1 4201 114 METABOLIC REWIRING AND REDOX ALTERATIONS IN MALIGNANT PLEURAL MESOTHELIOMA. MALIGNANT PLEURAL MESOTHELIOMA (MPM) IS A RARE MALIGNANCY OF MESOTHELIAL CELLS WITH INCREASING INCIDENCE, AND IN MANY CASES, DISMAL PROGNOSIS DUE TO ITS AGGRESSIVENESS AND LACK OF EFFECTIVE THERAPIES. ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO ASBESTOS IS CONSIDERED THE MAIN AETIOLOGICAL FACTOR FOR MPM. INHALED ASBESTOS FIBRES ACCUMULATE IN THE LUNGS AND INDUCE THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) DUE TO THE PRESENCE OF IRON ASSOCIATED WITH THE FIBROUS SILICATES AND TO THE ACTIVATION OF MACROPHAGES AND INFLAMMATION. CHRONIC INFLAMMATION AND A ROS-ENRICHED MICROENVIRONMENT CAN FOSTER THE MALIGNANT TRANSFORMATION OF MESOTHELIAL CELLS. IN ADDITION, MPM CELLS HAVE A HIGHLY GLYCOLYTIC METABOLIC PROFILE AND ARE POSITIVE IN (18)F-FDG PET ANALYSIS. LOSS-OF-FUNCTION MUTATIONS OF BRCA-ASSOCIATED PROTEIN 1 (BAP1) ARE A MAJOR CONTRIBUTOR TO THE METABOLIC REWIRING OF MPM CELLS. A SUBSET OF MPM TUMOURS SHOW LOSS OF THE METHYLADENOSINE PHOSPHORYLASE (MTAP) LOCUS, RESULTING IN PROFOUND ALTERATIONS IN POLYAMINE METABOLISM, ATP AND METHIONINE SALVAGE PATHWAYS, AS WELL AS CHANGES IN EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW PROVIDES AN OVERVIEW OF THE PERTURBATIONS IN METABOLISM AND ROS HOMOEOSTASIS OF MPM CELLS AND THE ROLE OF THESE ALTERATIONS IN MALIGNANT TRANSFORMATION AND TUMOUR PROGRESSION. 2020 2 6906 27 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 3 5491 30 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 4 3599 32 IMPORTANCE OF EPIGENETIC CHANGES IN CANCER ETIOLOGY, PATHOGENESIS, CLINICAL PROFILING, AND TREATMENT: WHAT CAN BE LEARNED FROM HEMATOLOGIC MALIGNANCIES? EPIGENETIC ALTERATIONS REPRESENT A KEY CANCER HALLMARK, EVEN IN HEMATOLOGIC MALIGNANCIES (HMS) OR BLOOD CANCERS, WHOSE CLINICAL FEATURES DISPLAY A HIGH INTER-INDIVIDUAL VARIABILITY. EVIDENCE ACCUMULATED IN RECENT YEARS INDICATES THAT INACTIVATING DNA HYPERMETHYLATION PREFERENTIALLY TARGETS THE SUBSET OF POLYCOMB GROUP (PCG) GENES THAT ARE REGULATORS OF DEVELOPMENTAL PROCESSES. CONVERSELY, ACTIVATING DNA HYPOMETHYLATION TARGETS ONCOGENIC SIGNALING PATHWAY GENES, BUT OUTCOMES OF BOTH EVENTS LEAD IN THE OVEREXPRESSION OF ONCOGENIC SIGNALING PATHWAYS THAT CONTRIBUTE TO THE STEM-LIKE STATE OF CANCER CELLS. ON THE BASIS OF RECENT EVIDENCE FROM POPULATION-BASED, CLINICAL AND EXPERIMENTAL STUDIES, WE HYPOTHESIZE THAT FACTORS ASSOCIATED WITH RISK FOR DEVELOPING A HM, SUCH AS METABOLIC SYNDROME AND CHRONIC INFLAMMATION, TRIGGER EPIGENETIC MECHANISMS TO INCREASE THE TRANSCRIPTIONAL EXPRESSION OF ONCOGENES AND ACTIVATE ONCOGENIC SIGNALING PATHWAYS. AMONG OTHERS, SIGNALING PATHWAYS ASSOCIATED WITH SUCH RISK FACTORS INCLUDE PRO-INFLAMMATORY NUCLEAR FACTOR KAPPAB (NF-KAPPAB), AND MITOGENIC, GROWTH, AND SURVIVAL JANUS KINASE (JAK) INTRACELLULAR NON-RECEPTOR TYROSINE KINASE-TRIGGERED PATHWAYS, WHICH INCLUDE SIGNALING PATHWAYS SUCH AS TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT), RAS GTPASES/MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS)/EXTRACELLULAR SIGNAL-RELATED KINASES (ERKS), PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), AND BETA-CATENIN PATHWAYS. RECENT FINDINGS ON EPIGENETIC MECHANISMS AT WORK IN HMS AND THEIR IMPORTANCE IN THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES ARE HEREIN SUMMARIZED AND DISCUSSED. FURTHERMORE, THE ROLE OF EPIGENETIC PROCESSES IN THE DETERMINATION OF BIOLOGICAL IDENTITY, THE CONSEQUENCES FOR INTERINDIVIDUAL VARIABILITY IN DISEASE CLINICAL PROFILE, AND THE POTENTIAL OF EPIGENETIC DRUGS IN HMS ARE ALSO CONSIDERED. 2013 5 3950 22 LNFLAMMATION-INDUCED EPIGENETIC SWITCHES IN CANCER. THE LINK BETWEEN INFLAMMATION AND CANCER IS WELL ESTABLISHED. CHRONIC INFLAMMATION PROMOTES CANCER INITIATION AND PROGRESSION. VARIOUS STUDIES SHOWED THAT THE UNDERLYING MECHANISMS INVOLVE EPIGENETIC ALTERATIONS. THESE EPIGENETIC ALTERATIONS MIGHT CULMINATE INTO AN EPIGENETIC SWITCH THAT TRANSFORMS PREMALIGNANT CELLS INTO TUMOR CELLS OR NON-INVASIVE INTO INVASIVE TUMOR CELLS, THEREBY PROMOTING METASTASIS. EPIGENETIC SWITCHES REQUIRE AN INITIATING EVENT, WHICH CAN BE INFLAMMATION, WHEREAS THE RESULTING PHENOTYPE IS INHERITED WITHOUT THE INITIATING SIGNAL. EPIGENETIC SWITCHES ARE INDUCED AND MAINTAINED BY DNA METHYLATION, HISTONE MODIFICATIONS, POLYCOMB GROUP (PCG)/TRITHORAX GROUP (TRXG) PROTEINS, AND FEEDBACK LOOPS CONSISTING OF TRANSCRIPTION FACTORS AND MICRORNAS. SINCE EPIGENETIC SWITCHES ARE REVERSIBLE, THEY MIGHT REPRESENT AN IMPORTANT BASIS FOR THE DESIGN OF NOVEL ANTICANCER THERAPEUTICS. THIS REVIEW SUMMARIZES PUBLISHED EVIDENCE OF EPIGENETIC SWITCHES IN CANCER DEVELOPMENT THAT ARE INDUCED BY INFLAMMATION. 2016 6 5461 26 RESEARCH PROGRESS OF BAP1 IN STRUCTURE, FUNCTION, AND CANCER. CANCER IS AN IMPORTANT CHRONIC NON-COMMUNICABLE DISEASE THAT ENDANGERS HUMAN HEALTH AND HAS BECOME THE MAIN CAUSE OF DEATH OF RESIDENTS AROUND THE WORLD IN THE 21ST CENTURY. AT PRESENT, MOST OF THE MATURE TREATMENT METHODS STAY AT THE LEVEL OF CELL AND TISSUE, WHICH IS DIFFICULT TO FUNDAMENTALLY SOLVE THE PROBLEM OF CANCER. THEREFORE, EXPLAINING THE PATHOGENESIS OF CANCER AT THE MOLECULAR LEVEL BECOMES THE ANSWER TO THE KEY PROBLEM OF CANCER REGULATION. BRCA-ASSOCIATED PROTEIN 1 (BRCA1- ASSOCIATED PROTEIN 1) IS A KIND OF UBIQUITINATION ENZYME ENCODED BY THE BAP1 GENE AND COMPOSED OF 729 AMINO ACIDS. AS A CARCINOGENIC PROTEIN, BAP1 CAN AFFECT THE CANCER CELL CYCLE AND PROLIFERATION CAPACITY, MUTATION, AND DELETION. FOR EXAMPLE, DEPENDING ON CATALYTIC ACTIVITY, IT PARTICIPATES IN THE REGULATION OF INTRACELLULAR FUNCTION THROUGH TRANSCRIPTION, EPIGENETIC, AND DNA DAMAGE REPAIR. THIS ARTICLE MAINLY REVIEWS THE BASIC STRUCTURE AND FUNCTION OF BAP1 IN CELLS, ITS ROLE IN CANCER DEVELOPMENT, AND CANCER-RELATED MUTANTS. 2023 7 3917 29 LINK BETWEEN CHRONIC INFLAMMATION AND HUMAN PAPILLOMAVIRUS-INDUCED CARCINOGENESIS (REVIEW). INFLAMMATION IS A DEFENSE STRATEGY AGAINST INVADING AGENTS AND HARMFUL MOLECULES THAT IS ACTIVATED IMMEDIATELY FOLLOWING A STIMULUS, AND INVOLVES THE RELEASE OF CYTOKINES AND CHEMOKINES, WHICH ACTIVATE THE INNATE IMMUNE RESPONSE. THESE MEDIATORS ACT TOGETHER TO INCREASE BLOOD FLOW AND VASCULAR PERMEABILITY, FACILITATING RECRUITMENT OF EFFECTOR CELLS TO THE SITE OF INJURY. FOLLOWING RESOLUTION OF THE INJURY AND REMOVAL OF THE STIMULUS, INFLAMMATION IS DISABLED, BUT IF THE STIMULUS PERSISTS, INFLAMMATION BECOMES CHRONIC AND IS STRONGLY ASSOCIATED WITH CANCER. THIS IS LIKELY TO BE DUE TO THE FACT THAT THE INFLAMMATION LEADS TO A WOUND THAT DOES NOT HEAL, REQUIRING A CONSTANT RENEWAL OF CELLS, WHICH INCREASES THE RISK OF NEOPLASTIC TRANSFORMATION. DEBRIS FROM PHAGOCYTOSIS, INCLUDING THE REACTIVE SPECIES OF OXYGEN AND NITROGEN THAT CAUSE DAMAGE TO DNA ALREADY DAMAGED BY THE LEUKOTRIENES AND PROSTAGLANDINS, HAS AN IMPACT ON INFLAMMATION AND VARIOUS CARCINOGENIC ROUTES. THERE IS AN ASSOCIATION BETWEEN CHRONIC INFLAMMATION, PERSISTENT INFECTION AND CANCER, WHERE ONCOGENIC ACTION IS MEDIATED BY AUTOCRINE AND PARACRINE SIGNALS, CAUSING CHANGES IN SOMATIC CELLS UNDER THE INFLUENCE OF THE MICROBIAL GENOME OR OF EPIGENETIC FACTORS. AMONG THE INFECTIOUS AGENTS ASSOCIATED WITH CANCER, CERTAIN GENOTYPES OF HUMAN PAPILLOMAVIRUS (HPV) STAND OUT. HPV IS RESPONSIBLE FOR VIRTUALLY ALL CASES OF CERVICAL CANCER AND A LOWER PROPORTION OF CANCERS OF THE VAGINA, VULVA, ANUS, PENIS AND A NUMBER OF EXTRAGENITAL CANCERS. IN THE PRESENT REVIEW, RECENT ADVANCES IN THE MECHANISMS INVOLVED IN THE INFLAMMATORY RESPONSE ARE PRESENTED WITH THEIR PARTICIPATION IN THE PROCESS OF CARCINOGENESIS, EMPHASIZING THE ROLE OF CHRONIC INFLAMMATION IN THE DEVELOPMENT OF HPV-INDUCED CERVICAL CANCER. 2015 8 5292 21 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. 2014 9 389 19 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 10 4675 26 NEW INSIGHTS INTO UNDERSTANDING THE MECHANISMS, PATHOGENESIS, AND MANAGEMENT OF MALIGNANT MESOTHELIOMAS. MALIGNANT MESOTHELIOMA (MM) IS A RELATIVELY RARE BUT DEVASTATING TUMOR THAT IS INCREASING WORLDWIDE. YET, BECAUSE OF DIFFICULTIES IN EARLY DIAGNOSIS AND RESISTANCE TO CONVENTIONAL THERAPIES, MM REMAINS A CHALLENGE FOR PATHOLOGISTS AND CLINICIANS TO TREAT. IN RECENT YEARS, MUCH HAS BEEN REVEALED REGARDING THE MECHANISMS OF INTERACTIONS OF PATHOGENIC FIBERS WITH MESOTHELIAL CELLS, CRUCIAL SIGNALING PATHWAYS, AND GENETIC AND EPIGENETIC EVENTS THAT MAY OCCUR DURING THE PATHOGENESIS OF THESE UNUSUAL, PLEIOMORPHIC TUMORS. THESE OBSERVATIONS SUPPORT A SCENARIO WHEREBY MESOTHELIAL CELLS UNDERGO A SERIES OF CHRONIC INJURY, INFLAMMATION, AND PROLIFERATION IN THE LONG LATENCY PERIOD OF MM DEVELOPMENT THAT MAY BE PERPETUATED BY DURABLE FIBERS, THE TUMOR MICROENVIRONMENT, AND INFLAMMATORY STIMULI. ONE CULPRIT IN SUSTAINED INFLAMMATION IS THE ACTIVATED INFLAMMASOME, A COMPONENT OF MACROPHAGES OR MESOTHELIAL CELLS THAT LEADS TO PRODUCTION OF CHEMOTACTIC, GROWTH-PROMOTING, AND ANGIOGENIC CYTOKINES. THIS INFORMATION HAS BEEN VITAL TO DESIGNING NOVEL THERAPEUTIC APPROACHES FOR PATIENTS WITH MM THAT FOCUS ON IMMUNOTHERAPY, TARGETING GROWTH FACTOR RECEPTORS AND PATHWAYS, OVERCOMING RESISTANCE TO APOPTOSIS, AND MODIFYING EPIGENETIC CHANGES. 2013 11 5526 22 RNA EDITING IN MESOTHELIOMA: A LOOK FORWARD. RNA EDITING IS A POST-TRANSCRIPTIONAL PROCESS INCREASING TRANSCRIPT DIVERSITY, THEREBY REGULATING DIFFERENT BIOLOGICAL PROCESSES. WE RECENTLY OBSERVED THAT MUTATIONS RESULTING FROM RNA EDITING DUE TO HYDROLYTIC DEAMINATION OF ADENOSINE INCREASE DURING THE DEVELOPMENT OF MESOTHELIOMA, A RARE CANCER LINKED TO CHRONIC EXPOSURE TO ASBESTOS. THIS REVIEW GATHERS INFORMATION FROM THE PUBLISHED LITERATURE AND PUBLIC DATA MINING TO EXPLORE SEVERAL ASPECTS OF RNA EDITING AND THEIR POSSIBLE IMPLICATIONS FOR CANCER GROWTH AND THERAPY. WE ADDRESS POSSIBLE LINKS BETWEEN RNA EDITING AND PARTICULAR TYPES OF MESOTHELIOMA GENETIC AND EPIGENETIC ALTERATIONS AND DISCUSS THE RELEVANCE OF AN EDITED SUBSTRATE IN THE CONTEXT OF CURRENT CHEMOTHERAPY OR IMMUNOTHERAPY. 2020 12 5291 35 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 13 45 29 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS. 2023 14 2338 30 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 15 2926 27 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 16 4539 28 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 17 2025 28 EPIGENETIC CHANGES DURING DISEASE PROGRESSION IN A MURINE MODEL OF HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC ALTERATIONS, INCLUDING GAIN OR LOSS OF DNA METHYLATION, ARE A HALLMARK OF NEARLY EVERY MALIGNANCY. CHANGES IN DNA METHYLATION CAN IMPACT EXPRESSION OF CANCER-RELATED GENES INCLUDING APOPTOSIS REGULATORS AND TUMOR SUPPRESSORS. BECAUSE SUCH EPIGENETIC CHANGES ARE REVERSIBLE, THEY ARE BEING AGGRESSIVELY INVESTIGATED AS POTENTIAL THERAPEUTIC TARGETS. HERE WE USE THE EMU-TCL1 TRANSGENIC MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TO DETERMINE THE TIMING AND PATTERNS OF ABERRANT DNA METHYLATION, AND TO INVESTIGATE THE MECHANISMS THAT LEAD TO ABERRANT DNA METHYLATION. WE SHOW THAT CLL CELLS FROM EMU-TCL1 MICE AT VARIOUS STAGES RECAPITULATE EPIGENETIC ALTERATIONS SEEN IN HUMAN CLL. ABERRANT METHYLATION OF PROMOTER SEQUENCES IS OBSERVED AS EARLY AS 3 MONTHS OF AGE IN THESE ANIMALS, WELL BEFORE DISEASE ONSET. ABNORMALLY METHYLATED PROMOTER REGIONS INCLUDE BINDING SITES FOR THE TRANSCRIPTION FACTOR FOXD3. WE SHOW THAT LOSS OF FOXD3 EXPRESSION DUE TO AN NF-KAPPAB P50/P50:HDAC1 REPRESSOR COMPLEX OCCURS IN TCL1-POSITIVE B CELLS BEFORE METHYLATION. THEREFORE, SPECIFIC TRANSCRIPTIONAL REPRESSION IS AN EARLY EVENT LEADING TO EPIGENETIC SILENCING OF TARGET GENES IN MURINE AND HUMAN CLL. THESE RESULTS PROVIDE STRONG RATIONALE FOR THE DEVELOPMENT OF STRATEGIES TO TARGET NF-KAPPAB COMPONENTS IN CLL AND POTENTIALLY OTHER B-CELL MALIGNANCIES. 2009 18 1232 32 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 19 6896 21 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 20 5889 23 SYSTEMS APPROACHES TO MODELING CHRONIC MUCOSAL INFLAMMATION. THE RESPIRATORY MUCOSA IS A MAJOR COORDINATOR OF THE INFLAMMATORY RESPONSE IN CHRONIC AIRWAY DISEASES, INCLUDING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SIGNALS PRODUCED BY THE CHRONIC INFLAMMATORY PROCESS INDUCE EPITHELIAL MESENCHYMAL TRANSITION (EMT) THAT DRAMATICALLY ALTERS THE EPITHELIAL CELL PHENOTYPE. THE EFFECTS OF EMT ON EPIGENETIC REPROGRAMMING AND THE ACTIVATION OF TRANSCRIPTIONAL NETWORKS ARE KNOWN, ITS EFFECTS ON THE INNATE INFLAMMATORY RESPONSE ARE UNDEREXPLORED. WE USED A MULTIPLEX GENE EXPRESSION PROFILING PLATFORM TO INVESTIGATE THE PERTURBATIONS OF THE INNATE PATHWAYS INDUCED BY TGF BETA IN A PRIMARY AIRWAY EPITHELIAL CELL MODEL OF EMT. EMT HAD DRAMATIC EFFECTS ON THE INDUCTION OF THE INNATE PATHWAY AND THE COUPLING INTERVAL OF THE CANONICAL AND NONCANONICAL NF- KAPPA B PATHWAYS. SIMULATION EXPERIMENTS DEMONSTRATE THAT RAPID, COORDINATED CAP-INDEPENDENT TRANSLATION OF TRAF-1 AND NF- KAPPA B2 IS REQUIRED TO REDUCE THE NONCANONICAL PATHWAY COUPLING INTERVAL. EXPERIMENTS USING AMANTADINE CONFIRMED THE PREDICTION THAT TRAF-1 AND NF- KAPPA B2/P100 PRODUCTION IS MEDIATED BY AN IRES-DEPENDENT MECHANISM. THESE DATA INDICATE THAT THE EPIGENETIC CHANGES PRODUCED BY EMT INDUCE DYNAMIC STATE CHANGES OF THE INNATE SIGNALING PATHWAY. FURTHER APPLICATIONS OF SYSTEMS APPROACHES WILL PROVIDE UNDERSTANDING OF THIS COMPLEX PHENOTYPE THROUGH DETERMINISTIC MODELING AND MULTIDIMENSIONAL (GENOMIC AND PROTEOMIC) PROFILING. 2013