1 5795 104 STAT3 INDUCTION OF MIR-146B FORMS A FEEDBACK LOOP TO INHIBIT THE NF-KAPPAB TO IL-6 SIGNALING AXIS AND STAT3-DRIVEN CANCER PHENOTYPES. INTERLEUKIN-6 (IL-6)-MEDIATED ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) IS A MECHANISM BY WHICH CHRONIC INFLAMMATION CAN CONTRIBUTE TO CANCER AND IS A COMMON ONCOGENIC EVENT. WE DISCOVERED A PATHWAY, THE LOSS OF WHICH IS ASSOCIATED WITH PERSISTENT STAT3 ACTIVATION IN HUMAN CANCER. WE FOUND THAT THE GENE ENCODING THE TUMOR SUPPRESSOR MICRORNA MIR-146B IS A DIRECT STAT3 TARGET GENE, AND ITS EXPRESSION WAS INCREASED IN NORMAL BREAST EPITHELIAL CELLS BUT DECREASED IN TUMOR CELLS. METHYLATION OF THE MIR-146B PROMOTER, WHICH INHIBITED STAT3-MEDIATED INDUCTION OF EXPRESSION, WAS INCREASED IN PRIMARY BREAST CANCERS. MOREOVER, WE FOUND THAT MIR-146B INHIBITED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT PRODUCTION OF IL-6, SUBSEQUENT STAT3 ACTIVATION, AND IL-6/STAT3-DRIVEN MIGRATION AND INVASION IN BREAST CANCER CELLS, THEREBY ESTABLISHING A NEGATIVE FEEDBACK LOOP. IN ADDITION, HIGHER EXPRESSION OF MIR-146B WAS POSITIVELY CORRELATED WITH PATIENT SURVIVAL IN BREAST CANCER SUBTYPES WITH INCREASED IL6 EXPRESSION AND STAT3 PHOSPHORYLATION. OUR RESULTS IDENTIFY AN EPIGENETIC MECHANISM OF CROSSTALK BETWEEN STAT3 AND NF-KAPPAB RELEVANT TO CONSTITUTIVE STAT3 ACTIVATION IN MALIGNANCY AND THE ROLE OF INFLAMMATION IN ONCOGENESIS. 2014 2 4303 31 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE. 2014 3 1646 33 DOES THE HEPATITIS B ANTIGEN HBX PROMOTE THE APPEARANCE OF LIVER CANCER STEM CELLS? HEPATITIS B VIRUS (HBV) IS A MAJOR ETIOLOGIC AGENT OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV-ENCODED X ANTIGEN, HBX, AND PATHWAYS IMPLICATED IN THE SELF-RENEWAL OF STEM CELLS CONTRIBUTE TO HCC, BUT IT IS NOT CLEAR WHETHER HBX EXPRESSION PROMOTES "STEMNESS." THUS, EXPERIMENTS WERE DESIGNED TO TEST THE HYPOTHESIS THAT HBX TRIGGERS MALIGNANT TRANSFORMATION BY PROMOTING PROPERTIES THAT ARE CHARACTERISTIC OF CANCER STEM CELLS (CSC). TO TEST THIS HYPOTHESIS, HEPG2 CELLS WERE STABLY TRANSDUCED WITH HBX AND THEN ASSAYED FOR PHENOTYPIC AND MOLECULAR CHARACTERISTICS OF "STEMNESS." THE RELATIONSHIP BETWEEN HBX AND "STEMNESS"-ASSOCIATED MARKERS WAS ALSO EVALUATED BY IMMUNOHISTOCHEMICAL STAINING OF LIVER AND TUMOR TISSUE SECTIONS FROM HBV-INFECTED PATIENTS. THE RESULTS SHOWED THAT OCT-4, NANOG, KLF-4, BETA-CATENIN, AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) WERE ACTIVATED BY HBX IN VITRO AND IN VIVO. EPCAM WAS DETECTED IN THE NUCLEI OF HUMAN HCC CELLS FROM INFECTED PATIENTS. HBX PROMOTES "STEMNESS" BY ACTIVATING BETA-CATENIN AND EPIGENETIC UPREGULATION OF MIR-181, BOTH OF WHICH TARGET EPCAM. HBX EXPRESSION WAS ALSO ASSOCIATED WITH DEPRESSED LEVELS OF E-CADHERIN. MOREOVER, HBX STIMULATED CELL MIGRATION, GROWTH IN SOFT AGAR, AND SPHEROID FORMATION. THIS WORK IS THE FIRST TO PROPOSE THAT HBV PROMOTES "STEMNESS" IN THE PATHOGENESIS OF HCC. HBX-ASSOCIATED UPREGULATED EXPRESSION OF MULTIPLE "STEMNESS" MARKERS SUPPORTS THE HYPOTHESIS THAT HBX CONTRIBUTES TO HEPATOCARCINOGENESIS, AT LEAST IN PART, BY PROMOTING CHANGES IN GENE EXPRESSION THAT ARE CHARACTERISTICS OF CSCS. 2011 4 6661 38 UPREGULATION OF DNA METHYLTRANSFERASE-MEDIATED GENE SILENCING, ANCHORAGE-INDEPENDENT GROWTH, AND MIGRATION OF COLON CANCER CELLS BY INTERLEUKIN-6. INFLAMMATORY BOWEL DISEASE IS CHARACTERIZED BY CHRONIC INFLAMMATION WHICH PREDISPOSES TO COLORECTAL CANCER. THE MECHANISMS BY WHICH INFLAMMATION PROMOTES TUMORIGENESIS ARE NOT FULLY KNOWN. WE AIMED TO INVESTIGATE THE LINKS BETWEEN COLONIC INFLAMMATION AND TUMORIGENESIS VIA EPIGENETIC GENE SILENCING. COLON CANCER SPECIMENS WERE ASSESSED FOR THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT-1) USING IMMUNOHISTOCHEMISTRY. COLORECTAL CARCINOMA CELL LINES WERE ASSESSED FOR DNMT1 EXPRESSION, METHYLCYTOSINE CONTENT, PROMOTER METHYLATION, GENE EXPRESSION, AND TUMORIGENESIS IN RESPONSE TO INTERLEUKIN (IL)-6. DNMT1 WAS EXPRESSED AT HIGHER LEVELS IN BOTH THE PERITUMORAL STROMA AND TUMOR IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED CANCERS COMPARED WITH SPORADIC COLON CANCERS. IL-6 TREATMENT OF COLON CANCER CELLS RESULTED IN AN INCREASE IN DNMT1 EXPRESSION, INDEPENDENT OF DE NOVO GENE EXPRESSION. IL-6 INCREASED THE METHYLATION OF PROMOTER REGIONS OF GENES ASSOCIATED WITH TUMOR SUPPRESSION, ADHESION, AND APOPTOSIS RESISTANCE. EXPRESSION OF A SUBSET OF THESE GENES WAS DOWNREGULATED BY IL-6, AN EFFECT THAT WAS PREVENTED BY PREINCUBATION WITH 5-AZADEOXYCYTIDINE, A DNMT1 INHIBITOR. ANCHORAGE-INDEPENDENT GROWTH AND MIGRATION OF COLON CANCER CELLS WAS ALSO INCREASED BY IL-6 IN A 5-AZADEOXYCYTIDINE-SENSITIVE MANNER. OUR RESULTS INDICATE THAT DNMT-MEDIATED GENE SILENCING MAY PLAY A ROLE IN INFLAMMATION-ASSOCIATED COLON TUMORIGENESIS. 2010 5 3795 37 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 6 1632 32 DNMTS ARE INVOLVED IN TGF-BETA1-INDUCED EPITHELIAL-MESENCHYMAL TRANSITIONS IN AIRWAY EPITHELIAL CELLS. CHRONIC RHINOSINUSITIS (CRS) PATHOGENESIS IS CLOSELY RELATED TO TISSUE REMODELING, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION (EMT). EPIGENETIC MECHANISMS PLAY KEY ROLES IN EMT. DNA METHYLATION, MEDIATED BY DNA METHYLTRANSFERASES (DNMTS), IS AN EPIGENETIC MARKER THAT IS CRITICAL TO EMT. THE GOAL OF THIS STUDY WAS TO DETERMINE WHETHER DNMTS WERE INVOLVED IN TGF-BETA1-INDUCED EMT AND ELUCIDATE THE UNDERLYING MECHANISMS IN NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION AND DNMT ACTIVITY WERE QUANTIFIED. DNMT EXPRESSION WAS MEASURED USING REAL-TIME PCR (QRT-PCR) IN HUMAN CRS TISSUES. MRNA AND PROTEIN LEVELS OF DNMTS, E-CADHERIN, VIMENTIN, ALPHA-SMA, AND FIBRONECTIN WERE DETERMINED USING RT-PCR AND WESTERN BLOTTING, RESPECTIVELY. DNMT1, DNMT3A, AND DNMT3B GENE EXPRESSION WERE KNOCKED DOWN USING SIRNA TRANSFECTION. MAPK PHOSPHORYLATION AND EMT-RELATED TRANSCRIPTION FACTOR LEVELS WERE DETERMINED USING WESTERN BLOTTING. SIGNALING PATHWAYS WERE ANALYZED USING SPECIFIC INHIBITORS OF MAPK. WE DEMONSTRATED THESE DATA IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION, DNMT ACTIVITY, AND DNMT EXPRESSION INCREASED IN CRS TISSUES. DNMT EXPRESSION WAS POSITIVELY CORRELATED WITH LUND-MCKAY CT SCORES. TGF-BETA1 DOSE-DEPENDENTLY INDUCED DNMT EXPRESSION. FURTHER, 5-AZA INHIBITED TGF-BETA1-INDUCED DNMT, SNAIL, AND SLUG EXPRESSION RELATED TO EMT, AS WELL AS P38 AND JNK PHOSPHORYLATION IN A549 CELLS AND TGF-BETA1-INDUCED DNMT EXPRESSION AND EMT IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. TGF-BETA1-INDUCED DNMT EXPRESSION LEADS TO DNA METHYLATION AND EMT VIA P38, JNK, SNAIL, AND SLUG SIGNALING PATHWAYS. INHIBITION OF DNMT SUPPRESSED THE EMT PROCESS AND THEREFORE IS POTENTIALLY A CRS THERAPEUTIC STRATEGY. 2022 7 4357 34 MIR-30E* IS OVEREXPRESSED IN PROSTATE CANCER AND PROMOTES NF-KAPPAB-MEDIATED PROLIFERATION AND TUMOR GROWTH. ACCORDING TO THE CDC PROSTATE CANCER (CAP) HAS THE HIGHEST INCIDENCE AND SECOND HIGHEST MORTALITY RATE AMONGST CANCERS IN AMERICAN MEN. CONSTITUTIVE NF-KAPPAB ACTIVATION IS A HALLMARK OF CAP AND THIS PATHWAY DRIVES MANY PRO-TUMORIGENIC CHARACTERISTICS OF CAP CELLS, INCLUDING CELL PROLIFERATION AND SURVIVAL. AN ACTIVATED NF-KAPPAB GENE SIGNATURE IS PREDICTIVE OF CAP PROGRESSION AND BIOCHEMICAL RECURRENCE FOLLOWING THERAPEUTIC INTERVENTION. HOWEVER, THE MECHANISMS THAT PERPETUATE NF-KAPPAB ACTIVATION ARE INCOMPLETELY UNDERSTOOD. GENES THAT CONTROL NF-KAPPAB ACTIVITY ARE RARELY MUTATED IN CAP SUGGESTING THAT EPIGENETIC MECHANISMS MAY CONTRIBUTE TO CONSTITUTIVE NF-KAPPAB ACTIVATION. MICRORNAS (MIRS) EPIGENETICALLY REGULATE MANY GENES INVOLVED WITH NF-KAPPAB ACTIVATION. IKAPPABALPHA IS A DIRECT INHIBITOR OF NF-KAPPAB; IT BINDS TO AND SEQUESTERS NF-KAPPAB IN THE CYTOPLASM RESULTING IN FUNCTIONAL INHIBITION. IKAPPABALPHA IS A TARGET GENE OF MIR-30E* YET THE EXPRESSION AND ONCOLOGICAL IMPACT OF MIR-30E* IN CAP IS UNKNOWN. WE REPORT THAT MIR-30E* EXPRESSION IS ELEVATED IN MULTIPLE MURINE MODELS OF CAP AND IS MOST PRONOUNCED IN LATE STAGE DISEASE. MIR-30E* DRIVES CAP PROLIFERATION AND TUMOR GROWTH THROUGH INHIBITION OF IKAPPABALPHA, WHICH RESULTS IN CHRONIC ACTIVATION OF NF-KAPPAB. ADDITIONALLY, WE SHOW THAT INHIBITION OF MIR-30E* IMPROVES CHEMOTHERAPEUTIC CONTROL OF CAP. THUS, MIR-30E* MAY PROVE TO BE A NOVEL CLINICAL TARGET WHOSE INHIBITION LEADS TO DECREASED CAP CELL PROLIFERATION AND SENSITIZATION OF CAP CELLS TO CHEMOTHERAPEUTICS. 2017 8 1667 33 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL. 2012 9 922 34 CHRONIC IL-1BETA-INDUCED INFLAMMATION REGULATES EPITHELIAL-TO-MESENCHYMAL TRANSITION MEMORY PHENOTYPES VIA EPIGENETIC MODIFICATIONS IN NON-SMALL CELL LUNG CANCER. CHRONIC INFLAMMATION FACILITATES TUMOR PROGRESSION. WE DISCOVERED THAT A SUBSET OF NON-SMALL CELL LUNG CANCER CELLS UNDERWENT A GRADUALLY PROGRESSING EPITHELIAL-TO-MESENCHYMAL (EMT) PHENOTYPE FOLLOWING A 21-DAY EXPOSURE TO IL-1BETA, AN ABUNDANT PROINFLAMMATORY CYTOKINE IN THE AT-RISK FOR LUNG CANCER PULMONARY AND THE LUNG TUMOR MICROENVIRONMENTS. PATHWAY ANALYSIS OF THE GENE EXPRESSION PROFILE AND IN VITRO FUNCTIONAL STUDIES REVEALED THAT THE EMT AND EMT-ASSOCIATED PHENOTYPES, INCLUDING ENHANCED CELL INVASION, PD-L1 UPREGULATION, AND CHEMORESISTANCE, WERE SUSTAINED IN THE ABSENCE OF CONTINUOUS IL-1BETA EXPOSURE. WE REFERRED TO THIS PHENOMENON AS EMT MEMORY. UTILIZING A DOXYCYCLINE-CONTROLLED SLUG EXPRESSION SYSTEM, WE FOUND THAT HIGH EXPRESSION OF THE TRANSCRIPTION FACTOR SLUG WAS INDISPENSABLE FOR THE ESTABLISHMENT OF EMT MEMORY. HIGH SLUG EXPRESSION IN TUMORS OF LUNG CANCER PATIENTS WAS ASSOCIATED WITH POOR SURVIVAL. CHEMICAL OR GENETIC INHIBITION OF SLUG UPREGULATION PREVENTED EMT FOLLOWING THE ACUTE IL-1BETA EXPOSURE BUT DID NOT REVERSE EMT MEMORY. CHROMATIN IMMUNOPRECIPITATION AND METHYLATION-SPECIFIC PCR FURTHER REVEALED A SLUG-MEDIATED TEMPORAL REGULATION OF EPIGENETIC MODIFICATIONS, INCLUDING ACCUMULATION OF H3K27, H3K9, AND DNA METHYLATION, IN THE CDH1 (E-CADHERIN) PROMOTER FOLLOWING THE CHRONIC IL-1BETA EXPOSURE. CHEMICAL INHIBITION OF DNA METHYLATION NOT ONLY RESTORED E-CADHERIN EXPRESSION IN EMT MEMORY, BUT ALSO PRIMED CELLS FOR CHEMOTHERAPY-INDUCED APOPTOSIS. 2020 10 2437 29 EPIGENETIC SILENCING OF SONIC HEDGEHOG ELICITS ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HEDGEHOG SIGNALING PATHWAY IN METASTATIC SPINE TUMORS IN SPRAGUE-DAWLEY RATS. BACKGROUND: PATIENTS WITH METASTATIC SPINE TUMORS MAY SUFFER FROM PAIN OR NEUROLOGIC DEFICIT, AND THE DISEASE MAY BE DETECTED IN PATIENTS WITH A KNOWN MALIGNANCY. SONIC HEDGEHOG (SHH) HAS RECEIVED SPECIAL ATTENTION DUE TO ITS ROLE IN CANCERS. THEREFORE, THIS STUDY INVESTIGATED THE EFFECTS OF EPIGENETIC SILENCING OF SHH ON ANTITUMOR IMMUNE RESPONSE AND TUMOR GROWTH BY REGULATING THE HEDGEHOG (HH) SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. METHODS: RAT MODELS OF METASTATIC SPINE TUMORS WERE SUCCESSFULLY ESTABLISHED. WE FIRST CALCULATED THE TUMOR VOLUME AND THE INHIBITION RATE OF TUMOR GROWTH TO INVESTIGATE THE EFFECT OF SHH ON TUMOR GROWTH. AFTERWARDS, IMMUNOHISTOCHEMISTRY WAS USED TO DETERMINE WHETHER PROLIFERATION WAS DELAYED BY SHH DEPLETION, AND THE 3-(4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHENYLTETRAZOLIUM BROMIDE ASSAY WAS CONDUCTED TO TEST THE CHANGES IN THE LYMPHOCYTE TRANSFORMATION RATE IN THE SPLEEN TRIGGERED BY SHH SILENCING. THEN, THE INFLUENCE OF SHH DEPLETION ON IMMUNE FUNCTION WAS INVESTIGATED. LATER, QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION AND WESTERN BLOT ASSAY WERE PERFORMED TO EXPLORE THE HH SIGNALING PATHWAY-RELATED FACTORS. FINALLY, WE ADDED THE HH SIGNALING PATHWAY INHIBITOR, GDC-0449, TO CONFIRM THE ROLE OF THE PATHWAY IN TUMOR PROGRESSION. RESULTS: INITIALLY, WE OBSERVED THAT SHH DEPLETION WAS A NEGATIVE FACTOR FOR TUMOR GROWTH. AFTERWARDS, IT WAS REVEALED THAT EPIGENETIC SILENCING OF SHH SERVED AS AN INHIBITOR FACTOR FOR THE FUNCTION OF SPLEEN LYMPHOCYTE TRANSFORMATION AND INFLAMMATION WHILE PROMOTING ANTITUMOR IMMUNE FUNCTION. CONCLUSION: OUR PRELIMINARY RESULTS INDICATE THAT EPIGENETIC SILENCING OF SHH ELICITS AN ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HH SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. 2018 11 3289 37 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 12 3276 27 HEPATOCYTE GROWTH CONTROL BY SOCS1 AND SOCS3. THE EXTRAORDINARY CAPACITY OF THE LIVER TO REGENERATE FOLLOWING INJURY IS DEPENDENT ON COORDINATED AND REGULATED ACTIONS OF CYTOKINES AND GROWTH FACTORS. WHEREAS HEPATOCYTE GROWTH FACTOR (HGF) AND EPIDERMAL GROWTH FACTOR (EGF) ARE DIRECT MITOGENS TO HEPATOCYTES, INFLAMMATORY CYTOKINES SUCH AS TNFALPHA AND IL-6 ALSO PLAY ESSENTIAL ROLES IN THE LIVER REGENERATION PROCESS. THESE CYTOKINES AND GROWTH FACTORS ACTIVATE DIFFERENT SIGNALING PATHWAYS IN A SEQUENTIAL MANNER TO ELICIT HEPATOCYTE PROLIFERATION. THE KINETICS AND MAGNITUDE OF THESE HEPATOCYTE-ACTIVATING STIMULI ARE TIGHTLY REGULATED TO ENSURE RESTORATION OF A FUNCTIONAL LIVER MASS WITHOUT CAUSING UNCONTROLLED CELL PROLIFERATION. HEPATOCYTE PROLIFERATION CAN BECOME DEREGULATED UNDER CONDITIONS OF CHRONIC INFLAMMATION, LEADING TO ACCUMULATION OF GENETIC ABERRATIONS AND EVENTUAL NEOPLASTIC TRANSFORMATION. AMONG THE CONTROL MECHANISMS THAT REGULATE HEPATOCYTE PROLIFERATION, NEGATIVE FEEDBACK INHIBITION BY THE 'SUPPRESSOR OF CYTOKINE SIGNALING (SOCS)' FAMILY PROTEINS SOCS1 AND SOCS3 PLAY CRUCIAL ROLES IN ATTENUATING CYTOKINE AND GROWTH FACTOR SIGNALING. LOSS OF SOCS1 OR SOCS3 IN THE MOUSE LIVER INCREASES THE RATE OF LIVER REGENERATION AND RENDERS HEPATOCYTES SUSCEPTIBLE TO NEOPLASTIC TRANSFORMATION. THE FREQUENT EPIGENETIC REPRESSION OF THE SOCS1 AND SOCS3 GENES IN HEPATOCELLULAR CARCINOMA HAS STIMULATED RESEARCH IN UNDERSTANDING THE GROWTH REGULATORY MECHANISMS OF SOCS1 AND SOCS3 IN HEPATOCYTES. WHEREAS SOCS3 IS IMPLICATED IN REGULATING JAK-STAT SIGNALING INDUCED BY IL-6 AND ATTENUATING EGFR SIGNALING, SOCS1 IS CRUCIAL FOR THE REGULATION OF HGF SIGNALING. THESE TWO PROTEINS ALSO MODULE THE FUNCTIONS OF CERTAIN KEY PROTEINS THAT CONTROL THE CELL CYCLE. IN THIS REVIEW, WE DISCUSS THE CURRENT UNDERSTANDING OF THE FUNCTIONS OF SOCS1 AND SOCS3 IN CONTROLLING HEPATOCYTE PROLIFERATION, AND ITS IMPLICATIONS TO LIVER HEALTH AND DISEASE. 2019 13 1862 33 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011 14 1479 25 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 15 3688 36 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 16 4284 50 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 17 3946 34 LNCRNA MALAT1 BINDS CHROMATIN REMODELING SUBUNIT BRG1 TO EPIGENETICALLY PROMOTE INFLAMMATION-RELATED HEPATOCELLULAR CARCINOMA PROGRESSION. HEPATOCELLULAR CARCINOMA (HCC) IS ONE TYPE OF CANCERS WHOSE CARCINOGENESIS AND PROGRESSION ARE CLOSELY RELATED TO CHRONIC INFLAMMATION. IDENTIFYING THE MOLECULAR MECHANISMS FOR INFLAMMATION-RELATED HCC PROGRESSION WILL CONTRIBUTE TO IMPROVE THE EFFICACY OF CURRENT THERAPEUTICS FOR HCC PATIENTS. MANY KINDS OF EPIGENETIC FACTORS, INCLUDING LONG NON-CODING RNAS (LNCRNAS), HAVE BEEN DISCOVERED TO BE IMPORTANT IN HCC GROWTH AND METASTASIS. HOWEVER, HOW THE LNCRNAS PROMOTE HCC PROGRESSION AND WHAT'S THE APPLICATION OF LNCRNA SILENCING IN VIVO IN SUPPRESSING HCC REMAIN TO BE FURTHER INVESTIGATED. HERE, WE FOUND THAT LNCRNA METASTASIS ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT1 (MALAT1) WAS UPREGULATED IN HCC TUMOR TISSUES, AND KNOCKDOWN OF MALAT1 SUPPRESSED PROLIFERATION, CELL CYCLE AND INVASION OF HCC CELLS IN RESPONSE TO LIPOPOLYSACCHARIDE (LPS) STIMULATION. KNOCKDOWN OF MALAT1 SIGNIFICANTLY INHIBITED LPS-INDUCED PRO-INFLAMMATORY MEDIATORS IL-6 AND CXCL8 EXPRESSION IN HCC CELLS, WHICH COULD BE RESTORED BY OVEREXPRESSING MALAT1. MECHANISTICALLY, MALAT1 RECRUITED BRAHMA-RELATED GENE 1 (BRG1), A CATALYTIC SUBUNIT OF CHROMATIN REMODELING COMPLEX SWITCHING/SUCROSE NON-FERMENTABLE (SWI/SNF), TO THE PROMOTER REGION OF IL-6 AND CXCL8, AND THUS FACILITATED NF-KAPPAB TO INDUCE THE EXPRESSION OF THESE INFLAMMATORY FACTORS. IMPORTANTLY, IN VIVO SILENCING OF MALAT1 IN HCC TISSUES INHIBITED GROWTH OF HCC XENOGRAFTS, AND ALSO SUPPRESSED THE EXPRESSION OF PRO-INFLAMMATORY FACTORS IN HCC TISSUES ACCORDINGLY. OUR RESULTS DEMONSTRATE THAT MALAT1 PROMOTES HCC PROGRESSION BY BINDING BRG1 TO EPIGENETICALLY ENHANCE INFLAMMATORY RESPONSE IN HCC TISSUES, AND SILENCING OF MALAT1 MAY BE A POTENTIAL APPROACH TO THE TREATMENT OF HCC. 2019 18 3218 36 HELICOBACTER INFECTION IS REQUIRED FOR INFLAMMATION AND COLON CANCER IN SMAD3-DEFICIENT MICE. ACCUMULATING EVIDENCE SUGGESTS THAT INTESTINAL MICROBIAL ORGANISMS MAY PLAY AN IMPORTANT ROLE IN TRIGGERING AND SUSTAINING INFLAMMATION IN INDIVIDUALS AFFLICTED WITH INFLAMMATORY BOWEL DISEASE (IBD). MOREOVER, INDIVIDUALS WITH IBD ARE AT INCREASED RISK FOR DEVELOPING COLORECTAL CANCER, SUGGESTING THAT CHRONIC INFLAMMATION MAY INITIATE GENETIC OR EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. WE TESTED THE HYPOTHESIS THAT BACTERIA MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER BY SYNERGIZING WITH DEFECTIVE TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, A PATHWAY COMMONLY MUTATED IN HUMAN COLON CANCER. ALTHOUGH OTHERS HAVE REPORTED THAT MICE DEFICIENT IN THE TGF-BETA SIGNALING MOLECULE SMAD3 DEVELOP COLON CANCER, WE FOUND THAT SMAD3-DEFICIENT MICE MAINTAINED FREE OF THE GRAM-NEGATIVE ENTEROHEPATIC BACTERIA HELICOBACTER SPP. FOR UP TO 9 MONTHS DO NOT DEVELOP COLON CANCER. FURTHERMORE, INFECTION OF SMAD3(-/-) MICE WITH HELICOBACTER TRIGGERS COLON CANCER IN 50% TO 66% OF THE ANIMALS. USING REAL-TIME PCR, WE FOUND THAT HELICOBACTER ORGANISMS CONCENTRATE IN THE CECUM, THE PREFERRED SITE OF TUMOR DEVELOPMENT. MUCINOUS ADENOCARCINOMAS DEVELOP 5 TO 30 WEEKS AFTER INFECTION AND ARE PRECEDED BY AN EARLY INFLAMMATORY PHASE, CONSISTING OF INCREASED PROLIFERATION OF EPITHELIAL CELLS; INCREASED NUMBERS OF CYCLOOXYGENASE-2-POSITIVE CELLS, CD4(+) T CELLS, MACROPHAGES; AND INCREASED MHC CLASS II EXPRESSION. COLONIC TISSUE REVEALED INCREASED TRANSCRIPTS FOR THE ONCOGENE C-MYC AND THE PROINFLAMMATORY CYTOKINES INTERLEUKIN-1ALPHA (IL-1ALPHA), IL-1BETA, IL-6, IFN-GAMMA, AND TUMOR NECROSIS FACTOR-ALPHA, SOME OF WHICH HAVE BEEN IMPLICATED IN COLON CANCER. THESE RESULTS SUGGEST THAT BACTERIA MAY BE IMPORTANT IN TRIGGERING COLORECTAL CANCER, NOTABLY IN THE CONTEXT OF GENE MUTATIONS IN THE TGF-BETA SIGNALING PATHWAY, ONE OF THE MOST COMMONLY AFFECTED CELLULAR PATHWAYS IN COLORECTAL CANCER IN HUMANS. 2006 19 5592 24 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE HUMAN SYSTEMIC ENDOTOXIN-INDUCED TRANSCRIPTOME. TNFALPHA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES. DIFFERENT STRATEGIES TO INHIBIT TNFALPHA IN PATIENTS WITH SEPSIS AND CHRONIC INFLAMMATORY CONDITIONS HAVE SHOWN CONTRASTING OUTCOMES. ALTHOUGH TNFALPHA INHIBITORS ARE WIDELY USED IN CLINICAL PRACTICE, THE IMPACT OF TNFALPHA ANTAGONISM ON WHITE BLOOD CELL GENE EXPRESSION PROFILES DURING ACUTE INFLAMMATION IN HUMANS IN VIVO HAS NOT BEEN ASSESSED. WE HERE LEVERAGED THE ESTABLISHED MODEL OF HUMAN ENDOTOXEMIA TO EXAMINE THE EFFECT OF THE TNFALPHA ANTAGONIST, ETANERCEPT, ON THE GENOME-WIDE TRANSCRIPTIONAL RESPONSES IN CIRCULATING LEUKOCYTES INDUCED BY INTRAVENOUS LPS ADMINISTRATION IN MALE SUBJECTS. ETANERCEPT PRE-TREATMENT RESULTED IN A MARKEDLY DAMPENED TRANSCRIPTIONAL RESPONSE TO LPS. GENE CO-EXPRESSION NETWORK ANALYSIS REVEALED THIS LPS-INDUCED TRANSCRIPTOME CAN BE CATEGORIZED AS TNFALPHA RESPONSIVE AND NON-RESPONSIVE MODULES. HIGHLY SIGNIFICANT TNFALPHA RESPONSIVE MODULES INCLUDE NF-KB SIGNALING, ANTIVIRAL RESPONSES AND T-CELL MEDIATED RESPONSES. WITHIN THESE TNFALPHA RESPONSIVE MODULES WE DELINEATE FUNDAMENTAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS, TRANSCRIPTIONAL INITIATION AND ELONGATION. THUS, WE PROVIDE COMPREHENSIVE INFORMATION ABOUT MOLECULAR PATHWAYS THAT MIGHT BE TARGETED BY THERAPEUTIC INTERVENTIONS THAT SEEK TO INHIBIT TNFALPHA ACTIVITY DURING HUMAN INFLAMMATORY DISEASES. 2013 20 1158 40 CONTEXT-DEPENDENT EPIGENETIC REGULATION OF NUCLEAR FACTOR OF ACTIVATED T CELLS 1 IN PANCREATIC PLASTICITY. BACKGROUND & AIMS: THE ABILITY OF EXOCRINE PANCREATIC CELLS TO CHANGE THE CELLULAR PHENOTYPE IS REQUIRED FOR TISSUE REGENERATION UPON INJURY, BUT ALSO CONTRIBUTES TO THEIR MALIGNANT TRANSFORMATION AND TUMOR PROGRESSION. WE INVESTIGATED CONTEXT-DEPENDENT SIGNALING AND TRANSCRIPTION MECHANISMS THAT DETERMINE PANCREATIC CELL FATE DECISIONS TOWARD REGENERATION AND MALIGNANCY. IN PARTICULAR, WE STUDIED THE FUNCTION AND REGULATION OF THE INFLAMMATORY TRANSCRIPTION FACTOR NUCLEAR FACTOR OF ACTIVATED T CELLS 1 (NFATC1) IN PANCREATIC CELL PLASTICITY AND TISSUE ADAPTATION. METHODS: WE ANALYZED CELL PLASTICITY DURING PANCREATIC REGENERATION AND TRANSFORMATION IN MICE WITH PANCREAS-SPECIFIC EXPRESSION OF A CONSTITUTIVELY ACTIVE FORM OF NFATC1, OR DEPLETION OF ENHANCER OF ZESTE 2 HOMOLOGUE 2 (EZH2), IN THE CONTEXT OF WILD-TYPE OR CONSTITUTIVELY ACTIVATE KRAS, RESPECTIVELY. ACUTE AND CHRONIC PANCREATITIS WERE INDUCED BY INTRAPERITONEAL INJECTION OF CAERULEIN. EZH2-DEPENDENT REGULATION OF NFATC1 EXPRESSION WAS STUDIED IN MOUSE IN HUMAN PANCREATIC TISSUE AND CELLS BY IMMUNOHISTOCHEMISTRY, IMMUNOBLOTTING, AND QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION. WE USED GENETIC AND PHARMACOLOGIC APPROACHES OF EZH2 AND NFATC1 INHIBITION TO STUDY THE CONSEQUENCES OF PATHWAY DISRUPTION ON PANCREATIC MORPHOLOGY AND FUNCTION. EPIGENETIC MODIFICATIONS ON THE NFATC1 GENE WERE INVESTIGATED BY CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: NFATC1 WAS RAPIDLY AND TRANSIENTLY INDUCED IN EARLY ADAPTATION TO ACINAR CELL INJURY IN HUMAN SAMPLES AND IN MICE, WHERE IT PROMOTED ACINAR CELL TRANSDIFFERENTIATION AND BLOCKED PROLIFERATION OF METAPLASTIC PANCREATIC CELLS. HOWEVER, IN LATE STAGES OF REGENERATION, NFATC1 WAS EPIGENETICALLY SILENCED BY EZH2-DEPENDENT HISTONE METHYLATION, TO ENABLE ACINAR CELL REDIFFERENTIATION AND PREVENT ORGAN ATROPHY AND EXOCRINE INSUFFICIENCY. IN CONTRAST, ONCOGENIC ACTIVATION OF KRAS SIGNALING IN PANCREATIC DUCTAL ADENOCARCINOMA CELLS REVERSED THE EZH2-DEPENDENT EFFECTS ON THE NFATC1 GENE AND WAS REQUIRED FOR EZH2-MEDIATED TRANSCRIPTIONAL ACTIVATION OF NFATC1. CONCLUSIONS: IN STUDIES OF HUMAN AND MOUSE PANCREATIC CELLS AND TISSUE, WE IDENTIFIED CONTEXT-SPECIFIC EPIGENETIC REGULATION OF NFATC1 ACTIVITY AS AN IMPORTANT MECHANISM OF PANCREATIC CELL PLASTICITY. INHIBITORS OF EZH2 MIGHT THEREFORE INTERFERE WITH ONCOGENIC ACTIVITY OF NFATC1 AND BE USED IN TREATMENT OF PANCREATIC DUCTAL ADENOCARCINOMA. 2017