1  4521 192 MULTI?LAYERED PREVENTION AND TREATMENT OF CHRONIC INFLAMMATION, ORGAN FIBROSIS AND CANCER ASSOCIATED WITH CANONICAL WNT/BETA?CATENIN SIGNALING ACTIVATION (REVIEW). BETA?CATENIN/CTNNB1 IS AN INTRACELLULAR SCAFFOLD PROTEIN THAT INTERACTS WITH ADHESION MOLECULES (E?CADHERIN/CDH1, N?CADHERIN/CDH2, VE?CADHERIN/CDH5 AND ALPHA?CATENINS), TRANSMEMBRANE?TYPE MUCINS (MUC1/CD227 AND MUC16/CA125), SIGNALING REGULATORS (APC, AXIN1, AXIN2 AND NHERF1/EBP50) AND EPIGENETIC OR TRANSCRIPTIONAL REGULATORS (BCL9, BCL9L, CREBBP/CBP, EP300/P300, FOXM1, MED12, SMARCA4/BRG1 AND TCF/LEF). GAIN?OF?FUNCTION CTTNB1 MUTATIONS ARE DETECTED IN BLADDER CANCER, COLORECTAL CANCER, GASTRIC CANCER, LIVER CANCER, LUNG CANCER, PANCREATIC CANCER, PROSTATE CANCER AND UTERINE CANCER, WHEREAS LOSS?OF?FUNCTION CTNNB1 MUTATIONS ARE ALSO DETECTED IN HUMAN CANCER. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA AND ZNRF3 ARE REPRESENTATIVE BETA?CATENIN TARGET GENES. BETA?CATENIN SIGNALING IS INVOLVED IN MYOFIBROBLAST ACTIVATION AND SUBSEQUENT PULMONARY FIBROSIS, IN ADDITION TO OTHER TYPES OF FIBROSIS. BETA?CATENIN AND NF?KAPPAB SIGNALING ACTIVATION ARE INVOLVED IN FIELD CANCERIZATION IN THE STOMACH ASSOCIATED WITH HELICOBACTER PYLORI (H. PYLORI) INFECTION AND IN THE LIVER ASSOCIATED WITH HEPATITIS C VIRUS (HCV) INFECTION AND OTHER ETIOLOGIES. BETA?CATENIN?TARGETED THERAPEUTICS ARE FUNCTIONALLY CLASSIFIED INTO BETA?CATENIN INHIBITORS TARGETING UPSTREAM REGULATORS (AZ1366, ETC?159, G007?LK, GNF6231, IPAFRICEPT, NVP?TNKS656, ROSMANTUZUMAB, VANTICTUMAB, WNT?C59, WNT974 AND XAV939), BETA?CATENIN INHIBITORS TARGETING PROTEIN?PROTEIN INTERACTIONS (CGP049090, CWP232228, E7386, ICG?001, LF3 AND PRI?724), BETA?CATENIN INHIBITORS TARGETING EPIGENETIC REGULATORS (PKF118?310), BETA?CATENIN INHIBITORS TARGETING MEDIATOR COMPLEXES (CCT251545 AND CORTISTATIN A) AND BETA?CATENIN INHIBITORS TARGETING TRANSMEMBRANE?TYPE TRANSCRIPTIONAL OUTPUTS, INCLUDING CD44V6, FZD7 AND LGR5. ERADICATING H. PYLORI AND HCV IS THE OPTIMAL APPROACH FOR THE FIRST?LINE PREVENTION OF GASTRIC CANCER AND HEPATOCELLULAR CARCINOMA (HCC), RESPECTIVELY. HOWEVER, BETA?CATENIN INHIBITORS MAY BE APPLICABLE FOR THE PREVENTION OF ORGAN FIBROSIS, SECOND?LINE HCC PREVENTION AND TREATING BETA?CATENIN?DRIVEN CANCER. THE MULTI?LAYERED PREVENTION AND TREATMENT STRATEGY OF BETA?CATENIN?RELATED HUMAN DISEASES IS NECESSARY FOR THE PRACTICE OF PERSONALIZED MEDICINE AND IMPLEMENTATION OF PRECISION MEDICINE.	2018	

2  1937  21 EOMES IS ESSENTIAL FOR ANTITUMOR ACTIVITY OF CD8(+) T CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA. GENOME-WIDE ASSOCIATION STUDIES IDENTIFIED A SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AFFECTING THE TRANSCRIPTION FACTOR EOMESODERMIN (EOMES) ASSOCIATED WITH A SIGNIFICANTLY INCREASED RISK TO DEVELOP CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). EPIGENETIC ANALYSES, RNA SEQUENCING, AND FLOW CYTOMETRY REVEALED THAT EOMES IS NOT EXPRESSED IN CLL CELLS, BUT IN CD8(+) T CELLS FOR WHICH EOMES IS A KNOWN MASTER REGULATOR. WE THUS HYPOTHESIZED THAT THE INCREASED CLL RISK ASSOCIATED WITH THE EOMES SNP MIGHT BE EXPLAINED BY ITS NEGATIVE IMPACT ON CD8(+) T-CELL-MEDIATED IMMUNE CONTROL OF CLL. FLOW CYTOMETRY ANALYSES REVEALED A HIGHER EOMES EXPRESSION IN CD8(+) T CELLS OF CLL PATIENTS COMPARED TO HEALTHY INDIVIDUALS, AND AN ACCUMULATION OF PD-1(+) EOMES(+) CD8(+) T CELLS IN LYMPH NODES RATHER THAN BLOOD OR BONE MARROW IN CLL. THIS WAS IN LINE WITH AN OBSERVED EXPANSION OF EOMES(+) CD8(+) T CELLS IN THE SPLEEN OF LEUKEMIC EMICRO-TCL1 MICE. AS EOMES EXPRESSION WAS HIGHEST IN CD8(+) T CELLS THAT EXPRESS INHIBITORY RECEPTORS, AN INVOLVEMENT OF EOMES IN T-CELL EXHAUSTION AND DYSFUNCTION SEEMS LIKELY. INTERESTINGLY, EOMES-DEFICIENCY IN CD8(+) T CELLS RESULTED IN THEIR IMPAIRED EXPANSION ASSOCIATED WITH DECREASED CLL CONTROL IN MICE. OVERALL, THESE OBSERVATIONS SUGGEST THAT EOMES IS ESSENTIAL FOR CD8(+) T-CELL EXPANSION AND/OR MAINTENANCE, AND THEREFORE INVOLVED IN ADAPTIVE IMMUNE CONTROL OF CLL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  5411  33 REGULATION OF AIRWAY MUCIN GENE EXPRESSION. MUCINS ARE IMPORTANT COMPONENTS THAT EXERT A VARIETY OF FUNCTIONS IN CELL-CELL INTERACTION, EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING, AND AIRWAYS PROTECTION. IN THE CONDUCTING AIRWAYS OF THE LUNGS, MUCINS ARE THE MAJOR CONTRIBUTOR TO THE VISCOELASTIC PROPERTY OF MUCOUS SECRETION, WHICH IS THE MAJOR BARRIER TO TRAPPING INHALED MICROBIAL ORGANISM, PARTICULATES, AND OXIDATIVE POLLUTANTS. THE HOMEOSTASIS OF MUCIN PRODUCTION IS AN IMPORTANT FEATURE IN CONDUCTING AIRWAYS FOR THE MAINTENANCE OF MUCOCILIARY FUNCTION. ABERRANT MUCIN SECRETION AND ACCUMULATION IN AIRWAY LUMEN ARE CLINICAL HALLMARKS ASSOCIATED WITH VARIOUS LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, EMPHYSEMA, AND LUNG CANCER. AMONG 20 KNOWN MUCIN GENES IDENTIFIED, 11 OF THEM HAVE BEEN VERIFIED AT EITHER THE MRNA AND/OR PROTEIN LEVEL IN AIRWAYS. THE REGULATION OF MUCIN GENES IS COMPLICATED, AS ARE THE MEDIATORS AND SIGNALING PATHWAYS. THIS REVIEW SUMMARIZES THE CURRENT VIEW ON THE MEDIATORS, THE SIGNALING PATHWAYS, AND THE TRANSCRIPTIONAL UNITS THAT ARE INVOLVED IN THE REGULATION OF AIRWAY MUCIN GENE EXPRESSION. IN ADDITION, WE ALSO POINT OUT ESSENTIAL FEATURES OF EPIGENETIC MECHANISMS FOR THE REGULATION OF THESE GENES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  5228  29 PRMT7 TARGETS OF FOXM1 CONTROLS ALVEOLAR MYOFIBROBLAST PROLIFERATION AND DIFFERENTIATION DURING ALVEOLOGENESIS. ALTHOUGH ABERRANT ALVEOLAR MYOFIBROBLASTS (AMYFS) PROLIFERATION AND DIFFERENTIATION ARE OFTEN ASSOCIATED WITH ABNORMAL LUNG DEVELOPMENT AND DISEASES, SUCH AS BRONCHOPULMONARY DYSPLASIA (BPD), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND IDIOPATHIC PULMONARY FIBROSIS (IPF), EPIGENETIC MECHANISMS REGULATING PROLIFERATION AND DIFFERENTIATION OF AMYFS REMAIN POORLY UNDERSTOOD. PROTEIN ARGININE METHYLTRANSFERASE 7 (PRMT7) IS THE ONLY REPORTED TYPE III ENZYME RESPONSIBLE FOR MONOMETHYLATION OF ARGININE RESIDUE ON BOTH HISTONE AND NONHISTONE SUBSTRATES. HERE WE PROVIDE EVIDENCE FOR PRMT7'S FUNCTION IN REGULATING AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS. IN PRMT7-DEFICIENT MICE, WE FOUND REDUCED AMYFS PROLIFERATION AND DIFFERENTIATION, ABNORMAL ELASTIN DEPOSITION, AND FAILURE OF ALVEOLAR SEPTUM FORMATION. WE FURTHER SHOWN THAT ONCOGENE FORKHEAD BOX M1 (FOXM1) IS A DIRECT TARGET OF PRMT7 AND THAT PRMT7-CATALYZED MONOMETHYLATION AT HISTONE H4 ARGININE 3 (H4R3ME1) DIRECTLY ASSOCIATE WITH CHROMATIN OF FOXM1 TO ACTIVATE ITS TRANSCRIPTION, AND THEREBY REGULATE OF CELL CYCLE-RELATED GENES TO INHIBIT AMYFS PROLIFERATION AND DIFFERENTIATION. OVEREXPRESSION OF FOXM1 IN ISOLATED MYOFIBROBLASTS (MYFS) SIGNIFICANTLY RESCUED PRMT7-DEFICIENCY-INDUCED CELL PROLIFERATION AND DIFFERENTIATION DEFECTS. THUS, OUR RESULTS REVEAL A NOVEL EPIGENETIC MECHANISM THROUGH WHICH PRMT7-MEDIATED HISTONE ARGININE MONOMETHYLATION ACTIVATES FOXM1 TRANSCRIPTIONAL EXPRESSION TO REGULATE AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS AND MAY REPRESENT A POTENTIAL TARGET FOR INTERVENTION IN PULMONARY DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  1730  38 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE.	2007	
                                                                                                                                                                                                                                                                                                                                 
6  6758  36 WNT SIGNALING IN STEM CELL BIOLOGY AND REGENERATIVE MEDICINE. WNT FAMILY MEMBERS ARE SECRETED-TYPE GLYCOPROTEINS TO ORCHESTRATE EMBRYOGENESIS, TO MAINTAIN HOMEOSTASIS, AND TO INDUCE PATHOLOGICAL CONDITIONS. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, AND ROR2 ARE TRANSMEMBRANE RECEPTORS TRANSDUCING WNT SIGNALS BASED ON LIGAND-DEPENDENT PREFERENTIALITY FOR CAVEOLIN- OR CLATHRIN-MEDIATED ENDOCYTOSIS. WNT SIGNALS ARE TRANSDUCED TO CANONICAL PATHWAY FOR CELL FATE DETERMINATION, AND TO NON-CANONICAL PATHWAYS FOR REGULATION OF PLANAR CELL POLARITY, CELL ADHESION, AND MOTILITY. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 AND GLUCAGON ARE TARGET GENES OF CANONICAL WNT SIGNALING CASCADE, WHILE CD44, VIMENTIN AND STX5 ARE TARGET GENES OF NON-CANONICAL WNT SIGNALING CASCADES. HOWEVER, TARGET GENES OF WNT SIGNALING CASCADES ARE DETERMINED IN A CONTEXT-DEPENDENT MANNER DUE TO EXPRESSION PROFILE OF TRANSCRIPTION FACTORS AND EPIGENETIC STATUS. WNT SIGNALING CASCADES NETWORK WITH NOTCH, FGF, BMP AND HEDGEHOG SIGNALING CASCADES TO REGULATE THE BALANCE OF STEM CELLS AND PROGENITOR CELLS. HERE WNT SIGNALING IN EMBRYONIC STEM CELLS, NEURAL STEM CELLS, MESENCHYMAL STEM CELLS, HEMATOPOIETIC STEM CELLS, AND INTESTINAL STEM CELLS WILL BE REVIEWED. WNT3, WNT5A AND WNT10B ARE EXPRESSED IN UNDIFFERENTIATED HUMAN EMBRYONIC STEM CELLS, WHILE WNT6, WNT8B AND WNT10B IN ENDODERM PRECURSOR CELLS. WNT6 IS EXPRESSED IN INTESTINAL CRYPT REGION FOR STEM OR PROGENITOR CELLS. TNF/ALPHA-WNT10B SIGNALING IS A NEGATIVE FEEDBACK LOOP TO MAINTAIN HOMEOSTASIS OF ADIPOSE TISSUE AND GASTROINTESTINAL MUCOSA WITH CHRONIC INFLAMMATION. RECOMBINANT WNT PROTEIN OR WNT MIMETIC (CIRCULAR PEPTIDE, SMALL MOLECULE COMPOUND, OR RNA APTAMER) IN COMBINATION WITH NOTCH MIMETIC, FGF PROTEIN, AND BMP PROTEIN OPENS A NEW WINDOW TO TISSUE ENGINEERING FOR REGENERATIVE MEDICINE.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7   201  26 ACTIVATING TRANSCRIPTION FACTOR 3 PROTECTS AGAINST PRESSURE-OVERLOAD HEART FAILURE VIA THE AUTOPHAGY MOLECULE BECLIN-1 PATHWAY. ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3), A CAMP RESPONSE ELEMENT-BINDING PROTEIN/ATF FAMILY TRANSCRIPTION FACTORS MEMBER, HAS BEEN IMPLICATED IN THE CARDIOVASCULAR AND INFLAMMATORY SYSTEM AND IS RAPIDLY INDUCED BY ISCHEMIC-REPERFUSION INJURIES. WE PERFORMED TRANSVERSE AORTIC BANDING (TAB) EXPERIMENTS USING ATF3 GENE-DELETED MICE (ATF3(-/-)) AND WILD-TYPE (WT) MICE TO DETERMINE WHAT EFFECT IT MIGHT HAVE ON HEART FAILURE INDUCED BY PRESSURE OVERLOADING. COMPARED WITH THE WT MICE, ATF3(-/-) MICE WERE FOUND BY ECHOCARDIOGRAPHY TO HAVE DECREASED LEFT VENTRICULAR CONTRACTILITY WITH LOSS OF NORMAL CARDIAC HYPERTROPHIC REMODELING. THE ATF3(-/-) MICE HAD GREATER NUMBERS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-DEOXYURIDINE NICK-END LABELING-POSITIVE CELLS AND HIGHER LEVELS OF ACTIVATED CASPASE-3, AS WELL AS MORE APOPTOSIS. RESTORATION OF ATF3 EXPRESSION IN THE HEART OF ATF3(-/-) MICE BY ADENOVIRUS-INDUCED ATF3 TREATMENT SIGNIFICANTLY IMPROVED CARDIAC CONTRACTILITY AFTER TAB. THE RESULTS FROM MOLECULAR AND BIOCHEMICAL ANALYSES, INCLUDING CHROMATIN IMMUNE-PRECIPITATION AND IN VITRO /IN VIVO PROMOTER ASSAYS, SHOWED THAT ATF3 BOUND TO THE ATF/CAMP RESPONSE ELEMENT OF THE BECLIN-1 PROMOTER AND THAT ATF3 REDUCED AUTOPHAGY VIA SUPPRESSION OF THE BECLIN-1-DEPENDENT PATHWAY. FURTHERMORE, INFUSION OF TERT-BUTYLHYDROQUINONE (TBHQ), A SELECTIVE ATF3 INDUCER, INCREASED THE EXPRESSION OF ATF3 VIA THE NUCLEAR FACTOR ERYTHROID 2-RELATED TRANSCRIPTIONAL FACTOR, INHIBITED TAB-INDUCED CARDIAC DILATATION, AND INCREASED LEFT VENTRICULAR CONTRACTILITY, THEREBY RESCUING HEART FAILURE. OUR STUDY IDENTIFIED A NEW EPIGENETIC REGULATION MEDIATED BY THE STRESS-INDUCIBLE GENE ATF3 ON TAB-INDUCED CARDIAC DYSFUNCTION. THESE FINDINGS SUGGEST THAT THE ATF3 ACTIVATOR TBHQ MAY HAVE THERAPEUTIC POTENTIAL FOR THE TREATMENT OF PRESSURE-OVERLOAD HEART FAILURE INDUCED BY CHRONIC HYPERTENSION OR OTHER PRESSURE OVERLOAD MECHANISMS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  5867  34 SUPPRESSIVE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON HEPATITIS C VIRUS REPLICATION. THE HISTONE DEACETYLASE (HDAC) INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) HAS A CLINICAL PROMISE FOR TREATMENT OF CANCER INCLUDING HEPATOCELLULAR CARCINOMA (HCC). TO INVESTIGATE EFFECT OF SAHA ON HEPATITIS C VIRUS (HCV) REPLICATION, WE TREATED THE HCV REPLICON CELL OR6 WITH SAHA. HCV REPLICATION WAS SIGNIFICANTLY INHIBITED BY SAHA AT CONCENTRATIONS BELOW 1 MUM WITH NO CELLULAR TOXICITY. ANOTHER HDAC INHIBITOR, TRICOSTATIN A, ALSO SHOWED REDUCTION OF HCV REPLICATION. THE MICROARRAY ANALYSIS AND QUANTITATIVE RT-PCR DEMONSTRATED UP-REGULATION OF OSTEOPONTIN (OPN) AND DOWN-REGULATION OF APOLIPOPROTEIN-A1 (APO-A1) AFTER SAHA TREATMENT. DIRECT GENE INDUCTION OF OPN AND KNOCKDOWN OF APO-A1 ALSO SHOWED REDUCTION OF HCV REPLICATION. THE LIVER SPECIFIC MICRORNA-122, WHICH IS INVOLVED IN HCV REPLICATION, WAS NOT AFFECTED BY SAHA TREATMENT. THESE RESULTS SUGGEST THAT SAHA HAS SUPPRESSIVE EFFECT ON HCV REPLICATION THROUGH ALTERATIONS OF GENE EXPRESSION SUCH AS OPN AND APO-A1 IN HOST CELLS. EPIGENETIC TREATMENT WITH HDAC INHIBITORS MAY BE A NOVEL THERAPEUTIC APPROACH FOR DISEASES ASSOCIATED WITH HCV INFECTION SUCH AS CHRONIC HEPATITIS, LIVER CIRRHOSIS, AND HCC.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  4296  29 MICRORNA-1 MODULATES CHONDROCYTE PHENOTYPE BY REGULATING FZD7 OF WNT/ BETA-CATENIN SIGNALING PATHWAY. OBJECTIVE: OSTEOARTHRITIS (OA) IS AN INCURABLE JOINT DISEASE CHARACTERIZED BY PRONOUNCED PAIN. MICRORNAS CONSTITUTE EPIGENETIC MECHANISMS THAT MAY AFFECT OA PROGRESSION BY CONTRIBUTING TO CHANGES IN CHONDROCYTE PHENOTYPE. THIS STUDY INVESTIGATES FOR THE FIRST TIME WHETHER THERE IS A LINK BETWEEN MIRNA-1 (MIR-1) AND OA PATHOGENESIS, AND THE MOLECULAR MECHANISMS INVOLVED. DESIGN: OA-ASSOCIATED GENE EXPRESSION, INCLUDING MMP-13, ADAMTS5, AND COL2A1 WAS COMPARED IN CHONDROCYTES FROM NON-OA AND OA CARTILAGE, AND IN SW1353 CELLS OVER- AND UNDEREXPRESSING MIR-1. BIOINFORMATICS AND LUCIFERASE REPORTER ASSAY WERE CONDUCTED TO CONFIRM WHETHER FZD7 WAS A TARGET OF MIR-1. THE EFFECTS OF MIR-1 ON FZD7 EXPRESSION AND DOWNSTREAM WNT/BETA-CATENIN SIGNALLING WERE INVESTIGATED. RESULTS: NON-OA AND OA CHONDROCYTES DIFFERED SIGNIFICANTLY IN THE EXPRESSION OF MIR-1 AND OA-ASSOCIATED GENES. MIR-1 OVER- AND UNDEREXPRESSION IN SW1353 CELLS, RESPECTIVELY, REDUCED AND ENHANCED GENE EXPRESSION ASSOCIATED WITH CARTILAGE CATABOLISM. FZD7, WHICH HAS AN IMPORTANT ROLE IN THE WNT/BETA-CATENIN SIGNALING PATHWAY, WAS SHOWN TO BE A POTENTIAL TARGET OF MIR-1. MIR-1 BINDING TO FZD7 INCREASED THE LEVELS OF PHOSPHORYLATED (INACTIVATED) BETA-CATENIN, THEREBY PREVENTING DOWNSTREAM BETA-CATENIN SIGNALING. CONCLUSIONS: INHIBITION OF WNT/BETA-CATENIN SIGNALING BY MIR-1 IN CHONDROCYTES MAY ATTENUATE THE EXPRESSION OF GENES THAT REGULATE THE ACTIVITY OF CATABOLIC ENZYMES. THIS FINDING MAY BE USEFUL FOR FUTURE INVESTIGATIONS OF MOLECULAR TARGETS FOR OA TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  4000  24 LOSS OF HISTONE H3 K79 METHYLTRANSFERASE DOT1L FACILITATES KIDNEY FIBROSIS BY UPREGULATING ENDOTHELIN 1 THROUGH HISTONE DEACETYLASE 2. BACKGROUND: THE PROGRESSION RATE OF CKD VARIES SUBSTANTIALLY AMONG PATIENTS. THE GENETIC AND EPIGENETIC CONTRIBUTIONS THAT MODIFY HOW INDIVIDUAL PATIENTS RESPOND TO KIDNEY INJURY ARE LARGELY UNKNOWN. EMERGING EVIDENCE HAS SUGGESTED THAT HISTONE H3 K79 METHYLTRANSFERASE DOT1L HAS AN ANTIFIBROTIC EFFECT BY REPRESSING EDN1, WHICH ENCODES ENDOTHELIN 1 IN THE CONNECTING TUBULE/COLLECTING DUCT. METHODS: TO DETERMINE IF DELETION OF THE DOT1L GENE IS A GENETIC AND EPIGENETIC RISK FACTOR THROUGH REGULATING EDN1, WE STUDIED FOUR GROUPS OF MICE: WILD-TYPE MICE, CONNECTING TUBULE/COLLECTING DUCT-SPECIFIC DOT1L CONDITIONAL KNOCKOUT MICE (DOT1L(AC) ), DOT1L AND EDN1 DOUBLE-KNOCKOUT MICE (DE(AC) ), AND EDN1 CONNECTING TUBULE/COLLECTING DUCT-SPECIFIC CONDITIONAL KNOCKOUT MICE (EDN1(AC) ), UNDER THREE EXPERIMENTAL CONDITIONS (STREPTOZOTOCIN-INDUCED DIABETES, DURING NORMAL AGING, AND AFTER UNILATERAL URETERAL OBSTRUCTION). WE USED SEVERAL APPROACHES (COLOCALIZATION, GLUTATHIONE S-TRANSFERASE PULLDOWN, COIMMUNOPRECIPITATION, YEAST TWO-HYBRID, GEL SHIFT, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS) TO IDENTIFY AND CONFIRM INTERACTION OF DOT1A (THE MAJOR DOT1L SPLICING VARIANT IN THE MOUSE KIDNEY) WITH HISTONE DEACETYLASE 2 (HDAC2), AS WELL AS THE FUNCTION OF THE DOT1A-HDAC2 COMPLEX IN REGULATING EDN1 TRANSCRIPTION. RESULTS: IN EACH CASE, DOT1L(AC) MICE DEVELOPED MORE PRONOUNCED KIDNEY FIBROSIS AND KIDNEY MALFUNCTION COMPARED WITH WILD-TYPE MICE. THESE DOT1L(AC) PHENOTYPES WERE AMELIORATED IN THE DOUBLE-KNOCKOUT DE(AC) MICE. THE INTERACTION BETWEEN DOT1A AND HDAC2 PREVENTS THE DOT1A-HDAC2 COMPLEX FROM ASSOCIATION WITH DNA, PROVIDING A COUNTERBALANCING MECHANISM GOVERNING EDN1 TRANSCRIPTION BY MODULATING H3 K79 DIMETHYLATION AND H3 ACETYLATION AT THE EDN1 PROMOTER. CONCLUSIONS: OUR STUDY CONFIRMS DOT1L TO BE A GENETIC AND EPIGENETIC MODIFIER OF KIDNEY FIBROSIS, REVEALS A NEW MECHANISM REGULATING EDN1 TRANSCRIPTION BY DOT1A AND HDAC2, AND REINFORCES ENDOTHELIN 1 AS A THERAPEUTIC TARGET OF KIDNEY FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  2844  33 FREQUENT EPIGENETIC INACTIVATION OF SFRP GENES IN HEPATOCELLULAR CARCINOMA. BACKGROUND: ACTIVATION OF THE WNT SIGNALING PATHWAY IS FREQUENTLY OBSERVED IN HEPATOCELLULAR CARCINOMA (HCC), THOUGH MUTATION OF THREE OF ITS COMPONENTS, CTNNB1, AXIN1, AND AXIN2, IS OBSERVED SUBSTANTIALLY LESS OFTEN. METHODS: WE EXAMINED THE RELATIONSHIP BETWEEN WNT SIGNALING AND EPIGENETIC ALTERATION OF SECRETED FRIZZLED-RELATED PROTEIN (SFRP) GENES IN HCC. RESULTS: WE FREQUENTLY DETECTED THE ACTIVE FORM OF BETA-CATENIN AND ACCUMULATION OF NUCLEAR BETA-CATENIN IN LIVER CANCER CELL LINES. WE DETECTED METHYLATION OF SFRP FAMILY GENES IN LIVER CANCER CELL LINES (SFRP1, 9/12, 75%; SFRP2, 7/12, 58%; SFRP4, 3/12, 25%; SFRP5, 7/12, 58%) AND PRIMARY HCCS (SFRP1, 9/19, 47%; SFRP2, 12/19, 63%; SFRP5, 8/19, 42%), THOUGH METHYLATION OF SFRP4 WAS NOT FOUND IN PRIMARY HCCS. SFRP METHYLATION ALSO WAS DETECTED IN HEPATITIS B OR C VIRUS-ASSOCIATED CHRONIC HEPATITIS (SFRP1, 6/37, 16%; SFRP2, 14/37, 38%; SFRP5, 5/37, 14%) AND LIVER CIRRHOSIS (SFRP1, 10/28, 36%; SFRP2, 9/28, 32%; SFRP5, 3/28, 11%), SUGGESTING THAT METHYLATION OF THESE GENES IS AN EARLY EVENT IN LIVER CARCINOGENESIS. ECTOPIC EXPRESSION OF SFRPS DOWNREGULATED T-CELL FACTOR/LYMPHOCYTE ENHANCER FACTOR (TCF/LEF) TRANSCRIPTIONAL ACTIVITY IN LIVER CANCER CELLS, WHILE OVEREXPRESSION OF A BETA-CATENIN MUTANT AND DEPLETION OF SFRP1 USING SIRNA SYNERGISTICALLY UPREGULATED TCF/LEF TRANSCRIPTIONAL ACTIVITY. CONCLUSIONS: OUR RESULTS CONFIRM THE FREQUENT METHYLATION AND SILENCING OF WNT ANTAGONIST GENES IN HCC, AND SUGGEST THAT THEIR LOSS OF FUNCTION CONTRIBUTES TO ACTIVATION OF WNT SIGNALING DURING HEPATOCARCINOGENESIS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  2811  37 FGFR2-RELATED PATHOGENESIS AND FGFR2-TARGETED THERAPEUTICS (REVIEW). FGFR2 GENE AT HUMAN CHROMOSOME 10Q26 ENCODES FGFR2B AND FGFR2C ISOFORMS FUNCTIONING AS FGF RECEPTORS WITH DISTINCT EXPRESSION DOMAIN AND LIGAND SPECIFICITY. FGFR2 PLAYS ONCOGENIC AND ANTI-ONCOGENIC ROLES IN A CONTEXT-DEPENDENT MANNER. SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITHIN INTRON 2 OF FGFR2 GENE ARE ASSOCIATED WITH BREAST CANCER THROUGH ALLELIC FGFR2 UPREGULATION. MISSENSE MUTATIONS OR COPY NUMBER GAINS OF FGFR2 GENE OCCUR IN BREAST CANCER AND GASTRIC CANCER TO ACTIVATE FGFR2 SIGNALING. ABERRANT FGFR2 SIGNALING ACTIVATION INDUCES PROLIFERATION AND SURVIVAL OF TUMOR CELLS. THE CLASS SWITCH FROM FGFR2B TO FGFR2C OCCURS DURING PROGRESSION OF PROSTATE CANCER AND BLADDER CANCER BECAUSE OF SPLICEOSOME DYSREGULATION. IN ADDITION, EPIDERMAL FGFR2B KNOCKOUT MICE SHOW INCREASED SENSITIVITY TO CHEMICAL CARCINOGENESIS PARTLY DUE TO THE FAILURE OF NFE2L2 (NRF2)-MEDIATED DETOXIFICATION OF REACTIVE OXYGEN SPECIES (ROS). LOSS OF FGFR2B SIGNALING INDUCES EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND UNRULY ROS. FGFR2 SIGNALING DYSREGULATION DUE TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS AND GENETIC ALTERATIONS DURING CHRONIC INFLAMMATION, SMOKING, INCREASED CALORIC UPTAKE, AND DECREASED EXERCISE LEADS TO CARCINOGENESIS. PD173074, SU5402, AZD2171, AND KI23057 ARE SMALL-MOLECULE FGFR INHIBITORS. HUMAN ANTIBODY, PEPTIDE MIMETIC, RNA APTAMER, SIRNA, AND SYNTHETIC MICRORNA (MIRNA) ARE EMERGING TECHNOLOGIES TO BE APPLIED FOR CANCER THERAPEUTICS TARGETED TO FGFR2. BECAUSE NOVEL SEQUENCE TECHNOLOGY AND PETA-SCALE SUPER-COMPUTER ARE OPENING UP THE SEQUENCE ERA FOLLOWING THE GENOME ERA, PERSONALIZED MEDICINE PRESCRIBING TARGETED DRUGS BASED ON GERMLINE AND/OR SOMATIC GENOMIC INFORMATION IS COMING REALITY. APPLICATION OF FGFR2 INHIBITORS FOR CANCER TREATMENT IN PATIENTS WITH FGFR2 MUTATION OR GENE AMPLIFICATION IS BENEFICIAL; HOWEVER, THAT FOR CANCER PREVENTION IN PEOPLE WITH FGFR2 RISK ALLELE MIGHT BE DISADVANTAGEOUS DUE TO THE IMPEDIMENT OF A CYTOPROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   134  20 ABCB1 REGULATION THROUGH LRPPRC IS INFLUENCED BY THE METHYLATION STATUS OF THE GC -100 BOX IN ITS PROMOTER. ONE OF THE POTENTIAL MECHANISMS OF IMATINIB MESYLATE (IM) RESISTANCE IN CHRONIC MYELOID LEUKEMIA (CML) IS INCREASED LEVEL OF P-GLYCOPROTEIN (PGP). PGP IS AN EFFLUX PUMP CAPABLE OF ACTIVATING THE MULTIDRUG RESISTANCE (MDR) PHENOTYPE. THE GENE ENCODING PGP (ABCB1) HAS SEVERAL BINDING SITES IN ITS PROMOTER REGION, ALONG WITH CPG ISLANDS AND GC BOXES, INVOLVED IN ITS EPIGENETIC CONTROL. IN PREVIOUS WORK, WE PERFORMED A PROTEOMIC STUDY TO IDENTIFY PROTEINS INVOLVED IN IM CROSS-RESISTANCE IN ACUTE LEUKEMIA. AMONG THESE PROTEINS, WE IDENTIFIED LRPPRC AS A POTENTIAL REGULATOR OF ABCB1 TRANSCRIPTION VIA AN INVMED1 BINDING SITE IN ABCB1. INTERESTINGLY, THIS INVMED1 BINDING SITE OVERLAPS WITH THE GC -100 BOX. IN THIS WORK, WE INVESTIGATED THE POTENTIAL ROLE OF LRPPRC IN THE REGULATION OF ABCB1 TRANSCRIPTIONAL ACTIVITY IN CML RESISTANCE. IN ADDITION, WE EVALUATED THE POTENTIAL CONNECTION BETWEEN THIS REGULATION AND THE METHYLATION STATUS OF THE ABCB1 PROMOTER IN ITS GC -100 BOX. OUR RESULTS SHOW THAT LRPPRC BINDS PROMINENTLY TO THE ABCB1 PROMOTER IN LUCENA CELLS, AN IM-RESISTANT CELL LINE. LUCIFERASE ASSAYS SHOWED THAT ABCB1 TRANSCRIPTION IS POSITIVELY REGULATED BY LRPPRC UPON ITS KNOCKDOWN. PYROSEQUENCING ANALYSIS SHOWED THAT THE ABCB1 PROMOTER IS DIFFERENTIALLY METHYLATED AT ITS GC -100 BOX IN K562 CELLS COMPARED WITH LUCENA CELLS, AND IN CML PATIENTS WITH DIFFERENT RESPONSE TO IM. CHROMATIN IMMUNOPRECIPITATION AND PGP EXPRESSION AFTER DNA DEMETHYLATION TREATMENT SHOWED THAT LRPPRC BINDING IS AFFECTED BY THE METHYLATION STATUS OF ABCB1 GC -100 BOX. TAKEN TOGETHER, OUR FINDINGS INDICATE THAT LRPPRC IS A TRANSCRIPTION FACTOR RELATED TO ABCB1 EXPRESSION AND HIGHLIGHT THE IMPORTANCE OF EPIGENETIC REGULATION IN CML RESISTANCE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  6709  23 VIRAL TRANSDUCTION OF PRIMARY HUMAN LYMPHOMA B CELLS REVEALS MECHANISMS OF NOTCH-MEDIATED IMMUNE ESCAPE. HOTSPOT MUTATIONS IN THE PEST-DOMAIN OF NOTCH1 AND NOTCH2 ARE RECURRENTLY IDENTIFIED IN B CELL MALIGNANCIES. TO ADDRESS HOW NOTCH-MUTATIONS CONTRIBUTE TO A DISMAL PROGNOSIS, WE HAVE GENERATED ISOGENIC PRIMARY HUMAN TUMOR CELLS FROM PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL), DIFFERING ONLY IN THEIR EXPRESSION OF THE INTRACELLULAR DOMAIN (ICD) OF NOTCH1 OR NOTCH2. OUR DATA DEMONSTRATE THAT BOTH NOTCH-PARALOGS FACILITATE IMMUNE-ESCAPE OF MALIGNANT B CELLS BY UP-REGULATING PD-L1, PARTLY DEPENDENT ON AUTOCRINE INTERFERON-GAMMA SIGNALING. IN ADDITION, NOTCH-ACTIVATION CAUSES SILENCING OF THE ENTIRE HLA-CLASS II LOCUS VIA EPIGENETIC REGULATION OF THE TRANSCRIPTIONAL CO-ACTIVATOR CIITA. NOTABLY, WHILE NOTCH1 AND NOTCH2 GOVERN SIMILAR TRANSCRIPTIONAL PROGRAMS, DISEASE-SPECIFIC DIFFERENCES IN THEIR EXPRESSION LEVELS CAN FAVOR PARALOG-SPECIFIC SELECTION. IMPORTANTLY, NOTCH-ICD ALSO STRONGLY DOWN-REGULATES THE EXPRESSION OF CD19, POSSIBLY LIMITING THE EFFECTIVENESS OF IMMUNE-THERAPIES. THESE NOTCH-MEDIATED IMMUNE ESCAPE MECHANISMS ARE ASSOCIATED WITH THE EXPANSION OF EXHAUSTED CD8(+) T CELLS IN VIVO.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15   234  32 ADDICTION OF CANCER STEM CELLS TO MUC1-C IN TRIPLE-NEGATIVE BREAST CANCER PROGRESSION. TRIPLE-NEGATIVE BREAST CANCER (TNBC) IS AN AGGRESSIVE MALIGNANCY WITH LIMITED TREATMENT OPTIONS. TNBC PROGRESSION IS ASSOCIATED WITH EXPANSION OF CANCER STEM CELLS (CSCS). FEW INSIGHTS ARE AVAILABLE REGARDING DRUGGABLE TARGETS THAT DRIVE THE TNBC CSC STATE. THIS REVIEW SUMMARIZES THE LITERATURE ON TNBC CSCS AND THE COMPELLING EVIDENCE THAT THEY ARE ADDICTED TO THE MUC1-C TRANSMEMBRANE PROTEIN. IN NORMAL EPITHELIA, MUC1-C IS ACTIVATED BY LOSS OF HOMEOSTASIS AND INDUCES REVERSIBLE WOUND-HEALING RESPONSES OF INFLAMMATION AND REPAIR. HOWEVER, IN SETTINGS OF CHRONIC INFLAMMATION, MUC1-C PROMOTES CARCINOGENESIS. MUC1-C INDUCES EMT, EPIGENETIC REPROGRAMMING AND CHROMATIN REMODELING IN TNBC CSCS, WHICH ARE DEPENDENT ON MUC1-C FOR SELF-RENEWAL AND TUMORIGENICITY. MUC1-C-INDUCED LINEAGE PLASTICITY IN TNBC CSCS CONFERS DNA DAMAGE RESISTANCE AND IMMUNE EVASION BY CHRONIC ACTIVATION OF INFLAMMATORY PATHWAYS AND GLOBAL CHANGES IN CHROMATIN ARCHITECTURE. OF THERAPEUTIC SIGNIFICANCE, AN ANTIBODY GENERATED AGAINST THE MUC1-C EXTRACELLULAR DOMAIN HAS BEEN ADVANCED IN A CLINICAL TRIAL OF ANTI-MUC1-C CAR T CELLS AND IN IND-ENABLING STUDIES FOR DEVELOPMENT AS AN ANTIBODY-DRUG CONJUGATE (ADC). AGENTS TARGETING THE MUC1-C CYTOPLASMIC DOMAIN HAVE ALSO ENTERED THE CLINIC AND ARE UNDERGOING FURTHER DEVELOPMENT AS CANDIDATES FOR ADVANCING TNBC TREATMENT. ELIMINATING TNBC CSCS WILL BE NECESSARY FOR CURING THIS RECALCITRANT CANCER AND MUC1-C REPRESENTS A PROMISING DRUGGABLE TARGET FOR ACHIEVING THAT GOAL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  1483  22 DKK1 IS EPIGENETICALLY DOWNREGULATED BY PROMOTER METHYLATION AND INHIBITS BILE ACID-INDUCED GASTRIC INTESTINAL METAPLASIA. DICKKOPF-RELATED PROTEIN 1 (DKK1) IS ESSENTIAL TO GASTRIC CANCER AS AN INHIBITOR OF WNT SIGNALING. GASTRIC INTESTINAL METAPLASIA (GIM) IS AN IMPORTANT PRECANCEROUS LESION OF GASTRIC CANCER THAT CAN BE ACTIVATED BY BILE ACID REFLUX AND CHRONIC INFLAMMATION. HOWEVER, THE EXACT MECHANISM OF DKK1 IN BILE ACID-INDUCED GIM HAS NOT BEEN COMPLETELY ELUCIDATED. WE AIMED TO EXPLORE THE EPIGENETIC ALTERATIONS AND BIOLOGICAL FUNCTIONS OF DKK1 IN THE DEVELOPMENT OF GIM. IN THE PRESENT STUDY, BILE ACID WAS FOUND TO INDUCE THE EXPRESSION OF INTESTINAL MARKERS IN GASTRIC EPITHELIAL CELLS, WHEREAS DKK1 WAS DOWNREGULATED IN RESPONSE TO BILE ACID STIMULATION. THE MRNA AND PROTEIN EXPRESSION LEVELS OF DKK1 WERE DECREASED IN GIM TISSUES AS EVIDENCED BY QRT-PCR AND IMMUNOHISTOCHEMICAL STAINING. SURPRISINGLY, THE METHYLATION OF THE DKK1 PROMOTER INCREASED IN GIM TISSUES, AND WE DISCOVERED 28 DIFFERENTIAL METHYLATION SITES OF THE DKK1 PROMOTER IN GIM TISSUES. BILE ACID WAS ABLE TO INDUCE THE PARTIAL METHYLATION OF THE DKK1 PROMOTER, WHILE 5-AZA COULD INCREASE DKK1 EXPRESSION AS WELL AS DECREASE INTESTINAL MARKERS EXPRESSION IN GASTRIC EPITHELIAL CELLS. IN CONCLUSION, THE PROMOTER METHYLATION AND DOWNREGULATION OF DKK1 MIGHT PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF GIM, ESPECIALLY BILE ACID-INDUCED GIM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  5103  21 POLYCOMB YY1 IS A CRITICAL INTERFACE BETWEEN EPIGENETIC CODE AND MIRNA MACHINERY AFTER EXPOSURE TO HYPOXIA IN MALIGNANCY. YIN YANG 1 (YY1) IS A MEMBER OF POLYCOMB PROTEIN FAMILY INVOLVED IN EPIGENETIC MODIFICATIONS AND TRANSCRIPTIONAL CONTROLS. WE HAVE SHOWN THAT YY1 ACTS AS POSITIVE REGULATOR OF TUMOR GROWTH AND ANGIOGENESIS BY INTERFERING WITH THE VEGFA NETWORK. YET, THE LINK BETWEEN POLYCOMB CHROMATIN COMPLEX AND HYPOXIA REGULATION OF VEGFA IS STILL POORLY UNDERSTOOD. HERE, WE ESTABLISH THAT HYPOXIA IMPAIRS YY1 BINDING TO VEGFA MRNA 3'UTR (P<0.001) IN BONE MALIGNANCY. MOREOVER, RNA IMMUNOPRECIPITATION REVEALS THE FORMATION OF TRIPLEX NUCLEAR COMPLEXES AMONG YY1, VEGFA DNA, MRNA, AND UNREACHED ABOUT 200 FOLD PRIMIRNA 200B AND 200C VIA DICER PROTEIN. IN THIS COMPLEX, YY1 IS NECESSARY TO MAINTAIN THE STEADY-STATE LEVEL OF VEGFA EXPRESSION WHILE ITS SILENCING INCREASES VEGFA MRNA HALF-LIFE AT 4 H AND IMPAIRS THE MATURATION OF MIRNA 200B/C. HYPOXIA PROMOTES HISTONE MODIFICATION THROUGH UBIQUITINATION BOTH OF YY1 AND DICER PROTEINS. HYPOXIA-MEDIATED DOWN-REGULATION OF YY1 AND DICER CHANGES POST-TRANSCRIPTIONAL VEGFA REGULATION BY RESULTING IN THE ACCUMULATION OF PRIMIRNA200B/C IN COMPARISON TO MATURE MIRNAS (P<0.001). GIVEN THE REGULATORY FUNCTIONS OF VEGFA ON CELLULAR ACTIVITIES TO PROMOTE NEOANGIOGENESIS, WE CONCLUDE THAT YY1 ACTS AS NOVEL CRITICAL INTERFACE BETWEEN EPIGENETIC CODE AND MIRNAS MACHINERY UNDER CHRONIC HYPOXIA IN MALIGNANCY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  3216  37 HEDGEHOG SIGNALING PATHWAY AND GASTROINTESTINAL STEM CELL SIGNALING NETWORK (REVIEW). HEDGEHOG, BMP/TGFBETA, FGF, WNT AND NOTCH SIGNALING PATHWAYS CONSTITUTE THE STEM CELL SIGNALING NETWORK, WHICH PLAYS A KEY ROLE IN A VARIETY OF PROCESSES, SUCH AS EMBRYOGENESIS, MAINTENANCE OF ADULT TISSUE HOMEOSTASIS, TISSUE REPAIR DURING CHRONIC PERSISTENT INFLAMMATION, AND CARCINOGENESIS. SONIC HEDGEHOG (SHH), INDIAN HEDGEHOG (IHH) AND DESERT HEDGEHOG (DHH) BIND TO PTCH1/PTCH OR PTCH2 RECEPTOR TO RELEASE SMOOTHENED (SMO) SIGNAL TRANSDUCER FROM PATCHED-DEPENDENT SUPPRESSION. SMO THEN ACTIVATES STK36 SERINE/THREONINE KINASE TO STABILIZE GLI FAMILY MEMBERS AND TO PHOSPHORYLATE SUFU FOR NUCLEAR ACCUMULATION OF GLI. HEDGEHOG SIGNALING ACTIVATION LEADS TO GLI-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF TARGET GENES, SUCH AS GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1. GLI1-DEPENDENT POSITIVE FEEDBACK LOOP COMBINED WITH PTCH1-DEPENDENT NEGATIVE FEEDBACK LOOP GIVES RISE TO TRANSIENT PROLIFERATION OF HEDGEHOG TARGET CELLS. IGUANA HOMOLOGS (DZIP1 AND DZIP1L) AND COSTAL-2 HOMOLOGS (KIF7 AND KIF27) ARE IDENTIFIED BY COMPARATIVE INTEGROMICS. SHH-DEPENDENT PARIETAL CELL PROLIFERATION IS IMPLICATED IN GASTRIC MUCOSAL REPAIR DURING CHRONIC HELICOBACTER PYLORI INFECTION. BMP-RUNX3 SIGNALING INDUCES IHH EXPRESSION IN SURFACE DIFFERENTIATED EPITHELIAL CELLS OF STOMACH AND INTESTINE. HEDGEHOG SIGNALS FROM EPITHELIAL CELLS THEN INDUCES FOXL1-MEDIATED BMP4 UPREGULATION IN MESENCHYMAL CELLS. HEDGEHOG SIGNALING IS FREQUENTLY ACTIVATED IN ESOPHAGEAL CANCER, GASTRIC CANCER AND PANCREATIC CANCER DUE TO TRANSCRIPTIONAL UPREGULATION OF HEDGEHOG LIGANDS AND EPIGENETIC SILENCING OF HHIP1/HHIP GENE, ENCODING THE HEDGEHOG INHIBITOR. HOWEVER, HEDGEHOG SIGNALING IS RARELY ACTIVATED IN COLORECTAL CANCER DUE TO NEGATIVE REGULATION BY THE CANONICAL WNT SIGNALING PATHWAY. HEDGEHOG SIGNALING MOLECULES OR TARGETS, SUCH AS SHH, IHH, HHIP1, PTCH1 AND GLI1, ARE APPLIED AS BIOMARKERS FOR CANCER DIAGNOSTICS, PROGNOSTICS AND THERAPEUTICS. SMALL-MOLECULE INHIBITORS FOR SMO OR STK36 ARE SUITABLE TO BE USED FOR TREATMENT OF HEDGEHOG-DEPENDENT CANCER.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19   333  17 ALTERATION OF PTGS2 PROMOTER METHYLATION IN CHRONIC PERIODONTITIS. LEVELS OF PROSTAGLANDIN E(2) AND THE PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE-2 (PTGS2, OR COX-2) INCREASE IN ACTIVELY PROGRESSING PERIODONTAL LESIONS, BUT DECREASE IN CHRONIC DISEASE. WE HYPOTHESIZED THAT CHRONIC INFLAMMATION IS ASSOCIATED WITH ALTERED DNA METHYLATION LEVELS WITHIN THE PTGS2 PROMOTER, WITH EFFECTS ON COX-2 MRNA EXPRESSION. PTGS2 PROMOTER METHYLATION LEVELS FROM PERIODONTALLY INFLAMED GINGIVAL BIOPSIES SHOWED A 5.06-FOLD INCREASE AS COMPARED WITH NON-INFLAMED SAMPLES (P = 0.03), AND THE ODDS OF METHYLATION IN A CPG SITE IN THE INFLAMED GINGIVAL GROUP IS 4.46 TIMES HIGHER THAN IN THE SAME SITE IN THE NON-INFLAMED GROUP (P = 0.016). THE LEVEL OF METHYLATION AT -458 BP WAS INVERSELY ASSOCIATED WITH TRANSCRIPTIONAL LEVELS OF PTGS2 (RT-PCR) (P = 0.01). ANALYSIS OF THE DATA SUGGESTS THAT, IN CHRONICALLY INFLAMED TISSUES, THERE IS A HYPERMETHYLATION PATTERN OF THE PTGS2 PROMOTER IN ASSOCIATION WITH A LOWER LEVEL OF PTGS2 TRANSCRIPTION, CONSISTENT WITH A DAMPENING OF COX-2 EXPRESSION IN CHRONIC PERIODONTITIS. THESE FINDINGS SUGGEST THAT THE CHRONIC PERSISTENCE OF THE BIOFILM AND INFLAMMATION MAY BE ASSOCIATED WITH EPIGENETIC CHANGES IN LOCAL TISSUES AT THE BIOFILM-GINGIVAL INTERFACE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  1863  26 EMERGENCE OF MUC1 IN MAMMALS FOR ADAPTATION OF BARRIER EPITHELIA. THE MUCIN 1 (MUC1) GENE WAS DISCOVERED BASED ON ITS OVEREXPRESSION IN HUMAN BREAST CANCERS. SUBSEQUENT WORK DEMONSTRATED THAT MUC1 IS ABERRANTLY EXPRESSED IN CANCERS ORIGINATING FROM OTHER DIVERSE ORGANS, INCLUDING SKIN AND IMMUNE CELLS. THESE FINDINGS SUPPORTED A ROLE FOR MUC1 IN THE ADAPTATION OF BARRIER TISSUES TO INFECTION AND ENVIRONMENTAL STRESS. OF FUNDAMENTAL IMPORTANCE FOR THIS EVOLUTIONARY ADAPTATION WAS INCLUSION OF A SEA DOMAIN, WHICH CATALYZES AUTOPROTEOLYSIS OF THE MUC1 PROTEIN AND FORMATION OF A NON-COVALENT HETERODIMERIC COMPLEX. THE RESULTING MUC1 HETERODIMER IS POISED AT THE APICAL CELL MEMBRANE TO RESPOND TO LOSS OF HOMEOSTASIS. DISRUPTION OF THE COMPLEX RELEASES THE MUC1 N-TERMINAL (MUC1-N) SUBUNIT INTO A PROTECTIVE MUCOUS GEL. CONVERSELY, THE TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT ACTIVATES A PROGRAM OF LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING AND REPAIR. THIS MUC1-C-ACTIVATED PROGRAM APPARENTLY EVOLVED FOR BARRIER TISSUES TO MOUNT SELF-REGULATING PROLIFERATIVE, INFLAMMATORY AND REMODELING RESPONSES ASSOCIATED WITH WOUND HEALING. EMERGING EVIDENCE INDICATES THAT MUC1-C UNDERPINS INFLAMMATORY ADAPTATION OF TISSUE STEM CELLS AND IMMUNE CELLS IN THE BARRIER NICHE. THIS REVIEW FOCUSES ON HOW PROLONGED ACTIVATION OF MUC1-C BY CHRONIC INFLAMMATION IN THESE NICHES PROMOTES THE CANCER STEM CELL (CSC) STATE BY ESTABLISHING AUTO-INDUCTIVE NODES THAT DRIVE SELF-RENEWAL AND TUMORIGENICITY.	2022