1  6758 141 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2  6242  24 THE MATRICELLULAR PROTEIN SPARC DECREASES IN THE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. PURPOSE: SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC) IS A MATRICELLULAR GLYCOPROTEIN ABUNDANTLY EXPRESSED IN BASEMENT MEMBRANES AND CAPSULES SURROUNDING A VARIETY OF ORGANS AND TISSUES. IT MEDIATES EXTRACELLULAR MATRIX ORGANIZATION AND HAS BEEN IMPLICATED IN CELL CONTRACTION. HERE, WE EVALUATED THE EXPRESSION OF SPARC IN THE MURINE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. METHODS: LACRIMAL GLANDS OF YOUNG MICE (4-6 WEEKS OLD) AND ADULT MICE (32-40 WEEKS OLD) WERE USED FOR EXTRACTION OF DNA, RNA, AND PROTEIN. THE PRESENCE OF SPARC WAS ASSESSED BY QUANTITATIVE PCR, ELISA, AND IMMUNOFLUORESCENCE MICROSCOPY. 5-METHYLCYTOSINE AND DNA METHYLATION WERE EVALUATED USING ELISA AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. THE EFFECTS OF CYTOKINES AND INFLAMMATION IN SPARC EXPRESSION WERE EVALUATED IN VITRO AND IN THE NON-OBESE DIABETIC (NOD) MOUSE MODEL OF SJOGREN'S SYNDROME. RESULTS: THE MRNA AND PROTEIN LEVELS OF SPARC WERE DOWNREGULATED IN LACRIMAL GLANDS OF MATURE ADULT MICE PRESENTING AGE-RELATED HISTOLOGICAL ALTERATIONS SUCH AS INCREASED DEPOSITION OF LIPOFUSCIN AND LIPIDS. EPIGENETIC ANALYSES INDICATED THAT GLANDS IN ADULT MICE CONTAIN HIGHER LEVELS OF GLOBAL DNA METHYLATION AND SHOW INCREASED HYPERMETHYLATION OF SPECIFIC CPG SITES WITHIN THE SPARC GENE PROMOTER. ANALYSIS OF SMOOTH MUSCLE ACTIN (SMA)-GREEN FLUORESCENT PROTEIN (GFP) TRANSGENIC MICE REVEALED THAT SPARC LOCALIZES PRIMARILY TO MYOEPITHELIAL CELLS WITHIN THE GLAND. TREATMENT OF MYOEPITHELIAL CELLS WITH IL-1BETA OR TNF-ALPHA AND THE DEVELOPMENT OF INFLAMMATION IN THE NOD MICE LED TO DECREASED TRANSCRIPTION OF SPARC. CONCLUSIONS: SPARC IS A NOVEL MATRICELLULAR GLYCOPROTEIN EXPRESSED BY MYOEPITHELIAL CELLS IN THE LACRIMAL GLAND. LOSS OF SPARC DURING ADULTHOOD AND CHRONIC INFLAMMATION MIGHT HAVE DETRIMENTAL CONSEQUENCES ON MYOEPITHELIAL CELL CONTRACTION AND THE SECRETION OF TEAR FLUID.	2022	
                                                                                                                                                                                                                                                                                                                                                       
3  3861  20 ISOLATION OF HUMAN ANTIGEN-SPECIFIC REGULATORY T CELLS WITH HIGH SUPPRESSIVE FUNCTION. ADOPTIVE TRANSFER OF REGULATORY T (TREG) CELLS COULD BE AN ALTERNATIVE TO CHRONIC IMMUNOSUPPRESSION FOR PREVENTION OF ALLOGENEIC GRAFT REJECTION. WHILE POLYSPECIFIC TREG CELLS CAN PREVENT IMMUNE RESPONSES UNDER LYMPHOPENIC CONDITIONS, AG-SPECIFIC TREG CELLS ARE NEEDED TO TREAT AUTOIMMUNITY AND GRAFT REJECTION. YET, RELIABLE MARKERS FOR AG-SPECIFIC TREG CELLS ARE MISSING. WE REPORT THAT LATENCY-ASSOCIATED PEPTIDE (LAP) AND GLYCOPROTEIN A REPETITIONS PREDOMINANT (GARP) CAN IDENTIFY HUMAN AG-SPECIFIC TREG CELLS. IN ADDITION, WE SHOW THAT THE DEPLETION OF CD154(+) CELLS FROM LAP(+) OR GARP(+) TREG CELLS INCREASES THE TREG-CELL PURITY TO OVER 90%, AS ASSESSED BY EPIGENETIC ANALYSIS. THESE AG-SPECIFIC TREG CELLS CAN BE ISOLATED MAGNETICALLY AND MIGHT CONTRIBUTE TO THE DEVELOPMENT OF GMP-BASED PROTOCOLS. IN ADDITION, AG-SPECIFIC TREG CELLS ARE FUNCTIONALLY FAR SUPERIOR TO CD4(+) CD25(HIGH) OR CD4(+) CD25(HIGH) CD127(LOW) TREG CELLS IN VITRO AND IN PREVENTING STRONG ALLOREACTIONS IN HUMANIZED MICE. THEY COULD, THEREFORE, HAVE A HIGH THERAPEUTIC POTENTIAL FOR THE CONTROL OF ALLOIMMUNE, AUTOIMMUNE, AND ALLERGIC IMMUNE RESPONSES IN PATIENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  2302  22 EPIGENETIC REGULATION OF CANCER STEM CELL MARKER CD133 BY TRANSFORMING GROWTH FACTOR-BETA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER MORTALITY WORLDWIDE. CD133, A TRANSMEMBRANE GLYCOPROTEIN, IS AN IMPORTANT CELL SURFACE MARKER FOR BOTH STEM CELLS AND CANCER STEM CELLS IN VARIOUS TISSUES INCLUDING LIVER. CD133 EXPRESSION HAS BEEN RECENTLY LINKED TO POOR PROGNOSIS IN HCC PATIENTS. CD133+ LIVER CANCER CELLS ARE CHARACTERIZED BY RESISTANCE TO CHEMOTHERAPY, SELF-RENEWAL, MULTILINEAGE POTENTIAL, INCREASED COLONY FORMATION, AND IN VIVO CANCER INITIATION AT LIMITED DILUTION. RECENT STUDIES DEMONSTRATE THAT CD133 EXPRESSION IS REGULATED BY DNA METHYLATION. IN THIS STUDY, WE EXPLORED THE ROLE OF TRANSFORMING GROWTH FACTOR BETA (TGFBETA), A MULTIFUNCTIONAL CYTOKINE THAT PLAYS A CRITICAL ROLE IN CHRONIC LIVER INJURY, IN THE REGULATION OF CD133 EXPRESSION. TGFBETA1 IS CAPABLE OF UP-REGULATING CD133 EXPRESSION SPECIFICALLY WITHIN THE HUH7 HCC CELL LINE IN A TIME- AND DOSE-DEPENDENT MANNER. MOST IMPORTANT, TGFBETA1-INDUCED CD133+ HUH7 CELLS DEMONSTRATE INCREASED TUMOR INITIATION IN VIVO. FORCED EXPRESSION OF INHIBITORY SMADS, INCLUDING SMAD6 AND SMAD7, ATTENUATED TGFBETA1-INDUCED CD133 EXPRESSION. WITHIN CD133- HUH7 CELLS, TGFBETA1 STIMULATION INHIBITED THE EXPRESSION OF DNA METHYLTRANSFERASES (DNMT) 1 AND DNMT3BETA, WHICH ARE CRITICAL IN THE MAINTENANCE OF REGIONAL DNA METHYLATION, AND GLOBAL DNMT ACTIVITY IN CD133- HUH7 CELLS WAS INHIBITED BY TGFBETA1. DNMT3BETA INHIBITION BY TGFBETA1 WAS PARTIALLY RESCUED WITH OVEREXPRESSION OF INHIBITORY SMADS. LASTLY, TGFBETA1 TREATMENT LED TO SIGNIFICANT DEMETHYLATION IN CD133 PROMOTER-1 IN CD133- HUH7 CELLS. CONCLUSION: TGFBETA1 IS ABLE TO REGULATE CD133 EXPRESSION THROUGH INHIBITION OF DNMT1 AND DNMT3BETA EXPRESSION AND SUBSEQUENT DEMETHYLATION OF PROMOTER-1. TGFBETA1-INDUCED CD133+ HUH7 CELLS ARE TUMORIGENIC. THE MECHANISM BY WHICH TGFBETA INDUCES CD133 EXPRESSION IS PARTIALLY DEPENDENT ON THE SMADS PATHWAY.	2010	
                                                                                                                                                                                                                                                                                                                                                         
5  1393  24 DIAGNOSTIC VALUE OF THE HYPOMETHYLATION OF THE WISP1 PROMOTER IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ASSOCIATED WITH HEPATITIS B VIRUS. WNT1-INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1) REGULATES CELL PROLIFERATION, DIFFERENTIATION, ADHESION, MIGRATION AND SURVIVAL. ABNORMAL WISP1 EXPRESSION IS ASSOCIATED WITH THE CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA (HCC). ABERRANT DNA METHYLATION IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HCC. HOWEVER, THE METHYLATION STATUS OF THE WISP1 PROMOTER IS STILL UNCLEAR. WE THEREFORE AIMED TO DETERMINE THE METHYLATION STATUS OF THE WISP1 PROMOTER AND EVALUATE ITS CLINICAL VALUE IN HCC. THE STUDY ENROLLED 251 PARTICIPANTS, INCLUDING 123 PARTICIPANTS WITH HCC, 90 PARTICIPANTS WITH CHRONIC HEPATITIS B (CHB) AND 38 HEALTHY CONTROLS (HCS). WISP1 METHYLATION STATUS, MRNA LEVELS AND PLASMA SOLUBLE WISP1 WERE DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), QUANTITATIVE REAL-TIME PCR (RT-QPCR) AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. WE FOUND THAT THE METHYLATION FREQUENCY OF WISP1 IN PATIENTS WITH HCC WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH CHB AND HCS, WHILE THE RELATIVE EXPRESSION LEVELS OF WISP1 MRNA WERE MARKEDLY HIGHER IN PATIENTS WITH HCC THAN IN PATIENTS WITH CHB AND HCS. FURTHERMORE, THE PLASMA SOLUBLE WISP1 IN PATIENTS WITH HCC WAS OBVIOUSLY LOWER THAN IN THAT IN PATIENTS WITH CHB AND HCS. ALPHA-FETOPROTEIN (AFP) IS A WIDELY RECOGNIZED BIOMARKER TO DIAGNOSE HCC WHICH LACKS ENOUGH SENSITIVITY AND SPECIFICITY. WISP1 PROMOTER METHYLATION STATUS COMBINED WITH AFP SIGNIFICANTLY IMPROVED THE DIAGNOSTIC ABILITY IN DISCRIMINATING HCC FROM CHB COMPARED WITH AFP OR WISP1 METHYLATION STATUS ALONE. IN CONCLUSION, HYPOMETHYLATION OF THE WISP1 GENE PROMOTER MAY SERVE AS A NONINVASIVE BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  5591  20 ROLE OF THE EPIGENETIC FACTOR SIRT7 IN NEUROINFLAMMATION AND NEUROGENESIS. EPIGENETIC REGULATORS ARE INCREASINGLY RECOGNIZED AS RELEVANT MODULATORS IN THE IMMUNE AND NERVOUS SYSTEM. THE CLASS OF SIRTUINS CONSISTS OF NAD(+)-DEPENDENT HISTONE DEACETYLASES THAT REGULATE TRANSCRIPTION. SIRTUIN FAMILY MEMBER SIRT1 HAS ALREADY BEEN SHOWN TO INFLUENCE THE DISEASE COURSE IN AN ANIMAL MODEL OF AUTOIMMUNE NEUROINFLAMMATION (EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE). A ROLE OF SIRT7, A RELATED EPIGENETIC REGULATOR, ON IMMUNE SYSTEM REGULATION HAS BEEN PROPOSED BEFORE, AS THESE MICE ARE MORE SUSCEPTIBLE TO DEVELOP INFLAMMATORY CARDIOMYOPATHY. SIRT7(-/-) ANIMALS SHOWED NO DIFFERENCES IN CLINICAL SCORE COMPARED TO WILD-TYPE LITTERMATES AFTER EAE INDUCTION WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG) PEPTIDE (35-55), ALTHOUGH WE FOUND SUBTLE IMMUNE ALTERATIONS AT DIFFERENT PHASES OF EAE AND DECREASED SURVIVAL OF NEWLY GENERATED NEURONS IN THE HIPPOCAMPUS. OUR DATA INDICATE THAT SIRT7 HAS A SLIGHT PROTECTIVE IMPACT ON BOTH THE ADAPTIVE IMMUNE SYSTEM AND NEUROGENESIS. HOWEVER, OVERALL THIS EPIGENETIC FACTOR IS NOT CAPABLE OF IMPACTING THE ACUTE OR CHRONIC PHASE OF NEUROINFLAMMATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  1730  46 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	

8  6529  24 TRANSCRIPTIONAL DOWN-REGULATION OF THE WNT ANTAGONIST SFRP1 IN HAEMATOPOIETIC CELLS OF PATIENTS WITH DIFFERENT RISK TYPES OF MDS. SECRETED FRIZZLED RELATED PROTEIN 1 (SFRP1) IS AN EXTRACELLULAR ANTAGONIST OF THE WNT SIGNALLING PATHWAY THAT PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SOLID TUMOURS AND HAEMATOPOIETIC MALIGNANCIES. SFRP1 HAS BEEN OBSERVED TO BE TRANSCRIPTIONALLY DOWN-REGULATED DUE TO HYPERMETHYLATION IN ACUTE AND CHRONIC LEUKAEMIA, BUT SO FAR NOT IN MYELODYSPLASTIC SYNDROME (MDS). MOREOVER, IT HAS BEEN SHOWN THAT THE EPIGENETIC INACTIVATION OF SFRP1 CORRELATES WITH AN OVEREXPRESSION OF THE WNT RECEPTOR FRIZZLED 3 (FZD3) IN ACUTE LEUKAEMIA. USING REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION (RT-PCR) WE EXAMINED MRNA EXPRESSION OF SFRP1 AND FZD3 IN BONE MARROW CELLS DERIVED FROM 121 PATIENTS WITH DIFFERENT RISK TYPES OF MDS, ACUTE MYELOID LEUKAEMIA (AML) AND ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL). WE EMPLOYED PYROSEQUENCING TO QUANTIFY PROMOTER DNA METHYLATION IN MDS AND ACUTE LEUKAEMIA. WE DETECTED SIGNIFICANT LOWER MRNA TRANSCRIPTION OF SFRP1 IN MDS COMPARED TO HEALTHY INDIVIDUALS. HOWEVER, DNA SEQUENCE MUTATIONS OR FREQUENT ELEVATED DNA METHYLATION LEVELS OF THE SFRP1 PROMOTER COULD NOT BE OBSERVED IN MDS BUT IN AML AND ALL AS PREVIOUSLY REPORTED. THE EXPRESSION LEVELS OF FZD3 WERE UP-REGULATED IN BOTH ACUTE LEUKAEMIA AND MDS. OUR DATA SHOW A SIGNIFICANT TRANSCRIPTIONAL DOWN-REGULATION OF SFRP1 AS A COMMON EVENT IN AML, ALL AND - AS DEMONSTRATED FOR THE FIRST TIME - IN MDS. AN INACTIVATION OF SFRP1 AND THE TRANSCRIPTIONAL UP-REGULATION OF FZD3 SEEM TO BE ASSOCIATED WITH AN ACTIVATION OF THE WNT SIGNALLING PATHWAY IN THESE HAEMATOPOIETIC DISEASES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  3442  20 HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH DIABETIC COMPLICATIONS AND BIOCHEMICAL INDICATORS. BACKGROUND: DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR REGULATING THE TRANSCRIPTION OF MANY GENES AND HAS BEEN LINKED TO THE DEVELOPMENT OF VARIOUS DISEASES. A PROMISING GENE TO INVESTIGATE IS METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR), SINCE THE ENZYME METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) PROMOTES METHYL RADICAL SYNTHESIS IN THE HOMOCYSTEINE CYCLE AND CAN PROVIDE METHYL GROUPS FOR DNA METHYLATION. IN ADDITION, SEVERAL STUDIES HAVE CORRELATED GENE POLYMORPHISMS OF THIS ENZYME WITH A GREATER RISK OF DIABETES, BUT LITTLE IS KNOWN REGARDING THE RELATIONSHIP BETWEEN EPIGENETIC CHANGES IN THIS GENE AND DIABETES AND ITS COMPLICATIONS. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN METHYLATION PROFILE IN THE MTHFR GENE PROMOTER AND BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS MARKERS IN INDIVIDUALS WITH TYPE 2 DIABETES (T2DM) WHO HAVE BEEN DIAGNOSED FOR 5-10 YEARS WITH OR WITHOUT DIABETIC RETINOPATHY (DR) AND NEPHROPATHY (DN). METHODS: SPECIFIC PCR FOR METHYLATION (MSP) WAS USED TO ANALYZE MTHFR METHYLATION PROFILE IN LEUCOCYTES DNA. BIOCHEMICAL MARKERS (GLYCEMIA, GLYCATED HEMOGLOBIN, TOTAL CHOLESTEROL, LDL, HDL, TRIGLYCERIDES, SERUM CREATININE), INFLAMMATORY MARKERS (C-REACTIVE PROTEIN AND ALPHA-1 ACID GLYCOPROTEIN) AND OXIDATIVE STRESS (TOTAL ANTIOXIDANT AND MALONALDEHYDE) WERE DETERMINED IN PERIPHERIC BLOOD SAMPLES AND MICROALBUMINURIA IN 24 H URINE SAMPLES. THE X(2) AND MANN-WHITNEY STATISTICAL TESTS WERE PERFORMED AND P < 0.05 WERE CONSIDERED SIGNIFICANT. RESULTS: THE HYPERMETHYLATED PROFILE WAS MOST FREQUENTLY OBSERVED IN INDIVIDUALS WITH RETINOPATHY (P < 0.01) AND WAS ASSOCIATED WITH HIGHER TOTAL CHOLESTEROL AND LDL LEVELS (P = 0.0046, 0.0267, RESPECTIVELY). INDIVIDUALS WITH DN AND HYPERMETHYLATED PROFILES HAD HIGHER LEVELS OF ALPHA-1 ACID GLYCOPROTEIN (P = 0.0080) AND TOTAL ANTIOXIDANT CAPACITY (P = 0.0169) COMPARED TO SUBJECTS WITHOUT COMPLICATIONS. CONCLUSIONS: HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH THE OCCURRENCE OF DR AND WITH BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS IN THE CONTEXT OF CHRONIC COMPLICATIONS.	2017	
                                                                                           
10  3642  22 INCREASED H3K4ME3 METHYLATION AND DECREASED MIR-7113-5P EXPRESSION LEAD TO ENHANCED WNT/BETA-CATENIN SIGNALING IN IMMUNE CELLS FROM PTSD PATIENTS LEADING TO INFLAMMATORY PHENOTYPE. BACKGROUND: POSTTRAUMATIC STRESS DISORDER (PTSD) IS A PSYCHIATRIC DISORDER ACCOMPANIED BY CHRONIC PERIPHERAL INFLAMMATION. WHAT TRIGGERS INFLAMMATION IN PTSD IS CURRENTLY UNCLEAR. IN THE PRESENT STUDY, WE IDENTIFIED POTENTIAL DEFECTS IN SIGNALING PATHWAYS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM INDIVIDUALS WITH PTSD. METHODS: RNASEQ (5 SAMPLES EACH FOR CONTROLS AND PTSD), CHIPSEQ (5 SAMPLES EACH) AND MIRNA ARRAY (6 SAMPLES EACH) WERE USED IN COMBINATION WITH BIOINFORMATICS TOOLS TO IDENTIFY DYSREGULATED GENES IN PBMCS. REAL TIME QRT-PCR (24 SAMPLES EACH) AND IN VITRO ASSAYS WERE EMPLOYED TO VALIDATE OUR PRIMARY FINDINGS AND HYPOTHESIS. RESULTS: BY RNA-SEQ ANALYSIS OF PBMCS, WE FOUND THAT WNT SIGNALING PATHWAY WAS UPREGULATED IN PTSD WHEN COMPARED TO NORMAL CONTROLS. SPECIFICALLY, WE FOUND INCREASED EXPRESSION OF WNT10B IN THE PTSD GROUP WHEN COMPARED TO CONTROLS. OUR FINDINGS WERE CONFIRMED USING NCBI'S GEO DATABASE INVOLVING A LARGER SAMPLE SIZE. ADDITIONALLY, IN VITRO ACTIVATION STUDIES REVEALED THAT ACTIVATED BUT NOT NAIVE PBMCS FROM CONTROL INDIVIDUALS EXPRESSED MORE IFNGAMMA IN THE PRESENCE OF RECOMBINANT WNT10B SUGGESTING THAT WNT SIGNALING PLAYED A CRUCIAL ROLE IN EXACERBATING INFLAMMATION. NEXT, WE INVESTIGATED THE MECHANISM OF INDUCTION OF WNT10B AND FOUND THAT INCREASED EXPRESSION OF WNT10B MAY RESULT FROM EPIGENETIC MODULATION INVOLVING DOWNREGULATION OF HSA-MIR-7113-5P WHICH TARGETED WNT10B. FURTHERMORE, WE ALSO OBSERVED THAT WNT10B OVEREXPRESSION WAS LINKED TO HIGHER EXPRESSION OF H3K4ME3 HISTONE MODIFICATION AROUND THE PROMOTOR OF WNT10B. ADDITIONALLY, KNOCKDOWN OF HISTONE DEMETHYLASE SPECIFIC TO H3K4ME3, USING SIRNA, LED TO INCREASED EXPRESSION OF WNT10B PROVIDING CONCLUSIVE EVIDENCE THAT H3K4ME3 INDEED CONTROLLED WNT10B EXPRESSION. CONCLUSIONS: IN SUMMARY, OUR DATA DEMONSTRATE FOR THE FIRST TIME THAT WNT SIGNALING PATHWAY IS UPREGULATED IN PBMCS OF PTSD PATIENTS RESULTING FROM EPIGENETIC CHANGES INVOLVING MICRORNA DYSREGULATION AND HISTONE MODIFICATIONS, WHICH IN TURN MAY PROMOTE THE INFLAMMATORY PHENOTYPE IN SUCH CELLS.	2020	
                                                                           
11  6756  44 WNT ANTAGONIST, SFRP1, IS HEDGEHOG SIGNALING TARGET. HEDGEHOG AND WNT SIGNALING PATHWAYS NETWORK TOGETHER DURING EMBRYOGENESIS AND CARCINOGENESIS. HEDGEHOG SIGNALING IN INTESTINAL EPITHELIUM REPRESSES CANONICAL WNT SIGNALING TO RESTRICT EXPRESSION OF WNT TARGET GENES TO STEM OR PROGENITOR CELLS; HOWEVER, THE MECHANISM REMAINS UNCLEAR. THE HEDGEHOG SIGNAL IS TRANSDUCED TO GLI FAMILY TRANSCRIPTION FACTORS THOUGH PATCHED RECEPTOR, SMOOTHENED SIGNAL TRANSDUCER, AND OTHER SIGNALING COMPONENTS, SUCH AS KIF27, KIF7, STK36, SUFU, AND DZIP1. HERE, WE SEARCHED FOR THE GLI-BINDING SITE WITHIN THE PROMOTER REGION OF GENES ENCODING SECRETED-TYPE WNT SIGNAL INHIBITORS, INCLUDING SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, AND WIF1. THE GLI-BINDING SITE WAS IDENTIFIED WITHIN THE HUMAN SFRP1 PROMOTER BASED ON BIOINFORMATICS AND HUMAN INTELLIGENCE. THE CHIMPANZEE SFRP1 GENE WAS IDENTIFIED WITHIN THE NW_110515.1 GENOME SEQUENCE. THE GLI-BINDING SITE OF THE HUMAN SFRP1 PROMOTER WAS CONSERVED IN CHIMPANZEE SFRP1, MOUSE SFRP1, AND RAT SFRP1 PROMOTERS. SFRP1 IS THE EVOLUTIONARILY CONSERVED TARGET OF THE HEDGEHOG-GLI SIGNALING PATHWAY. EXPRESSION DOMAIN ANALYSES BASED ON TEXT MINING REVEALED THAT INDIAN HEDGEHOG (IHH), SFRP1, AND WNT6 ARE EXPRESSED IN DIFFERENTIATED INTESTINAL EPITHELIAL CELLS, MESENCHYMAL CELLS, AND STEM/PROGENITOR CELLS, RESPECTIVELY. HEDGEHOG IS SECRETED FROM DIFFERENTIATED EPITHELIAL CELLS TO INDUCE SFRP1 EXPRESSION IN MESENCHYMAL CELLS, WHICH KEEPS DIFFERENTIATED EPITHELIAL CELLS AWAY FROM THE EFFECTS OF CANONICAL WNT SIGNALING. THESE FACTS INDICATE THAT SFRP1 IS THE HEDGEHOG TARGET TO CONFINE CANONICAL WNT SIGNALING WITHIN STEM OR PROGENITOR CELLS. THEREFORE, EPIGENETIC CPG HYPERMETHYLATION OF THE SFRP1 PROMOTER DURING CHRONIC PERSISTENT INFLAMMATION AND AGING LEADS TO THE OCCURRENCE OF GASTROINTESTINAL CANCERS, SUCH AS COLORECTAL CANCER AND GASTRIC CANCER, THROUGH THE BREAKDOWN OF HEDGEHOG-DEPENDENT WNT SIGNAL INHIBITION.	2006	
                                                                                                                                                                                                                                                                                                                                                                                
12  5458  20 RESEARCH ON EPIGENETIC MECHANISM OF SFRP2 IN ADVANCED CHRONIC MYELOID LEUKEMIA. SECRETED FRIZZLED-RELATED PROTEIN 2 (SFRP2) HAS BEEN REPORTED TO ACT AS A TUMOR SUPPRESSORS. THIS STUDY AIMS TO DETECT THE BIOLOGICAL ROLE OF SFRP2 IN ADVANCED CHRONIC MYELOID LEUKEMIA (CML). IN THIS STUDY WE EXAMINED BONE MARROW SAMPLES FROM 45 CML PATIENTS AND 10 HEALTHY DONORS. K562 AND KCL22 CELLS WERE CULTURED AND TREATED WITH DEMETHYLATION DRUG AND HISTONE DEACETYLASE INHIBITOR (HDACI). KCL22 AND K562 CELLS WERE TRANSFECTED WITH LENTIVIRAL VECTOR (LV)-SFRP2, LV-CONTROL. THE CELLS WERE THEN SUBJECTED TO PROLIFERATION AND APOPTOSIS ASSAYS, REAL TIME POLYMERASE CHAIN REACTION (PCR), METHYLATION-SPECIFIC PCR (MSP), WESTERN BLOTTING, CO-IMMUNOPRECIPITATION (COIP) AND CHROMATIN IMMUNOPRECIPITATION (CHIP), WE FOUND THAT SFRP2 WAS DOWN-REGULATED IN THE ACCELERATED AND BLAST PHASE OF CML, WHEREAS, THE LEVELS OF WNT1, WNT3 AND WNT5A WERE UP-REGULATED IN THE ACCELERATED AND BLAST PHASE OF CML. OVEREXPRESSION SFRP2 INHIBITED PROLIFERATION, PROMOTED APOPTOSIS AND ACTIVATED THE WNT PATHWAY. COIP-MS RESULTS SHOWED THAT SFRP2 INTERACTED WITH WNT1 AND WNT5A. CHIP-SEQ RESULT INDICATED THAT THE PROMOTER OF H3K4ME3 AND H3K27ME3 WERE ABLE TO INTERACT WITH SFRP2. IN CONCLUSION, OUR FINDINGS DEMONSTRATED THE SFRP2 ACT AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AND HDACI AS A POTENTIAL CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13  2842  22 FREQUENT CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) IN HUMAN HEPATOCELLULAR CARCINOMA. BACKGROUND AND AIM: EXCEPT FOR GENETIC MUTATIONS, EPIGENETIC CHANGES ARE ALSO INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS. RECENTLY, WE HAVE IDENTIFIED SOX1, SRY (SEX DETERMINING REGION Y)-BOX 1, IS HYPERMETHYLATED IN CERVICAL CANCER AND OVARIAN CANCER. THEREFORE, WE INVESTIGATED WHETHER PROMOTER HYPERMETHYLATION OF SOX1 IS COMMON IN HEPATOCELLULAR CARCINOMA (HCC). METHODS: WE USED METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MS-PCR) AND BISULFITE SEQUENCING TO ANALYZE THE METHYALTION LEVEL OF THE SOX1 PROMOTER IN SEVEN HCC CELL LINES, 54 CLINICAL HCCS, 42 CIRRHOTIC LIVERS, 21 LIVERS WITH CHRONIC HEPATITIS, AND 15 CONTROL LIVERS. THEN, WE EMPLOYED QUANTITATIVE MS-PCR (QMSP) TO VALIDATE IN AN INDEPENDENT SET OF SAMPLES (60 PAIRED HCCS AND 30 CONTROL LIVERS). FINALLY, WE USED LUCIFERASE REPORTER AND COLONY FORMATION ASSAY TO CHECK THE EFFECT OF SOX1 IN HCC. RESULTS: PROMOTER METHYLATION OF SOX1 WAS SIGNIFICANTLY FREQUENT IN HCC CELL LINES AND CLINICAL HCCS, CIRRHOTIC LIVERS, BUT NOT IN CONTROL LIVERS (P < 0.0001). THERE IS A SIGNIFICANT CORRELATION BETWEEN DOWNREGULATION OF SOX1 EXPRESSION AND PROMOTER METHYLATION. QMSP RESULTS CONFIRMED THAT PROMOTER HYPERMETHYLATION OF SOX1 IS SIGNIFICANTLY MORE FREQUENT IN HCCS THAN CONTROL LIVERS (P < 0.0001). THE FREQUENCY OF SOX1 METHYLATION IN PATIENTS WITH SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) METHYLATION IS SIGNIFICANTLY HIGHER THAN IN PATIENTS WITHOUT SFRPS METHYLATION (P < 0.0001). FURTHERMORE, ECTOPIC EXPRESSION OF SOX1 COULD SUPPRESS T-CELL FACTOR-DEPENDENT TRANSCRIPTIONAL ACTIVITY AND COLONY FORMATION NUMBER IN HCCS. CONCLUSIONS: CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SFRPS THROUGH PROMOTER HYPERMETHYLATION IS FREQUENT IN HCCS, AND THIS MIGHT CONTRIBUTE TO ABNORMAL ACTIVATION OF CANONICAL WNT SIGNAL PATHWAY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                         
14  2135  26 EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IN SERUM OF PATIENTS WITH CUTANEOUS MELANOMA. SMALL AMOUNTS OF CELL-FREE DNA CIRCULATE IN BOTH HEALTHY AND DISEASED HUMAN BLOOD, WHILE INCREASED CONCENTRATIONS OF DNA ARE PRESENT IN THE SERUM OF CANCER PATIENTS. TUMOR-SPECIFIC MUTATIONS OR EPIGENETIC MODIFICATIONS HAVE PREDOMINANTLY BEEN DETECTED IN TISSUE SPECIMENS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE METHYLATION OF FIVE DIFFERENT GENES INVOLVED IN TUMOR SUPPRESSION AND DNA REPAIR (SUPPRESSORS OF CYTOKINE SIGNALING 1 AND 2 (SOCS1, SOCS2)), RAS-ASSOCIATION DOMAIN FAMILY PROTEIN 1A (RASSF1A), D-TYPE P16(INK4A) CYCLIN-DEPENDENT KINASE INHIBITOR (CDKN), AND O6-METHYLGUANINE DNA-METHYLTRANSFERASE (MGMT)) IN THE SERUM OF 100 PATIENTS USING METHYLATION-SPECIFIC PCR. IN ALL, 41 MELANOMA PATIENTS (STAGE I = 18; STAGE II = 10; STAGE III/IV = 13), 13 HEALTHY CONTROLS WITHOUT NEVI, AND 10 INDIVIDUALS WITH MORE THAN 15 NEVI OF >5 MM IN SIZE WERE INVESTIGATED. FOR COMPARISON, SERA FROM PATIENTS WITH OTHER SKIN TUMORS (NINE BASAL CELL CANCERS, FIVE KAPOSI'S SARCOMA), DIFFERENT METASTASIZED CANCERS (FIVE BREAST CANCERS, FIVE COLON CANCERS), AND SEVERAL CHRONIC INFLAMMATORY DISEASES (N = 12) WERE ALSO ANALYZED. IN ADDITION, WE EXAMINED IF METHYLATION WAS INVOLVED IN SILENCING TRANSCRIPTION OF THESE GENES IN 12 MELANOMA SPECIMENS. SOCS1, SOCS2, RASSF1A, CDKN2A, AND MGMT WERE METHYLATED IN 75, 43, 64, 75, AND 64% OF MELANOMA SAMPLES, RESPECTIVELY. OF THE 41 MELANOMA PATIENTS, 83% HAD ONE HYPERMETHYLATED GENE, WHILE 66, 51, AND 41% HAD TWO, THREE, OR FOUR HYPERMETHYLATED GENES, RESPECTIVELY. ALSO, 20% OF THESE PATIENTS SHOWED HYPERMETHYLATION FOR ALL GENES, WHILE ONLY 17% SHOWED NO METHYLATION. IMPORTANTLY, THE METHYLATION PROFILE OF THE SELECTED GENES FROM MELANOMA PATIENTS WAS DISTINCT FROM THE OTHER ANALYZED TUMORS. TRANSCRIPTION OF SOCS1, SOCS2, CDKN2A, AND RASSF1A GENES WAS SIGNIFICANTLY REDUCED IN FRESH MELANOMA SAMPLES, WHILE MGMT SHOWED A 12-FOLD UPREGULATION AT THE MESSENGER RIBONUCLEIC ACID LEVEL (P < 0.001). OUR FINDINGS SUGGEST THAT EPIGENETIC SILENCING OF THE STUDIED TUMOR SUPPRESSOR GENES IS A COMMON AND PROBABLY IMPORTANT MECHANISM FOR MELANOMA FORMATION. THIS CONVENIENT METHOD USING A SIMPLE BLOOD SAMPLE MAY CONTRIBUTE TO CLASSIFICATION OF MELANOMA AND AWAITS CLINICAL VALIDATION.	2006	
              
15  3939  19 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                 
16  2379  27 EPIGENETIC REGULATION OF WNT PATHWAY ANTAGONISTS IN HUMAN GLIOBLASTOMA MULTIFORME. EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IS COMMON IN HUMAN CANCER. USING A LARGE-SCALE WHOLE-GENOME APPROACH IN AN EARLIER STUDY, THE AUTHORS IDENTIFIED EPIGENETICALLY SILENCED GENES WITH POTENTIAL TUMOR SUPPRESSOR FUNCTION IN GLIOBLASTOMA (GBM). THREE GENES IDENTIFIED IN THIS ANALYSIS-DKK1, SFRP1, AND WIF1-ARE POTENT INHIBITORS OF THE WNT SIGNAL TRANSDUCTION PATHWAY. HERE, THE AUTHORS CONFIRM DECREASED EXPRESSION OF THESE GENES IN GBM TUMOR TISSUE SAMPLES RELATIVE TO NONTUMOR BRAIN TISSUE SAMPLES USING REAL-TIME PCR. THEY THEN SHOW THAT EXPRESSION OF ALL 3 GENES IS RESTORED IN T98 GBM CELLS BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA), BUT ONLY DKK1 EXPRESSION IS RESTORED BY TREATMENT WITH THE DEMETHYLATING AGENT 5-AZACYTIDINE. BISULFITE SEQUENCING DID NOT REVEAL SIGNIFICANT METHYLATION IN THE PROMOTER REGION OF DKK1, WHEREAS HISTONE ACETYLATION AND CHROMATIN ACCESSIBILITY INCREASED SIGNIFICANTLY FOR ALL 3 GENES AFTER TSA TREATMENT. ECTOPIC EXPRESSION OF DKK1 SIGNIFICANTLY REDUCES COLONY FORMATION AND INCREASES CHEMOTHERAPY-INDUCED APOPTOSIS IN T98 CELLS. ECTOPIC EXPRESSION OF THE CANONICAL WNT PATHWAY INHIBITORS WIF1 AND SFRP1 SHOWS A RELATIVE LACK OF RESPONSE. CHRONIC WNT3A STIMULATION ONLY PARTIALLY REVERSES GROWTH SUPPRESSION AFTER DKK1 REEXPRESSION, WHEREAS A SPECIFIC INHIBITOR OF THE JNK PATHWAY SIGNIFICANTLY REVERSES THE EFFECT OF DKK1 REEXPRESSION ON COLONY FORMATION AND APOPTOSIS IN T98 CELLS. THESE RESULTS SUPPORT A POTENTIAL GROWTH-SUPPRESSIVE FUNCTION FOR EPIGENETICALLY SILENCED DKK1 IN GBM AND SUGGEST THAT DKK1 RESTORATION COULD MODULATE WNT SIGNALING THROUGH BOTH CANONICAL AND NONCANONICAL PATHWAYS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  6263  39 THE MULTIPLE WAYS WNT SIGNALING CONTRIBUTES TO ACUTE LEUKEMIA PATHOGENESIS. WNT PROTEINS CONSTITUTE A VERY CONSERVED FAMILY OF SECRETED GLYCOPROTEINS THAT ACT AS SHORT-RANGE LIGANDS FOR SIGNALING WITH CRITICAL ROLES IN HEMATOPOIESIS, EMBRYONIC DEVELOPMENT, AND TISSUE HOMEOSTASIS. THESE PROTEINS TRANSDUCE SIGNALS VIA THE CANONICAL PATHWAY, WHICH IS BETA-CATENIN-MEDIATED AND BETTER-CHARACTERIZED, OR VIA MORE DIVERSE NONCANONICAL PATHWAYS THAT ARE BETA-CATENIN INDEPENDENT AND COMPRISE THE PLANAR CELL POLARITY (PCP) PATHWAY AND THE WNT/CA(++) PATHWAYS. SEVERAL PROTEINS REGULATE WNT SIGNALING THROUGH A VARIETY OF SOPHISTICATED MECHANISMS. DISORDERS WITHIN THE PATHWAY CAN CONTRIBUTE TO VARIOUS HUMAN DISEASES, AND THE DYSREGULATION OF WNT PATHWAYS BY DIFFERENT MOLECULAR MECHANISMS IS IMPLICATED IN THE PATHOGENESIS OF MANY TYPES OF CANCER, INCLUDING THE HEMATOLOGICAL MALIGNANCIES. THE TYPES OF LEUKEMIA DIFFER CONSIDERABLY AND CAN BE SUBDIVIDED INTO CHRONIC, MYELOID OR LYMPHOCYTIC, AND ACUTE, MYELOID OR LYMPHOCYTIC, LEUKEMIA, ACCORDING TO THE DIFFERENTIATION STAGE OF THE PREDOMINANT CELLS, THE PROGENITOR LINEAGE, THE DIAGNOSTIC AGE STRATA, AND THE SPECIFIC MOLECULAR DRIVERS BEHIND THEIR DEVELOPMENT. HERE, WE REVIEW THE ROLE OF WNT SIGNALING IN NORMAL HEMATOPOIESIS AND DISCUSS IN DETAIL THE MULTIPLE WAYS CANONICAL WNT SIGNALING CAN BE DYSREGULATED IN ACUTE LEUKEMIA, INCLUDING ALTERATIONS IN GENE EXPRESSION AND PROTEIN LEVELS, EPIGENETIC REGULATION, AND MUTATIONS. FURTHERMORE, WE HIGHLIGHT THE DIFFERENT IMPACTS OF THESE ALTERATIONS, CONSIDERING THE DISTINCT FORMS OF THE DISEASE, AND THE THERAPEUTIC POTENTIAL OF TARGETING WNT SIGNALING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  1192  17 CORRELATION OF CPG METHYLATION OF THE PDCD1 GENE WITH PD-1 EXPRESSION ON CD8(+) T CELLS AND MEDICAL LABORATORY INDICATORS IN CHRONIC HEPATITIS B INFECTION. BACKGROUND: THE NEGATIVE SIGNAL PROVIDED BY SOME CO-INHIBITORY FACTORS SUCH AS PROGRAMMED CELL DEATH-1 (PD-1) HAS BEEN ASSOCIATED WITH CHRONIC HEPATITIS B (CHB) INFECTION INDUCED-T CELL EXHAUSTION, ALTHOUGH THE CORRELATION OF CPG METHYLATION OF THE PDCD1 GENE WITH PD-1 EXPRESSION AND MEDICAL LABORATORY INDICATORS IN CHB INFECTION HAS NOT YET BEEN ELUCIDATED. METHODS: BLOOD SAMPLES FROM 20 CHB INFECTION PATIENTS AND 20 SPONTANEOUS CLEARANCE (SC) PATIENTS WERE COLLECTED. PERCENTAGES OF PD-1-POSITIVE CD8(+) T CELLS WERE ANALYZED BY FLOW CYTOMETRY. THE PERCENTAGE OF CPG METHYLATION AT THE PDCD1 LOCUS WAS ANALYZED BY BISULFITE SEQUENCING. STUDENT'S T TEST, PEARSON AND SPEARMAN'S CORRELATION, AND MANN-WHITNEY TESTS WERE USED IN THE STATISTICAL ANALYSIS. RESULTS: PERCENTAGES OF PD-1-POSITIVE CD8(+) T CELLS IN PERIPHERAL BLOOD T CELLS WERE SIGNIFICANTLY HIGHER IN CHB PATIENTS THAN IN THE SC GROUP (P < 0.001). THE METHYLATION LEVEL OF PDCD1 WAS SIGNIFICANTLY LOWER IN CHB PATIENTS (P < 0.001) AND THE METHYLATION LEVEL OF PDCD1 WAS NEGATIVELY CORRELATED WITH PD-1 EXPRESSION LEVEL IN CD8(+) T CELLS (P < 0.001) AND HEPATITIS-B SURFACE ANTIGEN (HBSAG) (P < 0.001). CONCLUSIONS: THE RESULTS OF THE PRESENT STUDY SUGGEST THAT PDCD1 METHYLATION IS CORRELATED WITH PD-1 EXPRESSION ON CD8(+) T CELLS AND CORRELATED WITH HBSAG AND ALANINE AMINOTRANSFERASE. THE RESULTS MAY PROVIDE NEW IDEAS REGARDING ANTI-PD-1 INHIBITORS, AND EPIGENETIC REGULATORS SUCH AS DEMETHYLATION INHIBITORS COULD REPRESENT MORE SUCCESSFUL THERAPEUTIC STRATEGIES IN HEPATITIS B INFECTION PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19   852  18 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                         
20  5965  24 TEN-ELEVEN-TRANSLOCATION 2 (TET2) NEGATIVELY REGULATES HOMEOSTASIS AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS IN MICE. THE TEN-ELEVEN-TRANSLOCATION 2 (TET2) GENE ENCODES A MEMBER OF TET FAMILY ENZYMES THAT ALTERS THE EPIGENETIC STATUS OF DNA BY OXIDIZING 5-METHYLCYTOSINE TO 5-HYDROXYMETHYLCYTOSINE (5HMC). SOMATIC LOSS-OF-FUNCTION MUTATIONS OF TET2 ARE FREQUENTLY OBSERVED IN PATIENTS WITH DIVERSE MYELOID MALIGNANCIES, INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS, AND CHRONIC MYELOMONOCYTIC LEUKEMIA. BY ANALYZING MICE WITH TARGETED DISRUPTION OF THE TET2 CATALYTIC DOMAIN, WE SHOW HERE THAT TET2 IS A CRITICAL REGULATOR OF SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS (HSCS). TET2 DEFICIENCY LED TO DECREASED GENOMIC LEVELS OF 5HMC AND AUGMENTED THE SIZE OF THE HEMATOPOIETIC STEM/PROGENITOR CELL POOL IN A CELL-AUTONOMOUS MANNER. IN COMPETITIVE TRANSPLANTATION ASSAYS, TET2-DEFICIENT HSCS WERE CAPABLE OF MULTILINEAGE RECONSTITUTION AND POSSESSED A COMPETITIVE ADVANTAGE OVER WILD-TYPE HSCS, RESULTING IN ENHANCED HEMATOPOIESIS INTO BOTH LYMPHOID AND MYELOID LINEAGES. IN VITRO, TET2 DEFICIENCY DELAYED HSC DIFFERENTIATION AND SKEWED DEVELOPMENT TOWARD THE MONOCYTE/MACROPHAGE LINEAGE. OUR DATA INDICATE THAT TET2 HAS A CRITICAL ROLE IN REGULATING THE EXPANSION AND FUNCTION OF HSCS, PRESUMABLY BY CONTROLLING 5HMC LEVELS AT GENES IMPORTANT FOR THE SELF-RENEWAL, PROLIFERATION, AND DIFFERENTIATION OF HSCS.	2011