNA DAMAGE AND HOW THESE MODIFICATIONS MAY RESULT IN EPIGENETIC ALTERATIONS. 2019 18 2033 31 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 19 2416 31 EPIGENETIC SIGNALING OF CANCER STEM CELLS DURING INFLAMMATION. MALIGNANT TUMORS POSE A GREAT CHALLENGE TO HUMAN HEALTH, WHICH HAS LED TO MANY STUDIES INCREASINGLY ELUCIDATING THE TUMORIGENIC PROCESS. CANCER STEM CELLS (CSCS) HAVE PROFOUND IMPACTS ON TUMORIGENESIS AND DEVELOPMENT OF DRUG RESISTANCE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN THE RELATIONSHIP BETWEEN INFLAMMATION AND CSCS BUT THE MECHANISM UNDERLYING THIS RELATIONSHIP HAS NOT BEEN FULLY ELUCIDATED. INFLAMMATORY CYTOKINES PRODUCED DURING CHRONIC INFLAMMATION ACTIVATE SIGNALING PATHWAYS THAT REGULATE THE GENERATION OF CSCS THROUGH EPIGENETIC MECHANISMS. IN THIS REVIEW, WE FOCUS ON THE EFFECTS OF INFLAMMATION ON CANCER STEM CELLS, PARTICULARLY THE ROLE OF SIGNALING PATHWAYS SUCH AS NF-KAPPAB PATHWAY, STAT3 PATHWAY AND SMAD PATHWAY INVOLVED IN REGULATING EPIGENETIC CHANGES. WE HOPE TO PROVIDE A NOVEL PERSPECTIVE FOR IMPROVING STRATEGIES FOR TUMOR TREATMENT. 2021 20 6444 40 THERAPEUTIC ASPECTS OF C-MYC SIGNALING IN INFLAMMATORY AND CANCEROUS COLONIC DISEASES. COLONIC INFLAMMATION IS REQUIRED TO HEAL INFECTIONS, WOUNDS, AND MAINTAIN TISSUE HOMEOSTASIS. AS THE SEVENTH HALLMARK OF CANCER, HOWEVER, IT MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, INCLUDING TUMOR INITIATION, PROMOTION, INVASION AND METASTATIC DISSEMINATION, AND ALSO EVASION IMMUNE SURVEILLANCE. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY, AND, FURTHER, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. BOTH SPORADICAL AND COLITIS-ASSOCIATED COLORECTAL CARCINOGENESIS ARE MULTI-STEP, COMPLEX PROCESSES ARISING FROM THE UNCONTROLLED PROLIFERATION AND SPREADING OF MALIGNANTLY TRANSFORMED CELL CLONES WITH THE OBVIOUS ABILITY TO EVADE THE HOST'S PROTECTIVE IMMUNITY. IN CELLS UPON DNA DAMAGE SEVERAL PROTO-ONCOGENES, INCLUDING C-MYC ARE ACTIVATED IN PARELELL WITH THE INACTIVATION OF TUMOR SUPPRESSOR GENES. THE TARGET GENES OF THE C-MYC PROTEIN PARTICIPATE IN DIFFERENT CELLULAR FUNCTIONS, INCLUDING CELL CYCLE, SURVIVAL, PROTEIN SYNTHESIS, CELL ADHESION, AND MICRO-RNA EXPRESSION. THE TRANSCRIPTIONAL PROGRAM REGULATED BY C-MYC IS CONTEXT DEPENDENT, THEREFORE THE FINAL CELLULAR RESPONSE TO ELEVATED C-MYC LEVELS MAY RANGE FROM INCREASED PROLIFERATION TO AUGMENTED APOPTOSIS. CONSIDERING PHYSIOLOGICAL INTESTINAL HOMEOSTASIS, C-MYC DISPLAYS A FUNDAMENTAL ROLE IN THE REGULATION OF CELL PROLIFERATION AND CRYPT CELL NUMBER. HOWEVER, C-MYC GENE IS FREQUENTLY DEREGULATED IN INFLAMMATION, AND OVEREXPRESSED IN BOTH SPORADIC AND COLITIS-ASSOCIATED COLON ADENOCARCINOMAS. RECENT RESULTS DEMONSTRATED THAT ENDOGENOUS C-MYC IS ESSENTIAL FOR EFFICIENT INDUCTION OF P53-DEPENDENT APOPTOSIS FOLLOWING DNA DAMAGE, BUT C-MYC FUNCTION IS ALSO INVOLVED IN AND REGULATED BY AUTOPHAGY-RELATED MECHANISMS, WHILE ITS EXPRESSION IS AFFECTED BY DNA-METHYLATION, OR HISTONE ACETYLATION. MOLECULES DIRECTLY TARGETING C-MYC, OR AGENTS ACTING ON OTHER GENES INVOLVED IN THE C-MYC PATHWAY COULD BE SELECTED FOR COMBINED REGIMENTS. HOWEVER, DUE TO ITS CONTEXT-DEPENDENT CELLULAR FUNCTION, IT IS CLINICALLY ESSENTIAL TO CONSIDER WHICH CYTOTOXIC DRUGS ARE USED IN COMBINATION WITH C-MYC TARGETED AGENTS IN VARIOUS TISSUES. INCREASING OUR KNOWLEDGE ABOUT MYC-DEPENDENT PATHWAYS MIGHT PROVIDE DIRECTION TO NOVEL ANTI-INFLAMMATORY AND COLORECTAL CANCER THERAPIES. 2016