1  1646 130 DOES THE HEPATITIS B ANTIGEN HBX PROMOTE THE APPEARANCE OF LIVER CANCER STEM CELLS? HEPATITIS B VIRUS (HBV) IS A MAJOR ETIOLOGIC AGENT OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV-ENCODED X ANTIGEN, HBX, AND PATHWAYS IMPLICATED IN THE SELF-RENEWAL OF STEM CELLS CONTRIBUTE TO HCC, BUT IT IS NOT CLEAR WHETHER HBX EXPRESSION PROMOTES "STEMNESS." THUS, EXPERIMENTS WERE DESIGNED TO TEST THE HYPOTHESIS THAT HBX TRIGGERS MALIGNANT TRANSFORMATION BY PROMOTING PROPERTIES THAT ARE CHARACTERISTIC OF CANCER STEM CELLS (CSC). TO TEST THIS HYPOTHESIS, HEPG2 CELLS WERE STABLY TRANSDUCED WITH HBX AND THEN ASSAYED FOR PHENOTYPIC AND MOLECULAR CHARACTERISTICS OF "STEMNESS." THE RELATIONSHIP BETWEEN HBX AND "STEMNESS"-ASSOCIATED MARKERS WAS ALSO EVALUATED BY IMMUNOHISTOCHEMICAL STAINING OF LIVER AND TUMOR TISSUE SECTIONS FROM HBV-INFECTED PATIENTS. THE RESULTS SHOWED THAT OCT-4, NANOG, KLF-4, BETA-CATENIN, AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) WERE ACTIVATED BY HBX IN VITRO AND IN VIVO. EPCAM WAS DETECTED IN THE NUCLEI OF HUMAN HCC CELLS FROM INFECTED PATIENTS. HBX PROMOTES "STEMNESS" BY ACTIVATING BETA-CATENIN AND EPIGENETIC UPREGULATION OF MIR-181, BOTH OF WHICH TARGET EPCAM. HBX EXPRESSION WAS ALSO ASSOCIATED WITH DEPRESSED LEVELS OF E-CADHERIN. MOREOVER, HBX STIMULATED CELL MIGRATION, GROWTH IN SOFT AGAR, AND SPHEROID FORMATION. THIS WORK IS THE FIRST TO PROPOSE THAT HBV PROMOTES "STEMNESS" IN THE PATHOGENESIS OF HCC. HBX-ASSOCIATED UPREGULATED EXPRESSION OF MULTIPLE "STEMNESS" MARKERS SUPPORTS THE HYPOTHESIS THAT HBX CONTRIBUTES TO HEPATOCARCINOGENESIS, AT LEAST IN PART, BY PROMOTING CHANGES IN GENE EXPRESSION THAT ARE CHARACTERISTICS OF CSCS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  3805  33 INTESTINE-SPECIFIC HOMEOBOX (ISX) INDUCES INTESTINAL METAPLASIA AND CELL PROLIFERATION TO CONTRIBUTE TO GASTRIC CARCINOGENESIS. BACKGROUND: HELICOBACTER PYLORI INDUCES CHRONIC INFLAMMATION AND INTESTINAL METAPLASIA (IM) THROUGH GENETIC AND EPIGENETIC CHANGES AND ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS THAT CONTRIBUTE TO GASTRIC CARCINOGENESIS. HOWEVER, THE PRECISE MECHANISM OF IM IN GASTRIC CARCINOGENESIS HAS NOT BEEN FULLY ELUCIDATED. WE PREVIOUSLY FOUND THAT INTESTINE-SPECIFIC HOMEOBOX (ISX) MRNA EXPRESSION INCREASED IN ORGANOIDS CULTURED FROM HELICOBACTER-INFECTED MOUSE MUCOSA. IN THIS STUDY, WE ELUCIDATE THE ROLE OF ISX IN THE DEVELOPMENT OF IM AND GASTRIC CARCINOGENESIS. METHODS: ISX EXPRESSION WAS ASSESSED IN HELICOBACTER-INFECTED MOUSE AND HUMAN GASTRIC MUCOSA. MKN45 GASTRIC CANCER CELLS WERE CO-CULTURED WITH H. PYLORI TO DETERMINE WHETHER HELICOBACTER INFECTION INDUCED ISX EXPRESSION. WE ESTABLISHED STABLE MKN45 TRANSFECTED CELLS EXPRESSING ISX (STABLE-ISX MKN45) AND PERFORMED A SPHEROID COLONY FORMATION ASSAY AND A XENOGRAFT MODEL. WE PERFORMED ISX IMMUNOHISTOCHEMISTRY IN CANCER AND ADJACENT GASTRIC TISSUES. RESULTS: ISX EXPRESSION WAS INCREASED IN MOUSE AND HUMAN GASTRIC MUCOSA INFECTED WITH HELICOBACTER. THE PRESENCE OF IM AND H. PYLORI INFECTION IN HUMAN STOMACH WAS CORRELATED WITH ISX EXPRESSION. H. PYLORI INDUCED ISX MRNA AND PROTEIN EXPRESSION. CDX1/2, CYCLIND1, AND MUC2 WERE UPREGULATED IN STABLE-ISX MKN45, WHEREAS MUC5AC WAS DOWNREGULATED. STABLE-ISX MKN45 CELLS FORMED MORE SPHEROID COLONIES, AND HAD HIGH TUMORIGENIC ABILITY. ISX EXPRESSION IN GASTRIC CANCER AND ADJACENT MUCOSA WERE CORRELATED. CONCLUSIONS: ISX EXPRESSION INDUCED BY H. PYLORI INFECTION MAY LEAD TO IM AND HYPERPROLIFERATION OF GASTRIC MUCOSA THROUGH CDX1/2 AND CYCLIND1 EXPRESSION, CONTRIBUTING TO GASTRIC CARCINOGENESIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  6659  36 UPREGULATION OF AKT3 CONFERS RESISTANCE TO THE AKT INHIBITOR MK2206 IN BREAST CANCER. ACQUIRED RESISTANCE TO MOLECULAR TARGETED THERAPY REPRESENTS A MAJOR CHALLENGE FOR THE EFFECTIVE TREATMENT OF CANCER. HYPERACTIVATION OF THE PI3K/AKT PATHWAY IS FREQUENTLY OBSERVED IN VIRTUALLY ALL HUMAN MALIGNANCIES, AND NUMEROUS PI3K AND AKT INHIBITORS ARE CURRENTLY UNDER CLINICAL EVALUATION. HOWEVER, MECHANISMS OF ACQUIRED RESISTANCE TO AKT INHIBITORS HAVE YET TO BE DESCRIBED. HERE, WE USE A BREAST CANCER PRECLINICAL MODEL TO IDENTIFY RESISTANCE MECHANISMS TO A SMALL MOLECULE ALLOSTERIC AKT INHIBITOR, MK2206. USING A STEP-WISE AND CHRONIC HIGH-DOSE EXPOSURE, BREAST CANCER CELL LINES HARBORING ONCOGENIC PI3K RESISTANT TO MK2206 WERE ESTABLISHED. USING THIS MODEL, WE REVEAL THAT AKT3 EXPRESSION IS MARKEDLY UPREGULATED IN AKT INHIBITOR-RESISTANT CELLS. INDUCTION OF AKT3 IS REGULATED EPIGENETICALLY BY THE BROMODOMAIN AND EXTRA TERMINAL DOMAIN PROTEINS. IMPORTANTLY, KNOCKDOWN OF AKT3, BUT NOT AKT1 OR AKT2, IN RESISTANT CELLS RESTORES SENSITIVITY TO MK2206. AKT INHIBITOR-RESISTANT CELLS ALSO DISPLAY AN EPITHELIAL TO MESENCHYMAL TRANSITION PHENOTYPE AS ASSESSED BY ALTERATIONS IN THE LEVELS OF E-CADHERIN, N-CADHERIN, AND VIMENTIN, AS WELL AS ENHANCED INVASIVENESS OF TUMOR SPHEROIDS. NOTABLY, THE INVASIVE MORPHOLOGY OF RESISTANT SPHEROIDS IS DIMINISHED UPON AKT3 DEPLETION. WE ALSO SHOW THAT RESISTANCE TO MK2206 IS REVERSIBLE BECAUSE UPON DRUG REMOVAL RESISTANT CELLS REGAIN SENSITIVITY TO AKT INHIBITION, ACCOMPANIED BY REEXPRESSION OF EPITHELIAL MARKERS AND REDUCTION OF AKT3 EXPRESSION, IMPLYING THAT EPIGENETIC REPROGRAMMING CONTRIBUTES TO ACQUISITION OF RESISTANCE. THESE FINDINGS PROVIDE A RATIONALE FOR DEVELOPING THERAPEUTICS TARGETING AKT3 TO CIRCUMVENT ACQUIRED RESISTANCE IN BREAST CANCER. MOL CANCER THER; 15(8); 1964-74. (C)2016 AACR.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  1700  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  3232  23 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  5694  35 SILENCING THE OCT4-PG1 PSEUDOGENE REDUCES OCT-4 PROTEIN LEVELS AND CHANGES CHARACTERISTICS OF THE MULTIDRUG RESISTANCE PHENOTYPE IN CHRONIC MYELOID LEUKEMIA. CANCER STEM CELLS SHOW EPIGENETIC PLASTICITY AND INTRINSIC RESISTANCE TO ANTI-CANCER THERAPY, RENDERING CAPABLE OF INITIATING CANCER RELAPSE AND PROGRESSION. TRANSCRIPTION FACTOR OCT-4 REGULATES VARIOUS PATHWAYS IN STEM CELLS, BUT ITS EXPRESSION CAN BE REGULATED BY PSEUDOGENES. THIS WORK EVALUATED HOW OCT4-PG1 PSEUDOGENE CAN AFFECT OCT-4 EXPRESSION AND MECHANISMS RELATED TO THE MULTIDRUG RESISTANCE (MDR) PHENOTYPE IN FEPS CELLS. CONSIDERING THAT OCT-4 PROTEIN IS A TRANSCRIPTION FACTOR THAT REGULATES EXPRESSION OF ABC TRANSPORTERS, LEVEL OF GENE EXPRESSION, ACTIVITY OF ABC PROTEINS AND CELL SENSITIVITY TO CHEMOTHERAPY WERE EVALUATED AFTER OCT4-PG1 SILENCING. BESIDES WE SET UP A STRING NETWORK. RESULTS SHOWED THAT AFTER OCT4-PG1 SILENCING, CELLS EXPRESSED OCT-4 GENE AND PROTEIN TO A LESSER EXTENT THAN MOCK CELLS. THE GENE AND PROTEIN EXPRESSION OF ABCB1, AS WELL AS ITS ACTIVITY WERE REDUCED. ON THE OTHER HAND, ALOX5 AND ABCC1 GENES WAS INCREASED EVEN AS THE ACTIVITY OF THIS TRANSPORTER. MOREOVER, THE SILENCING CELLS BECOME SENSITIVE TO TWO CHEMOTHERAPICS TESTED. THE NETWORK STRUCTURE DEMONSTRATED THAT OCT4-PG1 PROTEIN INTERACTS DIRECTLY WITH OCT-4, SOX2, AND NANOG AND INDIRECTLY WITH ABC TRANSPORTERS. WE CONCLUDE THAT OCT4-PG1 PSEUDOGENE PLAYS A KEY ROLE IN THE REGULATION OCT-4 TRANSCRIPTION FACTOR, WHICH ALTERS MDR PHENOTYPE IN THE FEPS CELL LINE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  1483  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  4293  29 MICRORNA PROFILING IN MUC2 KNOCKOUT MICE OF COLITIS-ASSOCIATED CANCER MODEL REVEALS EPIGENETIC ALTERATIONS DURING CHRONIC COLITIS MALIGNANT TRANSFORMATION. OUR PREVIOUS STUDIES HAVE DEMONSTRATED THAT GENETIC DELETION OF THE MUC2 GENE CAUSES COLORECTAL CANCERS IN MICE. THE CURRENT STUDY FURTHER SHOWED THAT AT THE EARLY STAGE (<3 MONTHS) THE MUC2 KNOCKOUT MICE SPONTANEOUSLY DEVELOPED CHRONIC INFLAMMATION IN COLON AND RECTUM, SIMILAR PATHOLOGICAL FEATURES AS HUMAN COLITIS; AND AT THE LATE STAGE (>3 MONTHS) THE MICE EXHIBITED COLORECTAL CANCER, INCLUDING A UNIQUE PHENOTYPE OF RECTAL PROLAPSED (RECTAL SEVERE INFLAMMATION AND ADENOCARCINOMA). THUS, THE AGE OF 3 MONTHS MIGHT BE THE KEY POINT OF THE TRANSITION FROM CHRONIC INFLAMMATION TO CANCER. TO DETERMINE THE MECHANISMS OF THE MALIGNANT TRANSFORMATION, WE CONDUCTED MIRNA ARRAY ON THE COLONIC EPITHELIAL CELLS FROM THE 3-MONTH MUC2-/- AND +/+ MICE. MICRORNA PROFILING SHOWED DIFFERENTIAL EXPRESSION OF MIRNAS (I.E. LOWER OR HIGHER EXPRESSION ENRICHMENTS) IN MUC2-/- MICE. 15 OF THEM WERE VALIDATED BY QUANTITATIVE PCR. BASED ON RELEVANCE TO CYTOKINE AND CANCER, 4 MIRNAS (MIR-138, MIR-145, MIR-146A, AND MIR-150) WERE VALIDATE AND WERE FOUND SIGNIFICANTLY DOWNREGULATED IN HUMAN COLITIS AND COLORECTAL CANCER TISSUES. THE NETWORK OF THE TARGETS OF THESE MIRNAS WAS CHARACTERIZED, AND INTERESTEDLY, MIRNA-ASSOCIATED CYTOKINES WERE SIGNIFICANTLY INCREASED IN MUC2-/-MICE. THIS IS THE FIRST TO REVEAL THE IMPORTANCE OF ABERRANT EXPRESSION OF MIRNAS IN DYNAMICALLY TRANSFORMATION FROM CHRONIC COLITIS TO COLITIS-ASSOCIATED CANCER. THESE FINDINGS SHED LIGHT ON REVEALING THE MECHANISMS OF CHRONIC COLITIS MALIGNANT TRANSFORMATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  3227  32 HELICOBACTER PYLORI INFECTION-INDUCED H3SER10 PHOSPHORYLATION IN STEPWISE GASTRIC CARCINOGENESIS AND ITS CLINICAL IMPLICATIONS. BACKGROUND: OUR PREVIOUS WORKS HAVE DEMONSTRATED THAT HELICOBACTER PYLORI (HP) INFECTION CAN ALTER HISTONE H3 SERINE 10 PHOSPHORYLATION STATUS IN GASTRIC EPITHELIAL CELLS. HOWEVER, WHETHER HELICOBACTER PYLORI-INDUCED HISTONE H3 SERINE 10 PHOSPHORYLATION PARTICIPATES IN GASTRIC CARCINOGENESIS IS UNKNOWN. WE INVESTIGATE THE EXPRESSION OF HISTONE H3 SERINE 10 PHOSPHORYLATION IN VARIOUS STAGES OF GASTRIC DISEASE AND EXPLORE ITS CLINICAL IMPLICATION. MATERIALS AND METHODS: STOMACH BIOPSY SAMPLES FROM 129 PATIENTS WERE COLLECTED AND STAINED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION, KI67, AND HELICOBACTER PYLORI BY IMMUNOHISTOCHEMISTRY STAINING, EXPRESSED AS LABELING INDEX. THEY WERE CATEGORIZED INTO NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, LOW-GRADE INTRAEPITHELIAL NEOPLASIA, HIGH-GRADE INTRAEPITHELIAL NEOPLASIA, AND INTESTINAL-TYPE GASTRIC CANCER GROUPS. HELICOBACTER PYLORI INFECTION WAS DETERMINED BY EITHER (13) C-UREA BREATH TEST OR IMMUNOHISTOCHEMISTRY STAINING. RESULTS: IN HELICOBACTER PYLORI-NEGATIVE PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION WAS GRADUALLY INCREASED IN NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA GROUPS, PEAKED AT LOW-GRADE INTRAEPITHELIAL NEOPLASIA, AND DECLINED IN HIGH-GRADE INTRAEPITHELIAL NEOPLASIA AND GASTRIC CANCER GROUPS. IN HELICOBACTER PYLORI-INFECTED PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION FOLLOWED THE SIMILAR PATTERN AS ABOVE, WITH INCREASED EXPRESSION OVER THE CORRESPONDING HELICOBACTER PYLORI-NEGATIVE CONTROLS EXCEPT IN NONATROPHIC GASTRITIS PATIENT WHOSE LABELING INDEX WAS DECREASED WHEN COMPARED WITH HELICOBACTER PYLORI-NEGATIVE CONTROL. LABELING INDEX OF KI67 IN HELICOBACTER PYLORI-NEGATIVE GROUPS WAS HIGHER IN GASTRIC CANCER THAN CHRONIC ATROPHIC GASTRITIS AND LOW-GRADE INTRAEPITHELIAL NEOPLASIA GROUPS, AND HIGHER IN INTESTINAL METAPLASIA GROUP COMPARED WITH CHRONIC ATROPHIC GASTRITIS GROUP. IN HELICOBACTER PYLORI-POSITIVE GROUPS, KI67 LABELING INDEX WAS INCREASED STEPWISE FROM NONATROPHIC GASTRITIS TO GASTRIC CANCER EXCEPT SLIGHTLY DECREASE IN CHRONIC ATROPHIC GASTRITIS GROUP. IN ADDITION, WE NOTED THAT HISTONE H3 SERINE 10 PHOSPHORYLATION STAINING IS ACCOMPANIED WITH ITS LOCATION CHANGES FROM GASTRIC GLAND BOTTOM EXPANDED TO WHOLE GLAND AS DISEASE STAGE PROGRESS. CONCLUSIONS: THESE RESULTS INDICATE THAT STEPWISE GASTRIC CARCINOGENESIS IS ASSOCIATED WITH ALTERED HISTONE H3 SERINE 10 PHOSPHORYLATION, HELICOBACTER PYLORI INFECTION ENHANCES HISTONE H3 SERINE 10 PHOSPHORYLATION EXPRESSION IN THESE PROCESSES; IT IS ALSO ACCOMPANIED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION LOCATION CHANGE FROM GLAND BOTTOM STAINING EXPAND TO WHOLE GLAND EXPRESSION. THE RESULTS SUGGEST THAT EPIGENETIC DYSREGULATION MAY PLAY IMPORTANT ROLES IN HELICOBACTER PYLORI-INDUCED GASTRIC CANCER.	2018	

10  1730  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  2302  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12   767  32 CD24 MEDIATES GASTRIC CARCINOGENESIS AND PROMOTES GASTRIC CANCER PROGRESSION VIA STAT3 ACTIVATION. THE DEVELOPMENT OF GASTRIC CANCER (GC) IS A COMPLEX MULTISTEP PROCESS, INCLUDING NUMEROUS GENETIC AND EPIGENETIC CHANGES. CD24 IS ASSOCIATED WITH ENHANCED INVASIVENESS OF GC AND A POOR PROGNOSIS. HOWEVER, THE MECHANISM BY WHICH CD24 INDUCES GC PROGRESSION REMAINS POORLY CHARACTERIZED. HERE, WE FOUND THAT THE EXPRESSION OF CD24 GRADUALLY INCREASED IN SAMPLES OF NORMAL GASTRIC MUCOSA, NON-ATROPHIC CHRONIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS (CAG), CAG WITH INTESTINAL METAPLASIA, DYSPLASIA AND GC. MOREOVER, THE KNOCKDOWN OF CD24 INDUCED SIGNIFICANT LEVELS OF APOPTOSIS IN GC CELLS VIA THE MITOCHONDRIAL APOPTOTIC PATHWAY. CD24 MAY ALSO PROMOTE CELLULAR INVASION AND REGULATE THE EXPRESSION OF E-CADHERIN, FIBRONECTIN AND VITAMIN D RECEPTOR IN GC CELLS. THE ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) MAY MEDIATE CD24-INDUCED GC SURVIVAL AND INVASION IN VITRO. FURTHERMORE, CD24-INDUCED GC PROGRESSION AND STAT3 ACTIVATION COULD ALSO BE DETECTED IN VIVO AND IN CLINICAL GC TISSUES SAMPLES. TAKEN TOGETHER, OUR RESULTS INDICATE THAT CD24 MEDIATES GASTRIC CARCINOGENESIS AND MAY PROMOTE GC PROGRESSION BY SUPPRESSING APOPTOSIS AND PROMOTING INVASION, WITH THE ACTIVATION OF STAT3 PLAYING A CRITICAL ROLE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  2842  35 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  4903  31 P16 PROMOTER HYPERMETHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA WITH OR WITHOUT HEPATITIS VIRUS INFECTION. BACKGROUND: EPIGENETIC ALTERATION THROUGH METHYLATION IS ONE OF THE MOST IMPORTANT STEPS IN CARCINOGENESIS. HOWEVER, THE RELATION BETWEEN HEPATITIS VIRUS INFECTION AND EPIGENETIC ALTERATIONS IS POORLY UNDERSTOOD. METHODS: SIXTEEN PATIENTS WITHOUT HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) AND 35 PATIENTS WITH HBV OR HCV WHO UNDERWENT LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA (HCC) WERE STUDIED. MUTATION OF P53 WAS DETECTED BY DIRECT SEQUENCING. METHYLATION STATUS OF P16 WAS EVALUATED IN TUMOR AND NONCANCEROUS LIVER TISSUES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: IN HCC WITHOUT HBV AND HCV, P53 MUTATIONS WERE DETECTED IN 5 (31%) OF 16 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (25%) OF 8 MODERATELY DIFFERENTIATED HCCS, 6 (75%) OF 8 POORLY DIFFERENTIATED HCCS, AND NONE OF 16 NONCANCEROUS TISSUE SPECIMENS. IN HCC WITH HBV OR HCV, P53 MUTATIONS WERE DETECTED IN 8 (23%) OF 35 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (100%) OF 2 WELL-DIFFERENTIATED HCCS, 13 (76%) OF 17 MODERATELY DIFFERENTIATED HCCS, 12 (75%) OF 16 POORLY DIFFERENTIATED HCCS, AND 9 (26%) OF 35 NONCANCEROUS LIVER TISSUE SPECIMENS. CONCLUSIONS: OUR RESULTS SUGGEST THAT HEPATITIS VIRUSES MIGHT INDUCE METHYLATION OF P16 PROMOTER IN LIVER WITH CHRONIC INFLAMMATION, BEFORE APPEARANCE OF HCC.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15   878  44 CHRONIC CADMIUM EXPOSURE AGGRAVATES MALIGNANT PHENOTYPES OF NASOPHARYNGEAL CARCINOMA BY ACTIVATING THE WNT/BETA-CATENIN SIGNALING PATHWAY VIA HYPERMETHYLATION OF THE CASEIN KINASE 1ALPHA PROMOTER. BACKGROUND: OUR PREVIOUS STUDY HAS SHOWN THAT CADMIUM (CD) EXPOSURE IS NOT ONLY A RISK FACTOR FOR NASOPHARYNGEAL CARCINOMA (NPC), BUT ALSO CORRELATED WITH THE CLINICAL STAGE AND LYMPH NODE METASTASIS. HOWEVER, THE UNDERLYING MOLECULAR EVENTS OF CD INVOLVED IN NPC PROGRESSION REMAIN TO BE ELUCIDATED. PURPOSE: THE OBJECTIVE OF THIS STUDY WAS TO DECIPHER HOW CD IMPACTS THE MALIGNANT PHENOTYPES OF NPC CELLS. METHODS: NPC CELL LINES CNE-1 AND CNE-2 WERE CONTINUOUSLY EXPOSED WITH 1 MUM CD CHLORIDE FOR 10 WEEKS, DESIGNATING AS CHRONIC CD TREATED NPC CELLS (CCT-NPC). MTT ASSAY, COLONY FORMATION ASSAY AND XENOGRAFT TUMOR GROWTH WERE USED TO ASSESS CELL VIABILITY IN VITRO AND IN VIVO. TRANSWELL ASSAYS WERE PERFORMED TO DETECT CELL INVASION AND MIGRATION. THE PROTEIN LEVELS OF E-CADHERIN, N-CADHERIN, VIMENTIN AS WELL AS BETA-CATENIN AND CASEIN KINASE 1ALPHA(CK1ALPHA) WERE MEASURED BY WESTERN BLOT. IMMUNOFLUORESCENCE STAINING WAS USED TO OBSERVE THE DISTRIBUTION OF FILAMENT ACTIN (F-ACTIN), BETA-CATENIN AND CK1ALPHA. THE MRNA LEVELS OF DOWNSTREAM TARGET GENES OF BETA-CATENIN WERE DETECTED BY RT-PCR. WNT/BETA-CATENIN SIGNALING ACTIVITY WAS ASSESSED BY TOPFLASH/FOPFLASH DUAL LUCIFERASE REPORT SYSTEM. MS-PCR WAS USED TO DETECT THE METHYLATION STATUS OF CK1ALPHA. FINALLY, THE ACTIVATION OF WNT/BETA-CATENIN PATHWAY AND CELL BIOLOGICAL PROPERTIES WERE EXAMINED FOLLOWING TREATMENT OF CCT-NPC CELLS WITH 5-AZA-2-DEOXY-CYTIDINE(5-AZA-CDR). RESULTS: CCT-NPC CELLS SHOWED AN INCREASE IN CELL PROLIFERATION, COLONY FORMATION, INVASION AND MIGRATION COMPARED TO THE PARENTAL CELLS. CD ALSO INDUCED CYTOSKELETON REORGANIZATION AND EPITHELIAL-TO-MESENCHYMAL TRANSITION. UPREGULATION AND NUCLEAR TRANSLOCATION OF BETA-CATENIN AND INCREASED LUCIFERASE ACTIVITY ACCOMPANIED WITH TRANSCRIPTION OF DOWNSTREAM TARGET GENES WERE FOUND IN CCT-NPC CELLS. TREATMENT OF CCT-CNE1 CELLS WITH 5-AZA-CDR COULD REVERSE THE HYPERMETHYLATION OF CK1ALPHA AND ATTENUATE THE CELL MALIGNANCY. CONCLUSION: THESE RESULTS SUPPORT A ROLE FOR CHRONIC CD EXPOSURE AS A DRIVING FORCE FOR THE MALIGNANT PROGRESSION OF NPC VIA EPIGENETIC ACTIVATION OF THE WNT/BETA-CATENIN PATHWAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  3825  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  3794  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  3246  34 HEPATITIS B VIRUS (HBV) INDUCES THE EXPRESSION OF INTERLEUKIN-8 THAT IN TURN REDUCES HBV SENSITIVITY TO INTERFERON-ALPHA. HIGH LEVELS OF SERUM INTERLEUKIN-8 (IL-8) HAVE BEEN DETECTED IN CHRONIC HEPATITIS B (CHB) PATIENTS DURING EPISODES OF HEPATITIS FLARES. WE INVESTIGATED WHETHER HEPATITIS B VIRUS (HBV) MAY DIRECTLY INDUCE IL-8 PRODUCTION AND WHETHER IL-8 MAY ANTAGONIZE INTERFERON-ALPHA (IFN-ALPHA) ANTIVIRAL ACTIVITY AGAINST HBV. WE SHOWED THAT CHB PATIENTS HAD SIGNIFICANTLY HIGHER IL-8 LEVELS BOTH IN SERUM AND IN LIVER TISSUE THAN CONTROLS. IN HBV-REPLICATING HEPG2 CELLS, IL-8 TRANSCRIPTION WAS SIGNIFICANTLY ACTIVATED. AP-1, C/EBP AND NF-KB TRANSCRIPTION FACTORS WERE CONCURRENTLY NECESSARY FOR MAXIMUM IL-8 INDUCTION. MOREOVER, HBX VIRAL PROTEIN WAS RECRUITED ONTO THE IL-8 PROMOTER AND THIS WAS PARALLELED BY IL8-BOUND HISTONE HYPERACETYLATION AND BY ACTIVE RECRUITMENT OF TRANSCRIPTIONAL COACTIVATORS. INHIBITION OF IL-8 INCREASES THE ANTIVIRAL ACTIVITY OF IFN-ALPHA AGAINST HBV. OUR RESULTS INDICATE THAT HBV ACTIVATES IL-8 GENE EXPRESSION BY TARGETING THE EPIGENETIC REGULATION OF THE IL-8 PROMOTER AND THAT IL-8 MAY CONTRIBUTE TO REDUCE HBV SENSITIVITY TO IFN-ALPHA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  1122  38 COMPARISON OF GENE EXPRESSION PROFILES IN CHROMATE TRANSFORMED BEAS-2B CELLS. BACKGROUND: HEXAVALENT CHROMIUM [CR(VI)] IS A POTENT HUMAN CARCINOGEN. OCCUPATIONAL EXPOSURE HAS BEEN ASSOCIATED WITH INCREASED RISK OF RESPIRATORY CANCER. MULTIPLE MECHANISMS HAVE BEEN SHOWN TO CONTRIBUTE TO CR(VI) INDUCED CARCINOGENESIS, INCLUDING DNA DAMAGE, GENOMIC INSTABILITY, AND EPIGENETIC MODULATION, HOWEVER, THE MOLECULAR MECHANISM AND DOWNSTREAM GENES MEDIATING CHROMIUM'S CARCINOGENICITY REMAIN TO BE ELUCIDATED. METHODS/RESULTS: WE ESTABLISHED CHROMATE TRANSFORMED CELL LINES BY CHRONIC EXPOSURE OF NORMAL HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS TO LOW DOSES OF CR(VI) FOLLOWED BY ANCHORAGE-INDEPENDENT GROWTH. THESE TRANSFORMED CELL LINES NOT ONLY EXHIBITED CONSISTENT MORPHOLOGICAL CHANGES BUT ALSO ACQUIRED ALTERED AND DISTINCT GENE EXPRESSION PATTERNS COMPARED WITH NORMAL BEAS-2B CELLS AND CONTROL CELL LINES (UNTREATED) THAT AROSE SPONTANEOUSLY IN SOFT AGAR. INTERESTINGLY, THE GENE EXPRESSION PROFILES OF SIX CR(VI) TRANSFORMED CELL LINES WERE REMARKABLY SIMILAR TO EACH OTHER YET DIFFERED SIGNIFICANTLY FROM THAT OF EITHER CONTROL CELL LINES OR NORMAL BEAS-2B CELLS. A TOTAL OF 409 DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED IN CR(VI) TRANSFORMED CELLS COMPARED TO CONTROL CELLS. GENES RELATED TO CELL-TO-CELL JUNCTION WERE UPREGULATED IN ALL CR(VI) TRANSFORMED CELLS, WHILE GENES ASSOCIATED WITH THE INTERACTION BETWEEN CELLS AND THEIR EXTRACELLULAR MATRICES WERE DOWN-REGULATED. ADDITIONALLY, EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION AND APOPTOSIS WERE ALSO CHANGED. CONCLUSION: THIS STUDY IS THE FIRST TO REPORT GENE EXPRESSION PROFILING OF CR(VI) TRANSFORMED CELLS. THE GENE EXPRESSION CHANGES ACROSS INDIVIDUAL CHROMATE EXPOSED CLONES WERE REMARKABLY SIMILAR TO EACH OTHER BUT DIFFERED SIGNIFICANTLY FROM THE GENE EXPRESSION FOUND IN ANCHORAGE-INDEPENDENT CLONES THAT AROSE SPONTANEOUSLY. OUR ANALYSIS IDENTIFIED MANY NOVEL GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO CHROMATE INDUCED CELL TRANSFORMATION, AND COLLECTIVELY THIS TYPE OF INFORMATION WILL PROVIDE A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING CHROMATE CARCINOGENICITY.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  3231  25 HELICOBACTER PYLORI-INDUCED MODULATION OF THE PROMOTER METHYLATION OF WNT ANTAGONIST GENES IN GASTRIC CARCINOGENESIS. BACKGROUND: THIS STUDY AIMED TO INVESTIGATE THE CHANGES IN THE PROMOTER METHYLATION AND GENE EXPRESSION OF MULTIPLE WNT ANTAGONISTS BETWEEN THE CHRONIC INFECTION AND ERADICATION OF HELICOBACTER PYLORI (H. PYLORI) IN GASTRIC CARCINOGENESIS. METHODS: THE LEVELS OF METHYLATION AND CORRESPONDING MRNA EXPRESSION OF SEVEN WNT ANTAGONIST GENES (SFRP1, -2, -5, DKK1, -2, -3, WIF1) WERE COMPARED AMONG THE PATIENTS WITH H. PYLORI-POSITIVE GASTRIC CANCERS (GCS), AND H. PYLORI-POSITIVE AND H. PYLORI-NEGATIVE CONTROLS, BY QUANTITATIVE METHYLIGHT ASSAY AND REAL-TIME REVERSE TRANSCRIPTION (RT)-POLYMERASE CHAIN REACTION (PCR), RESPECTIVELY. THE CHANGES OF THE METHYLATION AND EXPRESSION LEVELS OF THE GENES WERE ALSO COMPARED BETWEEN THE H. PYLORI ERADICATION AND H. PYLORI-PERSISTENT GROUPS 1 YEAR AFTER ENDOSCOPIC RESECTION OF GCS. RESULTS: THE METHYLATION LEVELS OF SFRP AND DKK FAMILY GENES WERE SIGNIFICANTLY INCREASED IN THE PATIENTS WITH H. PYLORI-POSITIVE GCS AND FOLLOWED BY H. PYLORI-POSITIVE CONTROLS COMPARED WITH H. PYLORI-NEGATIVE CONTROLS (P < 0.001). SFRP1, -2, AND DKK3 GENE EXPRESSION WAS STEPWISE DOWNREGULATED FROM H. PYLORI-NEGATIVE CONTROLS, H. PYLORI-POSITIVE CONTROLS, AND TO H. PYLORI-POSITIVE GCS (P < 0.05). AMONG THE WNT ANTAGONISTS, ONLY THE DEGREES OF METHYLATION AND DOWNREGULATION OF DKK3 WERE SIGNIFICANTLY REDUCED AFTER H. PYLORI ERADICATION (P < 0.05). CONCLUSION: EPIGENETIC SILENCING OF SFRP AND DKK FAMILY GENES MAY FACILITATE THE FORMATION OF AN EPIGENETIC FIELD DURING H. PYLORI-ASSOCIATED GASTRIC CARCINOGENESIS. THE EPIGENETIC FIELD MAY NOT BE REVERSED EVEN AFTER H. PYLORI ERADICATION EXCEPT BY DKK3 METHYLATION.	2018