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 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 3 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 4 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 5 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 6 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 7 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 8 201 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 9 1700 31 DYNAMIC EXPRESSION OF ZNF382 AND ITS TUMOR-SUPPRESSOR ROLE IN HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOGENESIS. HEPATITIS B VIRUS (HBV) INFECTION IS THE PRIMARY CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). ZINC-FINGER PROTEIN 382 (ZNF382), WHICH BELONGS TO ZINC-FINGER PROTEIN FAMILY, HAS BEEN DOCUMENTED TO BE DOWNREGULATED IN CERTAIN TYPES OF CANCER. HOWEVER, ITS ROLE IN HCC REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DEMONSTRATED THAT ZNF382 EXPRESSION WAS SIGNIFICANTLY ELEVATED IN HBV-INFECTED LIVER CIRRHOSIS TISSUES RELATIVE TO HBV-NEGATIVE NORMAL LIVER TISSUES AT PROTEIN LEVELS, BUT NOT AT MRNA LEVELS, AND WAS POSITIVELY CORRELATED WITH THE LEVELS OF HBV DNA AND HEPATITIS B VIRUS X PROTEIN (HBX). FURTHER STUDIES REVEALED THAT ZNF382 WAS A TARGET OF MIR-6867, AND HBX PROMOTED THE TRANSLATION OF ZNF382 DURING HBV CHRONIC INFECTION THROUGH ERK-MEDIATED MIR-6867 INHIBITION. IN ADDITION, OUR DATA SHOWED THAT ZNF382 WAS FREQUENTLY DOWNREGULATED BY PROMOTER METHYLATION IN HBV-RELATED HCCS RELATIVE TO HBV-INFECTED LIVER CIRRHOSIS TISSUES, AND DECREASED EXPRESSION OF ZNF382 WAS STRONGLY CORRELATED WITH POOR SURVIVAL IN EARLY-STAGE HCC PATIENTS. FUNCTIONAL STUDIES DEMONSTRATED THAT ZNF382 WAS A POTENT TUMOR SUPPRESSOR IN HCC CELLS THROUGH INHIBITING CELL PROLIFERATION, COLONY FORMATION, MIGRATION, INVASION, AND TUMORIGENIC POTENTIAL IN NUDE MICE, AND INDUCING CELL APOPTOSIS. MECHANISTICALLY, ZNF382 EXERTED ITS TUMOR-SUPPRESSOR FUNCTIONS IN HCC THROUGH TRANSCRIPTIONALLY REPRESSING ITS DOWNSTREAM TARGETS SUCH AS FOS PROTO-ONCOGENE (FOS), JUN PROTO-ONCOGENE (JUN), DISHEVELED SEGMENT POLARITY PROTEIN 2 (DVL2), AND FRIZZLED CLASS RECEPTOR 1 (FZD1), THEREBY IMPAIRING THE ACTIVITIES OF ACTIVATING PROTEIN 1 (AP-1) AND WNT/BETA-CATENIN PATHWAYS AND ACTIVATING P53 SIGNALING. ALTOGETHER, OUR DATA SHOW THAT ZNF382 ACTS AS A TUMOR SUPPRESSOR, AND IS CO-REGULATED BY HBX AND EPIGENETIC MECHANISM IN HBV-RELATED HEPATOCELLULAR CARCINOGENESIS. 2019 10 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 11 3825 32 INVESTIGATION OF CTNNB1 GENE MUTATIONS AND EXPRESSION IN HEPATOCELLULAR CARCINOMA AND CIRRHOSIS IN ASSOCIATION WITH HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV), ALONG WITH HEPATITIS C VIRUS CHRONIC INFECTION, REPRESENTS A MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT. HOWEVER, MOLECULAR MECHANISMS INVOLVED IN THE DEVELOPMENT OF HCC ARE NOT YET COMPLETELY UNDERSTOOD. RECENT STUDIES HAVE INDICATED THAT MUTATIONS IN CTNNB1 GENE ENCODING FOR BETA-CATENIN PROTEIN LEAD TO ABERRANT ACTIVATION OF THE WNT/ BETA-CATENIN PATHWAY. THE MUTATIONS IN TURN ACTIVATE SEVERAL DOWNSTREAM GENES, INCLUDING C-MYC, PROMOTING THE NEOPLASTIC PROCESS. THE PRESENT STUDY EVALUATED THE MUTATIONAL PROFILE OF THE CTNNB1 GENE AND EXPRESSION LEVELS OF CTNNB1 AND C-MYC GENES IN HBV-RELATED HCC, AS WELL AS IN CIRRHOTIC AND CONTROL TISSUES. MUTATIONAL ANALYSIS OF THE BETA-CATENIN GENE AND HBV GENOTYPING WERE CONDUCTED BY DIRECT SEQUENCING. EXPRESSION OF BETA-CATENIN AND C-MYC GENES WAS ASSESSED USING REAL-TIME PCR. AMONG THE HCC CASES, 18.1% SHOWED MISSENSE POINT MUTATION IN EXON 3 OF CTNNB1, MORE FREQUENTLY IN CODONS 32, 33, 38 AND 45. THE FREQUENCY OF MUTATION IN THE HOTSPOTS OF EXON 3 WAS SIGNIFICANTLY HIGHER IN NON-VIRAL HCCS (29.4%) RATHER THAN HBV-RELATED CASES (12.7%, P = 0.021). THE EXPRESSION OF BETA-CATENIN AND C-MYC GENES WAS FOUND UPREGULATED IN CIRRHOTIC TISSUES IN ASSOCIATION WITH HBV INFECTION. MUTATIONS AT BOTH PHOSPHORYLATION AND NEIGHBORING SITES WERE ASSOCIATED WITH INCREASED ACTIVITY OF THE WNT PATHWAY. THE RESULTS DEMONSTRATED THAT MUTATED BETA-CATENIN CAUSED ACTIVATION OF THE WNT PATHWAY, BUT THE RATE OF CTNNB1 GENE MUTATIONS WAS NOT RELATED TO HBV INFECTION. HBV FACTORS MAY DEREGULATE THE WNT PATHWAY BY CAUSING EPIGENETIC ALTERATIONS IN THE HBV-RELATED HCC. 2020 12 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 13 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 14 134 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 15 5527 38 RNA HELICASE DEAD BOX PROTEIN 5 REGULATES POLYCOMB REPRESSIVE COMPLEX 2/HOX TRANSCRIPT ANTISENSE INTERGENIC RNA FUNCTION IN HEPATITIS B VIRUS INFECTION AND HEPATOCARCINOGENESIS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A MAJOR FACTOR IN HEPATOCELLULAR CARCINOMA (HCC) PATHOGENESIS BY A MECHANISM NOT YET UNDERSTOOD. ELUCIDATING MECHANISMS OF HBV-MEDIATED HEPATOCARCINOGENESIS IS NEEDED TO GAIN INSIGHTS INTO CLASSIFICATION AND TREATMENT OF HCC. IN HBV REPLICATING CELLS, INCLUDING VIRUS-ASSOCIATED HCCS, SUPPRESSOR OF ZESTE 12 HOMOLOG (SUZ12), A CORE SUBUNIT OF POLYCOMB REPRESSIVE COMPLEX2 (PRC2), UNDERGOES PROTEASOMAL DEGRADATION. THIS PROCESS REQUIRES THE LONG NONCODING RNA, HOX TRANSCRIPT ANTISENSE INTERGENIC RNA (HOTAIR). INTRIGUINGLY, HOTAIR INTERACTS WITH PRC2 AND ALSO BINDS RNA-BINDING E3 LIGASES, SERVING AS A UBIQUITINATION SCAFFOLD. HEREIN, WE IDENTIFIED THE RNA HELICASE, DEAD BOX PROTEIN 5 (DDX5), AS A REGULATOR OF SUZ12 STABILITY AND PRC2-MEDIATED GENE REPRESSION, ACTING BY REGULATING RNA-PROTEIN COMPLEXES FORMED WITH HOTAIR. SPECIFICALLY, KNOCKDOWN OF DDX5 AND/OR HOTAIR ENABLED REEXPRESSION OF PRC2-REPRESSED GENES EPITHELIAL CELL ADHESION MOLECULE (EPCAM) AND PLURIPOTENCY GENES. ALSO, KNOCKDOWN OF DDX5 ENHANCED TRANSCRIPTION FROM THE HBV MINICHROMOSOME. THE HELICASE ACTIVITY OF DDX5 STABILIZED SUZ12- AND PRC2-MEDIATED GENE SILENCING, BY DISPLACING THE RNA-BINDING E3 LIGASE, MEX-3 RNA-BINDING FAMILY MEMBER B (MEX3B), FROM HOTAIR. CONVERSELY, ECTOPIC EXPRESSION OF MEX3B UBIQUITINATED SUZ12, DISPLACED DDX5 FROM HOTAIR, AND INDUCED SUZ12 DOWN-REGULATION. IN G2 PHASE OF CELLS EXPRESSING THE HBV X PROTEIN (HBX), SUZ12 PREFERENTIALLY ASSOCIATED WITH MEX3B, BUT NOT DDX5, RESULTING IN DE-REPRESSION OF PRC2 TARGETS, INCLUDING EPCAM AND PLURIPOTENCY GENES. SIGNIFICANTLY, LIVER TUMORS FROM HBX/C-MYC BITRANSGENIC MICE AND CHRONICALLY HBV-INFECTED PATIENTS EXHIBITED A STRONG NEGATIVE CORRELATION BETWEEN DDX5 MESSENGER RNA LEVELS, PLURIPOTENCY GENE EXPRESSION, AND LIVER TUMOR DIFFERENTIATION. NOTABLY, CHRONICALLY INFECTED HBV PATIENTS WITH HCC EXPRESSING REDUCED DDX5 EXHIBITED POOR PROGNOSIS AFTER TUMOR RESECTION, IDENTIFYING DDX5 AS AN IMPORTANT PLAYER IN POOR PROGNOSIS HCC. CONCLUSION: THE RNA HELICASE DDX5, AND E3 LIGASE MEX3B, ARE IMPORTANT CELLULAR TARGETS FOR THE DESIGN OF NOVEL, EPIGENETIC THERAPIES TO COMBAT HBV INFECTION AND POOR PROGNOSIS HBV-ASSOCIATED LIVER CANCER. (HEPATOLOGY 2016;64:1033-1048). 2016 16 2379 25 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 17 442 25 ANTIVIRAL THERAPIES FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A CRITICAL RISK FACTOR FOR THE CARCINOGENESIS AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC). IT PROMOTES HCC DEVELOPMENT BY INDUCING LIVER FIBROGENESIS, GENETIC AND EPIGENETIC ALTERATIONS, AND THE EXPRESSION OF ACTIVE VIRAL-CODED PROTEINS. EFFECTIVE ANTIVIRAL TREATMENTS INHIBIT THE REPLICATION OF HBV, REDUCE SERUM VIRAL LOAD AND ACCELERATE HEPATITIS B E ANTIGEN SERUM CONVERSION. TIMELY INITIATION OF ANTIVIRAL TREATMENT IS NOT ONLY ESSENTIAL FOR PREVENTING THE INCIDENCE OF HCC IN CHRONIC HEPATITIS B PATIENTS, BUT ALSO IMPORTANT FOR REDUCING HBV REACTIVATION, IMPROVING LIVER FUNCTION, REDUCING OR DELAYING HCC RECURRENCE, AND PROLONGING OVERALL SURVIVAL OF HBV-RELATED HCC PATIENTS AFTER CURATIVE AND PALLIATIVE THERAPIES. THE SELECTION OF ANTIVIRAL DRUGS, MONITORING OF INDICATORS SUCH AS HBV DNA AND HEPATITIS B SURFACE ANTIGEN, AND TIMELY RESCUE TREATMENT WHEN NECESSARY, ARE ESSENTIAL IN ANTIVIRAL THERAPIES FOR HBV-RELATED HCC. 2015 18 1042 27 CLINICAL AND MOLECULAR BASIS OF HEPATOCELLULAR CARCINOMA AFTER HEPATITIS C VIRUS ERADICATION. HEPATOCELLULAR CARCINOMA (HCC) ARISES IN THE BACKGROUND OF CHRONIC LIVER DISEASES, INCLUDING HEPATITIS AND LIVER CIRRHOSIS CAUSED BY HEPATITIS C VIRUS (HCV) INFECTION. IT IS WELL KNOWN THAT HCV ERADICATION USING ANTIVIRAL DRUGS CAN EFFICIENTLY INHIBIT HEPATOCARCINOGENESIS. RECENT ADVANCES IN AND DEVELOPMENT OF DIRECT-ACTING ANTIVIRAL (DAA) DRUGS HAS REVOLUTIONIZED THE TREATMENT OF HCV INFECTION, AND THE VAST MAJORITY OF HCV PATIENTS CAN ACHIEVE HCV ERADICATION USING DAAS. HOWEVER, MOUNTING EVIDENCE CLEARLY INDICATES THAT HCC INEVITABLY OCCURS IN A SUBSET OF PATIENTS AFTER SUCCESSFUL VIRAL ERADICATION USING DAA THERAPY. CANCER IS A GENETIC DISEASE, AND THE ACCUMULATION OF GENETIC AND EPIGENETIC ABERRATIONS MAY CAUSE HEPATOCARCINOGENESIS IN CHRONICALLY DAMAGED LIVER, EVEN AFTER VIRUS ELIMINATION. IN THIS REVIEW, WE HIGHLIGHT HCC DEVELOPMENT AFTER HCV ERADICATION AND DISCUSS THE CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS OF TUMORIGENESIS AFTER VIRUS ELIMINATION, FOCUSING ON THE GENETIC AND EPIGENETIC BACKGROUND OF CHRONICALLY DAMAGED LIVER TISSUES. 2022 19 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 20 3794 35 INTERLEUKIN-33 MEDIATES BOTH IMMUNE-RELATED AND NON-IMMUNE-RELATED INHIBITORY EFFECTS AGAINST HEPATITIS B VIRUS. CHRONIC INFECTION BY HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH HIGH RISKS OF LIVER FIBROSIS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN THE NUCLEUS OF INFECTED HEPATOCYTE SERVES AS TRANSCRIPTION TEMPLATE. NEITHER NATURAL RESOLUTION OF ACUTE INFECTION NOR CURRENT TREATMENT OPTIONS FOR CHRONIC INFECTION ARE BELIEVED TO CAUSE CCCDNA CLEARANCE. WE PREVIOUSLY SHOWED THAT INJECTION OF IL-33-EXPRESSING PLASMID FACILITATED CLEARANCE OF INTRAHEPATIC HBV DNA IN A MOUSE MODEL OF HBV PERSISTENCE. IN THIS WORK, HBV-TARGETING THERAPEUTIC EFFECTS OF IL-33 WERE FURTHER EXPLORED. MURINE IL-33 DELIVERED BY RECOMBINANT ADENO-ASSOCIATED VIRUS (AAV-MIL-33) INDUCED CLEARANCE OF BOTH SERUM HBV MARKERS AND INTRAHEPATIC HBV DNA IN TWO MOUSE MODELS OF HBV PERSISTENCE BASED ON REPLICON PLASMID AND RECOMBINANT CCCDNA (RCCCDNA) RESPECTIVELY. CLEARANCE WAS ASSOCIATED WITH SERUM ALT ELEVATIONS AND LIVER INFILTRATIONS BY CD4(+) AND CD8(+) T CELLS, INDICATING IL-33-INDUCED CELLULAR IMMUNE RESPONSES AGAINST HBV-HARBORING CELLS. ADOPTIVE TRANSFER OF SPLENOCYTES FROM AAV-MIL-33-CURED MICE WAS INDEED SUFFICIENT TO ENGENDER SIMILAR CLEARANCE IN RECIPIENT MICE. IN VITRO, INTRACELLULAR, INSTEAD OF EXTRACELLULAR, IL-33 WAS MAINLY RESPONSIBLE FOR REPRESSING VIRAL TRANSCRIPTION, PROTEIN PRODUCTION AND GENOME REPLICATION IN HUH7 CELLS TRANSFECTED WITH HBV REPLICON OR RCCCDNA. IL-33 WAS SHOWN TO BE RECRUITED ONTO RCCCDNA MINICHROMOSOME ACCOMPANIED BY LOSS OF TRANSCRIPTIONAL ACTIVATION EPIGENETIC MARKS. FINALLY, TRANSFECTION OF IL-33 INTO HBV-INFECTED HEPG2/NTCP CELLS RESULTED IN REDUCED TRANSCRIPTION, ANTIGEN EXPRESSION AND GENOME REPLICATION, SUGGESTING REPRESSION OF CANONICAL CCCDNA. THESE DATA DEMONSTRATED DIVERSE INHIBITORY EFFECTS ON HBV AND HBV-INFECTED CELLS MEDIATED BY IL-33, AND SUGGEST IL-33 AS AN INTERESTING THERAPEUTIC CANDIDATE. 2022