1 6370 98 THE ROLE OF MICRORNAS IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. MICRORNAS (MIRNAS), AN IMPORTANT COMPONENT OF EPIGENETIC MECHANISMS OF CARCINOGENESIS, HAVE BEEN SHOWN TO PLAY CRUCIAL ROLES IN CANCER INITIATION, METASTASIS, PROGNOSIS AND RESPONSES TO DRUG TREATMENT AND MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS OF CANCER AND TOOLS FOR CANCER THERAPY. METAL CARCINOGENS, SUCH AS ARSENIC, CADMIUM, HEXAVALENT CHROMIUM AND NICKEL, ARE WELL-ESTABLISHED HUMAN CARCINOGENS CAUSING VARIOUS CANCERS UPON LONG TERM EXPOSURE. HOWEVER, THE MECHANISM OF METAL CARCINOGENESIS HAS NOT BEEN WELL UNDERSTOOD, WHICH LIMITS OUR CAPABILITY TO EFFECTIVELY DIAGNOSE AND TREAT HUMAN CANCERS RESULTING FROM CHRONIC METAL CARCINOGEN EXPOSURE. OVER RECENT YEARS, THE ROLE OF MIRNAS IN METAL CARCINOGENESIS HAS BEEN ACTIVELY EXPLORED AND A GROWING BODY OF EVIDENCE INDICATES THE CRITICAL INVOLVEMENT OF MIRNAS IN METAL CARCINOGENESIS. THIS REVIEW AIMS TO DISCUSS RECENT STUDIES SHOWING THAT MIRNAS PLAY IMPORTANT ROLES IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. SOME THOUGHTS FOR FUTURE FURTHER STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2016 2 4208 44 METAL CARCINOGEN EXPOSURE INDUCES CANCER STEM CELL-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING: A NOVEL MECHANISM OF METAL CARCINOGENESIS. ARSENIC, CADMIUM, NICKEL AND HEXAVALENT CHROMIUM ARE AMONG THE MOST COMMON ENVIRONMENTAL POLLUTANTS AND POTENT CARCINOGENS. CHRONIC EXPOSURE TO THESE METALS CAUSES VARIOUS TYPES OF CANCER IN HUMANS, REPRESENTING A SIGNIFICANT ENVIRONMENTAL HEALTH ISSUE. ALTHOUGH UNDER ACTIVE INVESTIGATION, THE MECHANISMS OF METAL CARCINOGENESIS HAVE NOT BEEN CLEARLY DEFINED. ONE COMMON FEATURE OF THESE METAL CARCINOGENS IS THAT THEY ARE ALL ABLE TO CAUSE VARIOUS EPIGENETIC DYSREGULATIONS, WHICH ARE BELIEVED TO PLAY IMPORTANT ROLES IN THEIR CARCINOGENICITY. HOWEVER, HOW METAL CARCINOGEN-CAUSED EPIGENETIC DYSREGULATION CONTRIBUTES TO METAL CARCINOGENESIS REMAINS LARGELY UNKNOWN. THE EVOLUTION OF CANCER STEM CELL (CSC) THEORY HAS OPENED EXCITING NEW AVENUES FOR STUDYING THE MECHANISM OF METAL CARCINOGENESIS. INCREASING EVIDENCE INDICATES THAT CHRONIC METAL CARCINOGEN EXPOSURE PRODUCES CSC-LIKE CELLS THROUGH DYSREGULATED EPIGENETIC MECHANISMS. THIS REVIEW WILL FIRST PROVIDE SOME BRIEF INTRODUCTIONS ABOUT CSC, EPIGENETICS AND EPIGENETIC REGULATION OF CSCS; THEN SUMMARIZE PROGRESSES IN RECENT STUDIES ON METAL CARCINOGEN-INDUCED CSC-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING AS A NOVEL MECHANISM OF METAL CARCINOGENESIS. SOME PERSPECTIVES FOR FUTURE STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2019 3 106 37 A REVIEW OF MOLECULAR EVENTS OF CADMIUM-INDUCED CARCINOGENESIS. CADMIUM (CD) IS A TOXIC, HEAVY INDUSTRIAL METAL THAT POSES SERIOUS ENVIRONMENTAL HEALTH HAZARDS TO BOTH HUMANS AND WILDLIFE. RECENTLY, CD AND CD-CONTAINING COMPOUNDS HAVE BEEN CLASSIFIED AS KNOWN HUMAN CARCINOGENS, AND EPIDEMIOLOGICAL DATA SHOW CAUSAL ASSOCIATIONS WITH PROSTATE, BREAST, AND LUNG CANCER. THE MOLECULAR MECHANISMS INVOLVED IN CD-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD AND ARE ONLY NOW BEGINNING TO BE ELUCIDATED. THE EFFECTS OF CHRONIC EXPOSURE TO CD HAVE RECENTLY ATTRACTED GREAT INTEREST DUE TO THE DEVELOPMENT OF MALIGNANCIES IN CD-INDUCED TUMORIGENESIS IN ANIMALS MODELS. BRIEFLY, VARIOUS IN VITRO STUDIES DEMONSTRATE THAT CD CAN ACT AS A MITOGEN, CAN STIMULATE CELL PROLIFERATION AND INHIBIT APOPTOSIS AND DNA REPAIR, AND CAN INDUCE CARCINOGENESIS IN SEVERAL MAMMALIAN TISSUES AND ORGANS. THUS, THE VARIOUS MECHANISMS INVOLVED IN CHRONIC CD EXPOSURE AND MALIGNANT TRANSFORMATIONS WARRANT FURTHER INVESTIGATION. IN THIS REVIEW, WE FOCUS ON RECENT EVIDENCE OF VARIOUS LEADING GENERAL AND TISSUE-SPECIFIC MOLECULAR MECHANISMS THAT FOLLOW CHRONIC EXPOSURE TO CD IN PROSTATE-, BREAST-, AND LUNG-TRANSFORMED MALIGNANCIES. IN ADDITION, IN THIS REVIEW, WE CONSIDER LESS DEFINED MECHANISMS SUCH AS EPIGENETIC MODIFICATION AND AUTOPHAGY, WHICH ARE THOUGHT TO PLAY A ROLE IN THE DEVELOPMENT OF CD-INDUCED MALIGNANT TRANSFORMATION. 2014 4 480 34 ARSENIC-INDUCED CARCINOGENESIS: THE IMPACT OF MIRNA DYSREGULATION. ARSENIC IS A TOXIC METALLOID WIDELY PRESENT IN THE EARTH'S CRUST, AND IS A PROVEN HUMAN CARCINOGEN. CHRONIC ARSENIC EXPOSURE MAINLY THROUGH DRINKING WATER CAUSES SKIN, LUNG, AND URINARY BLADDER CANCERS, AND IS ASSOCIATED WITH LIVER, PROSTATE, AND KIDNEY CANCERS, CARDIOVASCULAR AND NEUROLOGICAL DISORDERS, AND DIABETES. SEVERAL MODES OF ACTION HAVE BEEN SUGGESTED IN ARSENIC CARCINOGENESIS. HOWEVER, THE MOLECULAR ETIOLOGY OF ARSENIC-INDUCED CANCER REMAINS UNCLEAR. RECENT EVIDENCE CLEARLY INDICATES THAT GENE EXPRESSION MODIFICATIONS INDUCED BY ARSENIC MAY INVOLVE EPIGENETIC ALTERATIONS, INCLUDING MIRNA DYSREGULATION. MANY MIRNAS HAVE BEEN IMPLICATED IN DIFFERENT HUMAN CANCERS AS A CONSEQUENCE OF LOSSES AND OR GAINS OF MIRNA FUNCTION THAT CONTRIBUTE TO CANCER DEVELOPMENT. PROGRESS IN IDENTIFYING MIRNA DYSREGULATION INDUCED BY ARSENIC HAS BEEN MADE USING DIFFERENT APPROACHES AND MODELS. THE PRESENT REVIEW DISCUSSES THE RECENT DATA REGARDING DYSREGULATED EXPRESSION OF MIRNA IN ARSENIC-INDUCED MALIGNANT TRANSFORMATION IN VITRO, GAPS IN CURRENT UNDERSTANDING AND DEFICIENCIES IN CURRENT MODELS FOR ARSENIC-INDUCED CARCINOGENESIS, AND FUTURE DIRECTIONS OF RESEARCH THAT WOULD IMPROVE OUR KNOWLEDGE REGARDING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS. 2018 5 1925 32 ENVIRONMENTAL EPIGENETICS IN METAL EXPOSURE. ALTHOUGH IT IS WIDELY ACCEPTED THAT CHRONIC EXPOSURE TO ARSENITE, NICKEL, CHROMIUM AND CADMIUM INCREASES CANCER INCIDENCE IN INDIVIDUALS, THE MOLECULAR MECHANISMS UNDERLYING THEIR ABILITY TO TRANSFORM CELLS REMAIN LARGELY UNKNOWN. CARCINOGENIC METALS ARE TYPICALLY WEAK MUTAGENS, SUGGESTING THAT GENETIC-BASED MECHANISMS MAY NOT BE PRIMARILY RESPONSIBLE FOR METAL-INDUCED CARCINOGENESIS. GROWING EVIDENCE SHOWS THAT ENVIRONMENTAL METAL EXPOSURE INVOLVES CHANGES IN EPIGENETIC MARKS, WHICH MAY LEAD TO A POSSIBLE LINK BETWEEN HERITABLE CHANGES IN GENE EXPRESSION AND DISEASE SUSCEPTIBILITY AND DEVELOPMENT. HERE, WE REVIEW RECENT ADVANCES IN THE UNDERSTANDING OF METAL EXPOSURE AFFECTING EPIGENETIC MARKS AND DISCUSS ESTABLISHMENT OF HERITABLE GENE EXPRESSION IN METAL-INDUCED CARCINOGENESIS. 2011 6 4840 26 ONCOGENOMIC DISRUPTIONS IN ARSENIC-INDUCED CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE, AND HAS BEEN ASSOCIATED WITH MANY ADVERSE HEALTH EFFECTS, INCLUDING CANCER IN SEVERAL ORGANS. THERE IS ACCUMULATING EVIDENCE THAT ARSENIC BIOTRANSFORMATION, A STEP IN THE ELIMINATION OF ARSENIC FROM THE HUMAN BODY, CAN INDUCE CHANGES AT A GENETIC AND EPIGENETIC LEVEL, LEADING TO CARCINOGENESIS. AT THE GENETIC LEVEL, ARSENIC INTERFERES WITH KEY CELLULAR PROCESSES SUCH AS DNA DAMAGE-REPAIR AND CHROMOSOMAL STRUCTURE, LEADING TO GENOMIC INSTABILITY. AT THE EPIGENETIC LEVEL, ARSENIC PLACES A HIGH DEMAND ON THE CELLULAR METHYL POOL, LEADING TO GLOBAL HYPOMETHYLATION AND HYPERMETHYLATION OF SPECIFIC GENE PROMOTERS. THESE ARSENIC-ASSOCIATED DNA ALTERATIONS RESULT IN THE DEREGULATION OF BOTH ONCOGENIC AND TUMOUR-SUPPRESSIVE GENES. FURTHERMORE, RECENT REPORTS HAVE IMPLICATED ABERRANT EXPRESSION OF NON-CODING RNAS AND THE CONSEQUENTIAL DISRUPTION OF SIGNALING PATHWAYS IN THE CONTEXT OF ARSENIC-INDUCED CARCINOGENESIS. THIS ARTICLE PROVIDES AN OVERVIEW OF THE ONCOGENOMIC ANOMALIES ASSOCIATED WITH ARSENIC EXPOSURE AND CONVEYS THE IMPORTANCE OF NON-CODING RNAS IN THE ARSENIC-INDUCED CARCINOGENIC PROCESS. 2017 7 5291 31 PROSTATE CARCINOGENESIS: INSIGHTS IN RELATION TO EPIGENETICS AND INFLAMMATION. PROSTATE CANCER IS A MULTIFACTORIAL DISEASE THAT MAINLY OCCURS DUE TO THE ACCUMULATION OF SOMATIC, GENETIC, AND EPIGENETIC CHANGES, RESULTING IN THE INACTIVATION OF TUMOR-SUPPRESSOR GENES AND ACTIVATION OF ONCOGENES. MUTATIONS IN GENES, SPECIFICALLY THOSE THAT CONTROL CELL GROWTH AND DIVISION OR THE REPAIR OF DAMAGED DNA, MAKE THE CELLS GROW AND DIVIDE UNCONTROLLABLY TO FORM A TUMOR. THE RISK OF DEVELOPING PROSTATE CANCER DEPENDS UPON THE GENE THAT HAS UNDERGONE THE MUTATION. IDENTIFYING SUCH GENETIC RISK FACTORS FOR PROSTATE CANCER POSES A CHALLENGE FOR THE RESEARCHERS. BESIDES GENETIC MUTATIONS, MANY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS (METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION) NUCLEOSOMAL REMODELING, AND CHROMOSOMAL LOOPING, HAVE SIGNIFICANTLY CONTRIBUTED TO THE ONSET OF PROSTATE CANCER AS WELL AS THE PROGNOSIS, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER. CHRONIC INFLAMMATION ALSO PLAYS A MAJOR ROLE IN THE ONSET AND PROGRESSION OF HUMAN CANCER, VIA MODIFICATIONS IN THE TUMOR MICROENVIRONMENT BY INITIATING EPITHELIALMESENCHYMAL TRANSITION AND REMODELING THE EXTRACELLULAR MATRIX. IN THIS ARTICLE, THE AUTHORS PRESENT A BRIEF HISTORY OF THE MECHANISMS AND POTENTIAL LINKS BETWEEN THE GENETIC ABERRATIONS, EPIGENETIC CHANGES, INFLAMMATION, AND INFLAMMASOMES THAT ARE KNOWN TO CONTRIBUTE TO THE PROGNOSIS OF PROSTATE CANCER. FURTHERMORE, THE AUTHORS EXAMINE AND DISCUSS THE CLINICAL POTENTIAL OF PROSTATE CARCINOGENESIS IN RELATION TO EPIGENETICS AND INFLAMMATION FOR ITS DIAGNOSIS AND TREATMENT.. 2021 8 712 34 CADMIUM AND ITS EPIGENETIC EFFECTS. CADMIUM (CD) IS A TOXIC, NONESSENTIAL TRANSITION METAL AND CONTRIBUTES A HEALTH RISK TO HUMANS, INCLUDING VARIOUS CANCERS AND CARDIOVASCULAR DISEASES; HOWEVER, UNDERLYING MOLECULAR MECHANISMS REMAIN LARGELY UNKNOWN. CELLS TRANSMIT INFORMATION TO THE NEXT GENERATION VIA TWO DISTINCT WAYS: GENETIC AND EPIGENETIC. CHEMICAL MODIFICATIONS TO DNA OR HISTONE THAT ALTERS THE STRUCTURE OF CHROMATIN WITHOUT CHANGE OF DNA NUCLEOTIDE SEQUENCE ARE KNOWN AS EPIGENETICS. THESE HERITABLE EPIGENETIC CHANGES INCLUDE DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONE TAILS (ACETYLATION, METHYLATION, PHOSPHORYLATION, ETC), AND HIGHER ORDER PACKAGING OF DNA AROUND NUCLEOSOMES. APART FROM DNA METHYLTRANSFERASES, HISTONE MODIFICATION ENZYMES SUCH AS HISTONE ACETYLTRANSFERASE, HISTONE DEACETYLASE, AND METHYLTRANSFERASE, AND MICRORNAS (MIRNAS) ALL INVOLVE IN THESE EPIGENETIC CHANGES. RECENT STUDIES INDICATE THAT CD IS ABLE TO INDUCE VARIOUS EPIGENETIC CHANGES IN PLANT AND MAMMALIAN CELLS IN VITRO AND IN VIVO. SINCE ABERRANT EPIGENETICS PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF VARIOUS CANCERS AND CHRONIC DISEASES, CD MAY CAUSE THE ABOVE-MENTIONED PATHOGENIC RISKS VIA EPIGENETIC MECHANISMS. HERE WE REVIEW THE IN VITRO AND IN VIVO EVIDENCE OF EPIGENETIC EFFECTS OF CD. THE AVAILABLE FINDINGS INDICATE THAT EPIGENETICS OCCURRED IN ASSOCIATION WITH CD INDUCTION OF MALIGNANT TRANSFORMATION OF CELLS AND PATHOLOGICAL PROLIFERATION OF TISSUES, SUGGESTING THAT EPIGENETIC EFFECTS MAY PLAY A ROLE IN CD TOXIC, PARTICULARLY CARCINOGENIC EFFECTS. THE FUTURE OF ENVIRONMENTAL EPIGENOMIC RESEARCH ON CD SHOULD INCLUDE THE ROLE OF EPIGENETICS IN DETERMINING LONG-TERM AND LATE-ONSET HEALTH EFFECTS FOLLOWING CD EXPOSURE. 2012 9 2166 38 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 10 2122 33 EPIGENETIC IMPACT OF INFECTION ON CARCINOGENESIS: MECHANISMS AND APPLICATIONS. VIRAL AND BACTERIAL INFECTIONS ARE INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS, SUCH AS LIVER, NASOPHARYNGEAL, CERVICAL, HEAD AND NECK, AND GASTRIC CANCERS. ABERRANT DNA METHYLATION IS FREQUENTLY PRESENT IN THESE CANCERS, AND SOME OF THE ABERRANTLY METHYLATED GENES ARE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. NOTABLY, ABERRANT DNA METHYLATION CAN BE PRESENT EVEN IN NON-CANCEROUS OR PRECANCEROUS TISSUES, AND ITS LEVELS CORRELATE WITH THE RISK OF CANCER DEVELOPMENT, PRODUCING A SO-CALLED 'EPIGENETIC FIELD FOR CANCERIZATION'. MECHANISTICALLY, MOST VIRAL OR BACTERIAL INFECTIONS INDUCE DNA METHYLATION INDIRECTLY VIA CHRONIC INFLAMMATION, BUT RECENT STUDIES HAVE INDICATED THAT SOME VIRUSES HAVE DIRECT EFFECTS ON THE EPIGENETIC MACHINERY OF HOST CELLS. FROM A TRANSLATIONAL VIEWPOINT, A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THAT ASSESSMENT OF THE EXTENT OF ALTERATIONS IN DNA METHYLATION IN NON-CANCEROUS TISSUES CAN BE USED TO PREDICT CANCER RISK. FURTHERMORE, SUPPRESSION OF ABERRANT DNA METHYLATION WAS SHOWN TO BE A USEFUL STRATEGY FOR CANCER PREVENTION IN AN ANIMAL MODEL. HERE, WE REVIEW THE INVOLVEMENT OF ABERRANT DNA METHYLATION IN VARIOUS TYPES OF INFECTION-ASSOCIATED CANCERS, ALONG WITH INDIVIDUAL INDUCTION MECHANISMS, AND WE DISCUSS THE APPLICATION OF THESE FINDINGS FOR CANCER PREVENTION, DIAGNOSIS, AND THERAPY. 2016 11 928 23 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 12 2970 32 GENETIC AND EPIGENETIC SIGNATURES IN HUMAN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD MOST COMMON CAUSE OF CANCER DEATHS WORLDWIDE, AND THE INCIDENCE OF THIS FATAL DISEASE IS STILL ON RISE. THE MAJORITY OF HCCS EMERGE IN THE BACKGROUND OF A CHRONIC LIVER DISEASE, SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS. THE CURRENT UNDERSTANDING IS THAT MAJORITY OF HCCS EVOLVE AS A CONSEQUENCE OF CHRONIC INFLAMMATION AND DUE TO THE PRESENCE OF INFECTION WITH HEPATITIS VIRUSES. THESE UNDERLYING PATHOGENIC STIMULI SUBSEQUENTLY INDUCE A SPECTRUM OF GENETIC AND EPIGENETIC ALTERATIONS IN SEVERAL CANCER-RELATED GENES, WHICH ARE INVOLVED IN CELL-CYCLE REGULATION, CELL GROWTH AND ADHESION. SUCH WIDESPREAD GENOMIC ALTERATIONS CAUSE DISRUPTION OF NORMAL CELLULAR SIGNALING AND FINALLY LEAD TO THE ACQUISITION OF A MALIGNANT PHENOTYPE IN HCC. IN GENERAL, THE TYPE OF GENE ALTERATIONS, SUCH AS POINT MUTATIONS, DELETION OF CHROMOSOMAL REGIONS AND ABNORMAL METHYLATION OF GENE PROMOTERS DIFFER ACCORDING TO THE INDIVIDUAL TARGETED GENE. IN HCC, INCIDENCE OF GENETIC ALTERATIONS IS RELATIVELY RARE AND IS LIMITED TO A SUBSET OF FEW CANCER-SPECIFIC GENES, SUCH AS THE TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS THE CTNNB1. IN CONTRAST, EPIGENETIC CHANGES THAT INVOLVE ABERRANT METHYLATION OF GENES AND OTHER POST-TRANSCRIPTIONAL HISTONE MODIFICATIONS OCCUR FAR MORE FREQUENTLY, AND SOME OF THESE EPIGENETIC ALTERATIONS ARE NOW BEING EXPLOITED FOR THE DEVELOPMENT OF MOLECULAR DIAGNOSTIC SIGNATURES FOR HCC. IN ADDITION, RECENT FINDINGS OF UNIQUE MICRORNA EXPRESSION PROFILES ALSO PROVIDE AN EVIDENCE FOR THE EXISTENCE OF NOVEL MECHANISMS FOR GENE EXPRESSION REGULATION IN HCC. IN THIS REVIEW ARTICLE, WE WILL REVIEW THE CURRENT STATE OF KNOWLEDGE ON THE ACTIVATION OF VARIOUS ONCOGENIC PATHWAYS AND THE INACTIVATION OF TUMOR SUPPRESSOR PATHWAYS IN HCC THAT RESULT IN THE DISRUPTION OF CANCER-RELATED GENE FUNCTION. IN ADDITION, WE WILL SPECIFICALLY EMPHASIZE THE CLINICAL IMPLICATION OF SOME OF THESE GENETIC AND EPIGENETIC ALTERATIONS IN THE MANAGEMENT OF HEPATOCARCINOGENESIS. 2011 13 1522 34 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021 14 5557 27 ROLE OF GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENICITY. A REVIEW. EXPOSURE TO CHRONIC ARSENIC TOXICITY IS ASSOCIATED WITH CANCER. ALTHOUGH UNSTABLE GENOME IS A CHARACTERISTIC FEATURE OF CANCER CELLS, THE MECHANISMS LEADING TO GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD. WHILE THERE ARE EXCELLENT REVIEWS RELATING TO GENOMIC INSTABILITY IN GENERAL, THERE IS NO COMPREHENSIVE REVIEW PRESENTING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY. THIS REVIEW WAS UNDERTAKEN TO PRESENT THE CURRENT STATE OF RESEARCH IN THIS AREA AND TO HIGHLIGHT THE MAJOR MECHANISMS THAT MAY INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY LEADING TO CANCER. GENOMIC INSTABILITY IS BROADLY CLASSIFIED INTO CHROMOSOMAL INSTABILITY (CIN), PRIMARILY ASSOCIATED WITH MITOTIC ERRORS; AND MICROSATELLITE INSTABILITY (MIN), ASSOCIATED WITH DNA LEVEL INSTABILITY. ARSENIC-INDUCED GENOMIC INSTABILITY IS ESSENTIALLY MULTI-FACTORIAL IN NATURE AND INVOLVES MOLECULAR CROSS-TALK ACROSS SEVERAL CELLULAR PATHWAYS, AND IS MODULATED BY A NUMBER OF ENDOGENOUS AND EXOGENOUS FACTORS. ARSENIC AND ITS METABOLITES GENERATE OXIDATIVE STRESS, WHICH IN TURN INDUCES GENOMIC INSTABILITY THROUGH DNA DAMAGE, IRREVERSIBLE DNA REPAIR, TELOMERE DYSFUNCTION, MITOTIC ARREST AND APOPTOSIS. IN ADDITION TO GENETIC ALTERATION; EPIGENETIC REGULATION THROUGH PROMOTER METHYLATION AND MIRNA EXPRESSION ALTERS GENE EXPRESSION PROFILING LEADING TO GENOME MORE VULNERABLE AND UNSTABLE TOWARDS CANCER RISK. MOREOVER, MUTATIONS OR SILENCING OF PRO-APOPTOTIC GENES CAN LEAD TO GENOMIC INSTABILITY BY ALLOWING SURVIVAL OF DAMAGED CELLS THAT WOULD OTHERWISE DIE. ALTHOUGH A LARGE BODY OF INFORMATION IS NOW GENERATED REGARDING ARSENIC-INDUCED CARCINOGENESIS; FURTHER STUDIES EXPLORING GENOME-WIDE ASSOCIATION, ROLE OF ENVIRONMENT AND DIET ARE NEEDED FOR A BETTER UNDERSTANDING OF THE ARSENIC-INDUCED GENOMIC INSTABILITY. 2013 15 3958 33 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023 16 2335 33 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINES AND ASSOCIATED GENES IN HUMAN MALIGNANCIES. INFLAMMATION IS A MULTIFACETED DEFENSE RESPONSE OF IMMUNE SYSTEM AGAINST INFECTION. CHRONIC INFLAMMATION HAS BEEN IMPLICATED AS AN IMMINENT THREAT FOR MAJOR HUMAN MALIGNANCIES AND IS DIRECTLY LINKED TO VARIOUS STEPS INVOLVED IN TUMORIGENESIS. INFLAMMATORY CYTOKINES, INTERLEUKINS, INTERFERONS, TRANSFORMING GROWTH FACTORS, CHEMOKINES, AND ADHESION MOLECULES HAVE BEEN ASSOCIATED WITH CHRONIC INFLAMMATION. NUMEROUS CYTOKINES ARE REPORTED TO BE ABERRANTLY REGULATED BY DIFFERENT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS IN TUMOR TISSUES, CONTRIBUTING TO PATHOGENESIS OF TUMOR IN MULTIPLE WAYS. SOME OF THESE CYTOKINES ALSO WORK AS EPIGENETIC REGULATORS OF OTHER CRUCIAL GENES IN TUMOR BIOLOGY, EITHER DIRECTLY OR INDIRECTLY. SUCH REGULATIONS ARE REPORTED IN LUNG, BREAST, CERVICAL, GASTRIC, COLORECTAL, PANCREATIC, PROSTATE, AND HEAD AND NECK CANCERS. EPIGENETICS OF INFLAMMATORY MEDIATORS IN CANCER IS CURRENTLY SUBJECT OF EXTENSIVE RESEARCH. THESE INVESTIGATIONS MAY HELP IN UNDERSTANDING CANCER BIOLOGY AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES. THE PURPOSE OF THIS PAPER IS TO HAVE A BRIEF VIEW OF THE ABERRANT REGULATION OF INFLAMMATORY CYTOKINES IN HUMAN MALIGNANCIES. 2015 17 2854 31 FROM HEPATITIS TO HEPATOCELLULAR CARCINOMA: A PROPOSED MODEL FOR CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS. INFLAMMATION REPRESENTS THE BODY'S NATURAL RESPONSE TO TISSUE DAMAGE; HOWEVER, CHRONIC INFLAMMATION MAY ACTIVATE CELL PROLIFERATION AND INDUCE DEREGULATION OF CELL DEATH IN AFFECTED TISSUES. CHRONIC INFLAMMATION IS AN IMPORTANT FACTOR IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), ALTHOUGH THE PRECISE UNDERLYING MECHANISM REMAINS UNKNOWN. EPIGENETIC EVENTS, WHICH ARE CONSIDERED KEY MECHANISMS IN THE REGULATION OF GENE ACTIVITY STATES, ARE ALSO COMMONLY DEREGULATED IN HCC. HERE, WE REVIEW THE EVIDENCE THAT CHRONIC INFLAMMATION MIGHT DEREGULATE EPIGENETIC PROCESSES, THUS PROMOTING ONCOGENIC TRANSFORMATION, AND WE PROPOSE A WORKING HYPOTHESIS THAT EPIGENETIC DEREGULATION IS AN UNDERLYING MECHANISM BY WHICH INFLAMMATION MIGHT PROMOTE HCC DEVELOPMENT. IN THIS SCENARIO, DIFFERENT COMPONENTS OF THE INFLAMMATORY RESPONSE MIGHT DIRECTLY AND INDIRECTLY INDUCE CHANGES IN EPIGENETIC MACHINERIES ('EPIGENETIC SWITCH'), INCLUDING THOSE INVOLVED IN SETTING AND PROPAGATING NORMAL PATTERNS OF DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS IN HEPATOCYTES. WE DISCUSS THE POSSIBILITY THAT SELF-REINFORCING CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS MIGHT AMPLIFY INFLAMMATORY SIGNALS AND MAINTAIN A CHRONIC STATE OF INFLAMMATION CULMINATING IN CANCER DEVELOPMENT. THE POTENTIAL ROLE OF INFLAMMATION-EPIGENOME INTERACTIONS IN THE EMERGENCE AND MAINTENANCE OF CANCER STEM CELLS IS ALSO DISCUSSED. 2012 18 6213 34 THE INTESTINAL EPITHELIAL CELL CYCLE: UNCOVERING ITS 'CRYPTIC' NATURE. PURPOSE OF REVIEW: TO DISCUSS THE RECENT LANDMARK FINDINGS THAT HAVE INCREASED OUR UNDERSTANDING NOT ONLY OF THE ROLE OF THE EPITHELIAL CELL CYCLE IN THE HOMEOSTASIS OF THE SMALL INTESTINE, BUT ALSO ITS RELEVANCE TO INFLAMMATION AND CANCER. RECENT FINDINGS: RECENT DATA HAVE UNVEILED NOVEL INFORMATION ON PROTEIN INTERACTIONS DIRECTLY INVOLVED IN THE CELL CYCLE AS WELL AS IN THE PATHWAYS THAT TRANSDUCE EXTERNAL ENVIRONMENTAL SIGNALS TO THE CELL CYCLE. A GROWING BODY OF THE RECENT EVIDENCE CONFIRMS THE IMPORTANCE OF FOOD AS WELL AS HORMONAL REGULATION IN THE GUT ON CELL CYCLE. INFORMATION ON THE CONTRIBUTION OF THE EPITHELIAL MICROENVIRONMENT, INCLUDING THE MICROBIOTA, HAS GROWN SUBSTANTIALLY IN THE RECENT YEARS AS WELL AS ON THE GENE-ENVIRONMENT INTERACTIONS AND THE MULTIPLE EPIGENETIC MECHANISMS INVOLVED IN REGULATING CELL-CYCLE PROTEINS AND SIGNALLING. FINALLY, FURTHER STUDIES INVESTIGATING THE DYSREGULATION OF THE CELL CYCLE DURING INFLAMMATION AND PROLIFERATION HAVE INCREASED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCER. SUMMARY: THIS REVIEW HIGHLIGHTS SOME OF THE MOST RECENT ADVANCES THAT FURTHER EMPHASIZE THE IMPORTANCE OF THE CELL CYCLE IN THE SMALL INTESTINE DURING HOMEOSTASIS AS WELL AS IN INFLAMMATION AND CANCER. 2015 19 186 27 ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL CELLS AND CANCER RISK. CANCERS DEVELOP DUE TO THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. GENETIC ALTERATIONS ARE INDUCED BY AGING, MUTAGENIC CHEMICALS, ULTRAVIOLET LIGHT, AND OTHER FACTORS; WHEREAS, EPIGENETIC ALTERATIONS ARE MAINLY BY AGING AND CHRONIC INFLAMMATION. THE ACCUMULATION AND PATTERNS OF ALTERATIONS IN NORMAL CELLS REFLECT OUR PAST EXPOSURE LEVELS AND LIFE HISTORY. MOST ACCUMULATED ALTERATIONS ARE CONSIDERED AS PASSENGERS, BUT THEIR ACCUMULATION IS CORRELATED WITH CANCER DRIVERS. THIS HAS BEEN SHOWN FOR ABERRANT DNA METHYLATION BUT HAS ONLY BEEN SPECULATED FOR GENETIC ALTERATIONS. HOWEVER, RECENT TECHNOLOGICAL ADVANCEMENTS HAVE ENABLED MEASUREMENT OF RARE POINT MUTATIONS, AND STUDIES HAVE SHOWN THAT THEIR ACCUMULATION LEVELS ARE INDEED CORRELATED WITH CANCER RISK. WHEN THE ACCUMULATION LEVELS OF ABERRANT DNA METHYLATION AND POINT MUTATIONS ARE COMBINED, RISK PREDICTION BECOMES EVEN MORE ACCURATE. WHEN HIGH LEVELS OF ALTERATIONS ACCUMULATE, THE TISSUE HAS A HIGH RISK OF DEVELOPING CANCER OR EVEN MULTIPLE CANCERS AND IS CONSIDERED AS A "CANCERIZATION FIELD", WITH OR WITHOUT EXPANSION OF PHYSIOLOGICAL PATCHES OF CLONAL CELLS. IN THIS REVIEW, WE DESCRIBE THE FORMATION OF A CANCERIZATION FIELD AND HOW WE CAN APPLY ITS DETECTION IN PRECISION CANCER RISK DIAGNOSIS. 2019 20 1970 26 EPIGENETIC ALTERATIONS AND OCCUPATIONAL EXPOSURE TO BENZENE, FIBERS, AND HEAVY METALS ASSOCIATED WITH TUMOR DEVELOPMENT (REVIEW). THE CHRONIC OCCUPATIONAL EXPOSURE TO CONTAMINANTS AND CARCINOGENS LEADS TO THE DEVELOPMENT OF CANCER. OVER THE PAST DECADES, MANY CARCINOGENS HAVE BEEN FOUND IN THE OCCUPATIONAL ENVIRONMENT AND THEIR PRESENCE IS OFTEN ASSOCIATED WITH AN INCREASED INCIDENCE OF CANCER. ACCORDING TO THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), THE MAJORITY OF CARCINOGENS ARE CLASSIFIED AS 'PROBABLE' AND 'POSSIBLE' HUMAN CARCINOGENS, WHILE, DIRECT EVIDENCE OF CARCINOGENICITY IS PROVIDED IN EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES. ADDITIONALLY, ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS MAY BE EARLY INDICATORS OF GENOTOXIC AND NON-GENOTOXIC CARCINOGEN EXPOSURE. IN THE PRESENT REVIEW, THE RELATIONSHIP BETWEEN EXPOSURES TO BENZENE, MINERAL FIBERS, METALS AND EPIGENETIC ALTERATIONS ARE DISCUSSED AS THE MOST IMPORTANT CANCER RISK FACTORS DURING WORK ACTIVITIES. 2017