1    84 114 A NOVEL EPIGENETIC MECHANISM OF FXR INHIBITING GLP-1 SECRETION VIA MIR-33 AND ITS DOWNSTREAM TARGETS. TYPE II DIABETES IS A COMPLEX, CHRONIC, AND PROGRESSIVE DISEASE. PREVIOUSLY, WE DEMONSTRATE THAT FXR INHIBITS GLP-1 SECRETION VIA INTERACTING WITH CREB TO INHIBIT THE TRANSCRIPTIONAL ACTIVITY OF CREB, THUS PROMOTING THE DEVELOPMENT OF TYPE II DIABETES. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND POST-TRANSCRIPTIONAL RNA REGULATION, ARE ESSENTIAL MEDIATORS CONTRIBUTING TO DIABETES-ASSOCIATED MORBIDITY AND MORTALITY. THUS, WE ATTEMPTED TO INVESTIGATE THE EPIGENETIC MECHANISMS OF FXR MODULATING GLP-1 SECRETION. FIRSTLY, THE INVOLVEMENT OF HISTONE ACETYLATION, DNA METHYLATION, AND POST-TRANSCRIPTIONAL REGULATION IN FXR INHIBITING GLP-1 SECRETION WAS VERIFIED. AS FXR OVEREXPRESSION SIGNIFICANTLY INHIBITED THE ACTIVITY OF GCG 3'-UTR, WE HYPOTHESIZE THAT MIRNA MIGHT PARTICIPATE IN THE MECHANISM. TWO ONLINE TOOLS AND REAL-TIME PCR REVEALED THAT FXR PROMOTED MIR-33 EXPRESSION. MOREOVER, MIR-33 INHIBITED THE EXPRESSION OF GCG AND CREB1 THROUGH DIRECT TARGETING IN STC-1 CELLS. FXR OVEREXPRESSION IN STC-1 CELLS SIGNIFICANTLY REDUCED THE MRNA EXPRESSION AND PROTEIN LEVELS OF BOTH GCG AND CREB1, AS WELL AS THE SECRETION OF GLP-1; MIR-33 INHIBITION EXERTED OPPOSING EFFECTS. MORE IMPORTANTLY, THE EFFECTS OF FXR OVEREXPRESSION WERE SIGNIFICANTLY REVERSED BY MIR-33 INHIBITION, INDICATING THAT FXR INHIBITED GLP-1 SECRETION THROUGH PROMOTING MIR-33 EXPRESSION, THEREFORE INHIBITING THE EXPRESSION OF MIR-33 TARGETS, GCG AND CREB1. IN CONCLUSION, WE PROVIDE A NOVEL EPIGENETIC MECHANISM BY WHICH FXR INHIBITS THE SECRETION OF GLP-1 THROUGH MIR-33 AND ITS TWO DOWNSTREAM TARGETS, GCG AND CREB1. THESE FINDINGS MIGHT PROVIDE INNOVATIVE STRATEGIES FOR IMPROVING TYPE II DIABETES, WHICH NEEDS FURTHER IN VIVO AND CLINICAL INVESTIGATION.	2019	
                                                                                                                                                                                                                                                                                                                                
2  4904  27 P16INK4A GENE ALTERATIONS ARE NOT A PROGNOSTIC INDICATOR FOR SURVIVAL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA UNDERGOING CURATIVE HEPATECTOMY. BACKGROUND AND AIM: HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON MALIGNANCY WORLDWIDE THAT IS HIGHLY ASSOCIATED WITH CHRONIC HEPATITIS B OR C INFECTION AND CIRRHOSIS. THE TUMOR SUPPRESSOR GENE P16INK4A IS AN IMPORTANT COMPONENT OF THE CELL CYCLE AND INACTIVATION OF THE GENE HAS BEEN FOUND IN A VARIETY OF HUMAN CANCERS. THE PRESENT STUDY WAS PERFORMED TO DETERMINE GENETIC AND EPIGENETIC ALTERATIONS IN THE P16INK4A TUMOR SUPPRESSOR GENE AND THE EFFECT OF THESE ON HCC PROGRESSION. METHODS: THE STATUS OF P16INK4A WAS EVALUATED IN 117 HCC TUMORAL NODULES AND 110 CORRESPONDING PERITUMORAL TISSUES BY LOSS OF HETEROZIGOSITY (LOH) AT THE 9P21-22 REGION, HOMOZYGOUS DELETIONS, SINGLE-STRAND CONFORMATION POLYMORPHISM-POLYMERASE CHAIN REACTION (PCR) MUTATIONAL ANALYSIS AND METHYLATION SPECIFIC PCR. RESULTS: THE MOST FREQUENT INACTIVATION MECHANISM WAS HYPERMETHYLATION OF THE PROMOTER REGION, WHICH WAS FOUND IN 63.2% OF THE TUMOR SAMPLES AND IN 28.2% OF THE PERITUMORAL SAMPLES. LOSS OF HETEROZYGOSITY AT THE 9P21 REGION WAS DETECTED IN 27.3% AND 10% OF TUMOR AND PERITUMORAL TISSUES, RESPECTIVELY. HOMOZYGOUS DELETIONS AND MUTATIONS WERE LESS COMMON EVENTS IN HEPATOCARCINOGENESIS. THE AUTHORS FOUND 5.9% OF THE TUMOR CASES WITH EXON 2 HOMOZYGOUS DELETIONS AND 8.6% WITH MUTATIONS. TWO POLYMORPHISMS WERE DETECTED, ONE AT CODON 148 (GCG --> ACG, ALA --> THR) IN THREE CASES AND THE OTHER IN EXON 3 AT 540 BP (34.2% OF THE SAMPLES). NO ASSOCIATION WAS FOUND BETWEEN INACTIVATION OF P16INK4A AND CLINICOPATHOLOGICAL CHARACTERISTICS OR PROGNOSIS. CONCLUSION: P16INK4A IS ALTERED FREQUENTLY AND EARLY IN HCC, BEING THE PREDOMINANT MECHANISM OF INACTIVATION PROMOTER HYPERMETHYLATION. THE PRESENT RESULTS SUGGEST THAT THE P16INK4A GENE PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF HCC.	2004	
                                                                                                                                                                                                                                                                     
3  1996  25 EPIGENETIC AND GENETIC ALTERATIONS OF THE EDNRB GENE IN NASOPHARYNGEAL CARCINOMA. BACKGROUND: LOSS OF HETEROZYGOSITY (LOH) AT 13Q22 IS A COMMON EVENT IN NASOPHARYNGEAL CARCINOMA (NPC). EDNRB GENE LOCATED AT 13Q22 HAS BEEN DEMONSTRATED TO BE HYPERMETHYLATED IN SOME KINDS OF TUMORS. IN THE CURRENT STUDY, WE FOCUSED ON THE EPIGENETIC AND GENETIC ALTERATIONS OF EDNRB IN NPC. METHODS: THE MRNA EXPRESSION OF EDNRB WAS DETECTED BY SEMIQUANTITATIVE RT-PCR AND REAL-TIME QUANTITATIVE PCR IN 49 NPC AND 12 CHRONIC NASOPHARYNGITIS BIOPSIES. THE METHYLATION AND LOH STATUS OF EDNRB WERE EXAMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION, MICROSATELLITE PCR AND SEQUENCING. WE ALSO EXAMINED THE MRNA EXPRESSION OF EDNRB IN FOUR NPC CELL LINES AFTER 5-AZA-2'-DEOXYCYTIDINE TREATMENT. RESULTS: EDNRB WAS DOWNREGULATED IN PRIMARY NPC TISSUES AND NPC CELL LINES, AND A RELATIVELY HIGHER METHYLATION LEVEL OF EDNRB WAS FOUND IN NPC BIOPSIES (84%) COMPARED TO THAT IN CHRONIC NASOPHARYNGITIS BIOPSIES (42%). TREATMENT OF NPC CELL LINES WITH 5-AZA-2'-DEOXYCYTIDINE ACTIVATED EDNRB EXPRESSION. LOH OF EDNRB GENE WAS ALSO FOUND AT TWO MICROSATELLITE SITES WITH RATIOS OF 6.25 AND 16.67% IN NPC. CONCLUSION: OUR RESULTS SUGGESTED THAT EDNRB EXPRESSION MAY BE AFFECTED BY ABERRANT PROMOTER METHYLATION AND GENE DELETION AND MAY PLAY A ROLE IN THE DEVELOPMENT OF NPC.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  2942  26 GENETIC AND EPIGENETIC ALTERATIONS OF LTF AT 3P21.3 IN NASOPHARYNGEAL CARCINOMA. TO INVESTIGATE THE ROLES OF LACTOTRANSFERRIN GENE (LTF, ALSO REFERRED TO AS THE LACTOFERRIN GENE, LF), LOCATED AT 3P21.3 WITHIN THE COMMON MINIMAL DELETION REGION, IN THE PATHOGENESIS OF NASOPHARYNGEAL CARCINOMA (NPC), WE FIRST DETECTED ITS EXPRESSION LEVEL IN 33 PRIMARY NPC TISSUES AND 15 CHRONIC NASOPHARYNGITIS TISSUES. ABSENT EXPRESSION OR DOWNREGULATION OF LTF WERE OBSERVED IN 76% (25 OF 33) OF PRIMARY NPC TISSUES. WE FURTHER FOUND THAT 25% (5 OF 20) OF NPC SPECIMENS HAD LOSS OF HETEROZYGOSITY (LOH) AT THE LTF LOCUS. LTF MUTATION ASSESSED BY POLYMERASE CHAIN REACTION SINGLE-STRAND CONFORMATION POLYMORPHISM (PCR-SSCP) AND DNA SEQUENCING WAS NOTED IN 30% (6 OF 20) OF PRIMARY NPC TISSUES. IN ADDITION, HYPER-METHYLATION OF LTF PROMOTER REGION WAS FOUND IN 63.6% (21 OF 33) OF PRIMARY NPC SAMPLES BUT NOT IN CHRONIC NASOPHARYNGITIS TISSUES. THE LTF TRANSCRIPTS IN NPC CELL LINES INCREASED UPON TREATMENT WITH THE DEMETHYLATION COMPOUND, 5-AZA-2-DEOXYCYTIDINE. IN CONCLUSION, OUR DATA INDICATE THAT TWO-HIT SILENCING OF LTF THROUGH GENETIC AND EPIGENETIC CHANGES MAY BE A COMMON AND IMPORTANT EVENT IN THE CARCINOGENESIS OF NPC.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  6816  27 [EXPRESSION, GENETIC AND EPIGENETIC ALTERATIONS OF LTF GENE IN NASOPHARYNGEAL CARCINOMA CELL LINES]. OBJECTIVE: TO INVESTIGATE THE EXPRESSION OF LTF MRNA IN SEVERAL NASOPHARYNGEAL CANCER (NPC) CELL LINES, AND ANALYZE THE RELATIONSHIP BETWEEN THE GENETIC AND EPIGENETIC CHANGES AND EXPRESSION OF LTF GENE. METHODS: THE EXPRESSION LEVEL OF LTF WAS DETECTED IN NPC CELL LINES HNE1, HNE2, HNE3, CNE1, CNE2, 5-8F, 6-10B CELLS AND TISSUES OF 15 CASES OF CHRONIC NASOPHARYNGITIS BY RT-PCR. THE LTF PROTEIN LEVEL WAS ANALYZED BY WESTERN BLOTTING IN 6-10B CELLS. THEN LOH, MUTATION AND METHYLATION STATUS OF LTF WAS EXAMINED BY MICROSATELLITES ANALYSIS, PCR-SSCP, MSP AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. RESULTS: 15 CHRONIC NASOPHARYNGITIS TISSUES SHOWED STABLE LTF EXPRESSION, WHILE THERE WERE WEAK EXPRESSION IN 6-10B CELLS AND ABSENT EXPRESSION IN REMAINING DETECTED NPC CELL LINES. THERE WAS A SIGNIFICANTLY LOWER LTF EXPRESSION IN CHRONIC NASOPHARYNGITIS TISSUES (Z = -3.738, P = 0.000). NO LTF PROTEIN EXPRESSION WAS OBSERVED IN 6-10B CELLS. LOH ANALYSIS DEMONSTRATED THAT ALLELE LOSS OF LTF WASN'T FOUND IN NPC CELL LINES. LTF MUTATION WAS NOTED IN 14.3% (1/7) OF NPC CELL LINES. DNA SEQUENCING CONFIRMED THE MUTATION POINT IN THE PROMOTER REGION (-305 BP TO -50 BP) WAS AT -218 BP (DEL T) OF LTF GENE IN THE HNE1 CELL LINE. METHYLATION OF LTF GENE WAS NOT FOUND IN CHRONIC NASOPHARYNGITIS. HOWEVER, METHYLATION OF LTF PROMOTER WAS DETECTED IN ALL NPC CELL LINES. LTF MRNA EXPRESSION WAS INCREASED IN 5-8F AND 6-10B CELL LINES AFTER TREATMENT WITH 5-AZA-2-DEOXYCYTIDINE. CONCLUSION: THERE IS AN INACTIVATION OF EXPRESSION OF LTF GENE IN THE NPC CELL LINES. ITS MOLECULAR MECHANISM MAY BE RELATED WITH METHYLATION OF PROMOTER REGION AND DELETION MUTATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  3627  30 INACTIVATION OF LARS2, LOCATED AT THE COMMONLY DELETED REGION 3P21.3, BY BOTH EPIGENETIC AND GENETIC MECHANISMS IN NASOPHARYNGEAL CARCINOMA. ALLELIC LOSS OF CHROMOSOME 3P, INCLUDING THE 3P21.3 REGION, IS FOUND IN 95-100% OF PRIMARY NASOPHARYNGEAL CARCINOMA (NPC) BIOPSIES, SUGGESTING THAT THIS REGION SHOULD HARBOR SOME TUMOR SUPPRESSOR GENES (TSGS) CLOSELY RELATED TO NPC DEVELOPMENT. SEVERAL TSGS LOCATED AT 3P21.3, SUCH AS RASSF1A, LTF AND BLU, HAVE BEEN DEMONSTRATED TO BE INVOLVED IN NPC DEVELOPMENT. LARS2 (LEUCYL-TRNA SYNTHETASE 2, MITOCHONDRIAL) IS ANOTHER GENE LOCATED IN THE CHROMOSOME 3 COMMON ELIMINATED REGION-1 (C3CER1) AT 3P21.3. IN THIS STUDY, WE FOCUSSED ON THE EPIGENETIC AND GENETIC ALTERATIONS OF LARS2 IN NPC. THE MRNA EXPRESSION OF LARS2 WAS DETECTED IN 36 NPC AND 8 CHRONIC NASOPHARYNGITIS (NP) TISSUES BY SEMI-QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (RT-PCR) AND REAL-TIME RT-PCR. SUBSEQUENTLY, THE MUTATION, ALLELIC LOSS, AND METHYLATION STATUS OF LARS2 WERE ANALYSED BY POLYMERASE CHAIN REACTION-SINGLE-STRAND CONFORMATION POLYMORPHISM (PCR-SSCP), HOMOZYGOUS DELETION (HD) ANALYSIS AND METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION IN PRIMARY NPC TISSUES. NO EXPRESSION OR DOWNREGULATION OF LARS2 WAS OBSERVED IN 78% OF PRIMARY NPC TISSUES. NO MUTATIONS, ASSESSED BY PCR-SSCP AND DNA SEQUENCING, WERE FOUND IN THE PROMOTER REGION AND EXON 1 OF LARS2 IN NPC TISSUES, WHEREAS HD WAS DETECTED IN 28% OF NPC SPECIMENS AT THE LARS2 LOCUS. IN ADDITION, HYPERMETHYLATION OF LARS2 WAS FOUND IN 64% OF NPC SAMPLES BUT ONLY IN 12.5% OF NP BIOPSIES. OUR DATA INDICATE THAT INACTIVATION OF LARS2 BY BOTH GENETIC AND EPIGENETIC MECHANISMS MAY BE A COMMON AND IMPORTANT EVENT IN THE CARCINOGENESIS OF NPC.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  2842  32 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	
                                                                                                                                                                                                                                                                 
8  4905  30 P16INK4A HYPERMETHYLATION IS ASSOCIATED WITH HEPATITIS VIRUS INFECTION, AGE, AND GENDER IN HEPATOCELLULAR CARCINOMA. PURPOSE: THE TUMOR SUPPRESSOR GENE P16INK4A IS MAINLY INACTIVATED BY AN EPIGENETIC CHANGE INVOLVING PROMOTER HYPERMETHYLATION IN HEPATOCARCINOGENESIS. THE POSSIBLE CLINICAL IMPACT OF P16INK4A METHYLATION AND THE POTENTIAL RISK FACTORS FOR THIS EPIGENETIC ALTERATION HAVE NOT BEEN THOROUGHLY INVESTIGATED. EXPERIMENTAL DESIGN: WE STUDIED THE METHYLATION STATUS AND MRNA AND PROTEIN EXPRESSION OF P16INK4A IN 50 HEPATOCELLULAR CARCINOMAS AND CORRESPONDING NONNEOPLASTIC LIVER LESIONS USING METHYLATION-SPECIFIC PCR, REVERSE TRANSCRIPTION-PCR, AND IMMUNOHISTOCHEMICAL TECHNIQUES. RESULTS: P16INK4A HYPERMETHYLATION WAS OBSERVED IN 58% (29 OF 50) OF THE HEPATOCELLULAR CARCINOMAS AND 16% (6 OF 38) OF THE CORRESPONDING CHRONIC HEPATITIS AND CIRRHOSIS TISSUE SAMPLES. P16INK4A METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH MRNA AND PROTEIN EXPRESSION (P <0.001 AND P=0.003, RESPECTIVELY). ALL OF THE P16INK4A-METHYLATED TUMORS WERE POSITIVE FOR HEPATITIS B VIRUS OR HEPATITIS C VIRUS MARKERS, BUT NONE OF THE VIRUS-NEGATIVE TUMORS EXHIBITED P16INK4A METHYLATION (P=0.006). THE FREQUENCY OF P16INK4A HYPERMETHYLATION TENDED TO BE HIGHER IN HEPATITIS C VIRUS-RELATED TUMORS (23 OF 32, 72%) THAN IN HEPATITIS B VIRUS-RELATED TUMORS (6 OF 13, 46%; P=0.1). ABERRANT METHYLATION OF P16INK4A WAS ALSO RELATED SIGNIFICANTLY TO INCREASING AGE, FEMALE GENDER, AND NORMAL LEVELS OF SERUM PIVKA-II (P=0.02, 0.04, AND 0.04, RESPECTIVELY). NO STATISTICALLY SIGNIFICANT DIFFERENCE IN SURVIVAL WAS OBSERVED BETWEEN PATIENTS WITH P16INK4A HYPERMETHYLATION AND THOSE WITHOUT. CONCLUSIONS: OUR OBSERVATIONS SUGGEST THAT P16INK4A HYPERMETHYLATION MAY CONTRIBUTE TO HEPATOCARCINOGENESIS FROM AN EARLY STAGE AND THAT MULTIPLE RISK FACTORS, SUCH AS VIRAL INFECTIONS, AGE, AND GENDER, MAY BE ASSOCIATED WITH P16INK4A HYPERMETHYLATION IN HEPATOCARCINOGENESIS.	2004	
                                                                                                                                                                                                                                                 
9  1700  38 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  2126  31 EPIGENETIC INACTIVATION OF MIR-34B/C IN ADDITION TO MIR-34A AND DAPK1 IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: TP53 MUTATION/DELETION IS UNCOMMON IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WE POSTULATED THAT COMPONENTS OF TP53-CENTERED TUMOR SUPPRESSOR NETWORK, MIR-34B/C, IN ADDITION TO DAPK1 AND MIR-34A MIGHT BE INACTIVATED BY DNA HYPERMETHYLATION. MOREOVER, WE TESTED IF MIR-34B/C METHYLATION MIGHT CORRELATE WITH MIR-203 OR MIR-124-1 METHYLATION IN CLL. METHODS: MIR-34B/C, MIR-34A AND DAPK1 METHYLATION WAS STUDIED IN 11 NORMAL CONTROLS, 7 CLL CELL LINES, AND 78 DIAGNOSTIC CLL SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. MEC-1 CELLS WERE TREATED WITH 5-AZA-2'-DEOXYCYTIDINE FOR REVERSAL OF METHYLATION-ASSOCIATED MIRNA SILENCING. TUMOR SUPPRESSOR PROPERTIES OF MIR-34B WERE DEMONSTRATED BY OVER-EXPRESSION OF PRECURSOR MIR-34B IN MEC-1 CELLS. RESULTS: MIR-34B/C PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS, BUT COMPLETELY METHYLATED IN 4 CLL CELL LINES. MIR-34B/C EXPRESSION WAS INVERSELY CORRELATED WITH MIR-34B/C METHYLATION. DIFFERENT MSP STATUSES OF MIR-34B/C, INCLUDING COMPLETE METHYLATION AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE PYROSEQUENCING. 5-AZA-2'-DEOXYCYTIDINE TREATMENT RESULTED IN PROMOTER DEMETHYLATION AND MIR-34B RE-EXPRESSION IN MEC1 CELLS. MOREOVER, OVER-EXPRESSION OF MIR-34B RESULTED IN INHIBITION OF CELLULAR PROLIFERATION AND INCREASED CELL DEATH. IN PRIMARY CLL SAMPLES, MIR-34A, MIR-34B/C AND DAPK1 METHYLATION WAS DETECTED IN 2.6%, 17.9% AND 34.6% OF PATIENTS AT DIAGNOSIS RESPECTIVELY. FURTHERMORE, 39.7%, 3.8% AND 2.6% PATIENTS HAD METHYLATION OF ONE, TWO OR ALL THREE GENES RESPECTIVELY. OVERALL, 46.2% PATIENTS HAD METHYLATION OF AT LEAST ONE OF THESE THREE GENES. BESIDES, MIR-34B/C METHYLATION WAS ASSOCIATED WITH METHYLATION OF MIR-34A (P = 0.03) AND MIR-203 (P = 0.012) IN CLL. CONCLUSIONS: TAKEN TOGETHER, MIR-34B/C IS A TUMOR SUPPRESSOR MIRNA FREQUENTLY METHYLATED, AND HENCE SILENCED IN CLL. TOGETHER WITH DAPK1 METHYLATION, MIR-34B/C METHYLATION IS IMPLICATED IN THE DISRUPTION OF THE TP53-CENTERED TUMOR SUPPRESSOR NETWORK. MOREOVER, THE ASSOCIATION OF MIRNA METHYLATION WARRANTS FURTHER STUDY.	2014	

11  4903  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  1065  32 CLINICAL SIGNIFICANCE OF SERUM DRAM1 MRNA, ARSA MRNA, HSA-MIR-2053 AND LNCRNA-RP1-86D1.3 AXIS EXPRESSION IN MALIGNANT PLEURAL MESOTHELIOMA. AIM AND BACKGROUND: MALIGNANT PLEURAL MESOTHELIOMA (MPM) IS A LETHAL CANCER MAINLY CAUSED BY CHRONIC EXPOSURE OF ASBESTOS. IN THIS PILOT STUDY, WE AIMED TO ASSESS THE EXPRESSION OF SERUM RNA-BASED BIOMARKER PANEL EXPLORING THEIR CLINICAL UTILITY AS DIAGNOSTIC AND PROGNOSTIC BIOMARKERS FOR MPM. METHODS: WE HAVE SELECTED AN MPM-SPECIFIC RNA-BASED BIOMARKER PANEL THROUGH BIOINFORMATICS ANALYSIS BASED ON THE INTEGRATION OF DNA DAMAGE REGULATED AUTOPHAGY MODULATOR 1 (DRAM1) AND ARYLSULFATASE A ( ARSA) GENE EXPRESSION WITH THEIR EPIGENETIC REGULATORS MICRORNA ( MIR-2053) AND LONG NONCODING RNA ( LNCRNA-RP1-86D1.3). THEN, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR) VALIDATION IN SERA OF 60 MPM PATIENTS, 20 CHRONIC ASBESTOS EXPOSURE PATIENTS, AND 20 HEALTHY VOLUNTEERS WAS DONE. LASTLY, THE PROGNOSTIC POWER OF THE SELECTED PANEL WAS ASSESSED. RESULTS: THE EXPRESSION OF SERUM DRAM1 MESSENGER RNA (MRNA), ARSA MRNA, HSA-MIR-2053 AND LNCRNA-RP1-86D1.3 WERE POSITIVE IN 78.3%, 90%, 85%, AND 83.3% OF MPM PATIENTS, RESPECTIVELY. THE RNA-BASED BIOMARKER PANEL WAS ABLE TO DISCRIMINATE BETWEEN MPM PATIENTS AND CONTROLS WITH HIGH ACCURACY AND THEIR COMBINED SENSITIVITY REACHED 100% FOR THE DIAGNOSIS OF MPM. KAPLAN-MEIER ANALYSIS SHOWED THAT HSA-MIR-2053 IS AN INDEPENDENT PROGNOSTIC FACTOR OF MPM. CONCLUSION: OUR PRELIMINARY DATA REVEALED THAT THE CHOSEN RNAS PLAY AN IMPORTANT ROLE IN DRIVING MPM DEVELOPMENT AND PROGRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  6770  28 [ABERRANT METHYLATION OF MULTIPLE GENES AND ITS CLINICAL IMPLICATION IN HEPATOCELLULAR CARCINOMA]. OBJECTIVE: TO INVESTIGATE THE METHYLATION FREQUENCIES OF MULTIPLE TUMOR SUPPRESSOR GENES (TSGS) IN HEPATOCELLULAR CARCINOMA (HCC) AND THE CLINICAL IMPLICATION OF ABERRANT DNA METHYLATION IN MOLECULAR CARCINOGENESIS OF HCC. METHODS: SIXTY SAMPLES OF HCC AND THE PAIRED ADJACENT LIVER TISSUE, 16 SAMPLES FROM POST-HEPATITIS CIRRHOTIC LIVERS, 5 FROM LIVERS WITH CHRONIC HEPATITIS AND 5 FROM NORMAL LIVERS WERE COLLECTED. EIGHT TSGS FREQUENTLY SILENCED BY HYPERMETHYLATION OF THEIR PROMOTERS IN VARIOUS TYPES OF DIGESTIVE TUMORS WERE SELECTED, INCLUDING APC, RASSF1A, P16, GSTP1, MGMT, DAPK, SOCS-1 AND RIZ1. THE STATUS OF PROMOTER METHYLATION IN THESE 8 GENES WAS INVESTIGATED USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THE CLINICOPATHOLOGICAL DATA OF HCC WERE ALSO ANALYZED IN ORDER TO EVALUATE THE CLINICAL IMPLICATION OF ABERRANT METHYLATION IN HCC. RESULTS: METHYLATION OF THE 8 TSGS WAS QUITE FREQUENT IN HCC, WITH A METHYLATION RATE OF 95.0% IN RASSF1A, 90.0% IN APC, 73.3% IN GSTP1, 65.0% IN P16, 61.6% IN RIZ1 AND 60.0% IN MGMT. METHYLATION OF THE 6 GENES WAS MORE FREQUENT IN HCC THAN THAT IN ADJACENT TISSUES (P < 0.05). THE METHYLATION RATE OF MGMT, GSTP1 AND RIZ1 IN THE ADJACENT TISSUES WAS 41.6%, 40.0% AND 25.0%, RESPECTIVELY, SIGNIFICANTLY HIGHER THAN THAT IN CIRRHOTIC LIVER (P < 0.05). P16 METHYLATION WAS MORE FREQUENTLY OBSERVED IN HCC IN ELDERLY PATIENTS. THE FREQUENCY OF MGMT METHYLATION WAS TENDED TO BE HIGHER IN GIANT HCC THAN THAT IN THE OTHER TYPES OF HCC. PATIENTS WITH MGMT METHYLATION IN THE TUMOR WERE FOUND TO HAVE A SHORTER DISEASE FREE SURVIVAL. CONCLUSION: DIFFERENT FREQUENCY OF METHYLATION IN HEPATOCELLULAR CARCINOMAS, ADJACENT LIVER TISSUES AND CIRRHOTIC LIVERS IMPLIES THAT EPIGENETIC ALTERATION IN THE HEPATOCELLULAR CARCINOGENESIS MAY BE A GRADUALLY PROGRESSIVE PROCESS. METHYLATION STATUS OF MGMT, GSTP1 AND RIZ1 MAY BE PROMISING IN RISK ASSESSMENT OF HEPATOCELLULAR CARCINOMA AND IN EARLY DIAGNOSIS. FURTHERMORE, MGMT METHYLATION MIGHT BE ALSO USED AS A POTENTIAL PROGNOSTIC BIOMARKER FOR HEPATOCELLULAR CARCINOMA PATIENTS.	2008	
           
14  2131  26 EPIGENETIC INACTIVATION OF THE HSA-MIR-203 IN HAEMATOLOGICAL MALIGNANCIES. MIR-203 IS A TUMOUR SUPPRESSOR MICRORNA (MIRNA). WE STUDIED THE METHYLATION OF HSA-MIR-203 IN 150 SAMPLES INCLUDING ACUTE MYELOID LEUKAEMIA (AML), ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL), CHRONIC MYELOID LEUKAEMIA (CML), CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN'S LYMPHOMA (NHL) BY METHYLATION-SPECIFIC PCR, AND MIRNA EXPRESSION BY STEM-LOOP RT-QPCR. HSA-MIR-203 PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT HOMOZYGOUSLY METHYLATED IN TWO AML AND FOUR LYMPHOMA CELL LINES, IN WHICH 5-AZA-2'-DEOXYCYTIDINE TREATMENT LED TO PROMOTER DEMETHYLATION AND MIR-203 RE-EXPRESSION. RESTORATION OF MIR-203 EXPRESSION IN LYMPHOMA CELLS INHIBITED CELLULAR PROLIFERATION AND INCREASED CELL DEATH, SUGGESTING AN INHERENT TUMOUR SUPPRESSOR ACTIVITY. IN PRIMARY SAMPLES, HSA-MIR-203 METHYLATION WAS ABSENT IN CML BUT DETECTED IN 5.0% ALL, 10.0% AML, 42.0% CLL AND 38.8% OF NHL (INCLUDING SIX [60.0%] NATURAL KILLER-CELL, NINE [40.9%] B-CELL AND FOUR [23.5%] T CELL NHL). MOREOVER, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH HYPERMETHYLATION OF HSA-MIR-34A, -124A AND -196B IN NHL BUT NOT CLL. IN CLL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH A HIGHER PRESENTING HB LEVEL (P = 0.033). THE PROJECTED 10 YEAR OVERALL SURVIVAL OF THE CLL PATIENTS WAS 58.2%, WHICH WAS IMPACTED BY RAI STAGE AND HIGH-RISK KARYOTYPES BUT NOT HSA-MIR-203 METHYLATION. HSA-MIR-203 WAS MORE FREQUENTLY METHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES (P = 0.002). IN CONCLUSION, MIR-203, A TUMOUR SUPPRESSOR GENE, WAS HYPERMETHYLATED IN A TUMOUR-SPECIFIC MANNER WITH GENE SILENCING. HSA-MIR-203 WAS MORE FREQUENTLY HYPERMETHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES. IN NHL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH CONCOMITANT METHYLATION OF OTHER TUMOUR SUPPRESSOR MIRNAS. THE FREQUENT HSA-MIR-203 METHYLATION IN LYMPHOID MALIGNANCIES SUGGESTED A PATHOGENETIC ROLE OF HSA-MIR-203 METHYLATION.	2011	
                                                                                                                                                                                                                                               
15  2679  28 EVALUATION OF CIRCULATORY RNA-BASED BIOMARKER PANEL IN HEPATOCELLULAR CARCINOMA. BACKGROUND: THE CIRCULATING TRANSCRIPTOME (CODING AND NON-CODING) PLAYS A CRITICAL ROLE IN CANCER. NOVEL ACCURATE STRATEGIES FOR EARLY DETECTION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STRONGLY NEEDED. PATIENTS AND METHODS: WE CHOSE AN HCC-SPECIFIC RNA-BASED BIOMARKER PANEL BASED ON THE INTEGRATION OF DIFFERENTIAL LYSOSOMAL-ASSOCIATED MEMBRANE PROTEIN 2 (LAMP2) GENE EXPRESSION WITH ITS SELECTED EPIGENETIC REGULATORS USING BIOINFORMATIC METHODS. THIS WAS FOLLOWED BY RT-QPCR VALIDATION IN SERUM OF 78 PATIENTS WITH HCC, 36 PATIENTS WITH CHRONIC HEPATITIS C (CHC) INFECTION AND 44 HEALTHY VOLUNTEERS. WE USED RISK-SCORE ANALYSIS TO EVALUATE THE DIAGNOSTIC EFFICACY OF THE SERUM PROFILING SYSTEM. MOREOVER, IN TWENTY OF THE 78 HCC CASES INVOLVED IN THE STUDY WE EXAMINED THE EXPRESSION OF RNA-BASED BIOMARKER PANEL IN BOTH HCC AND ADJACENT NON-TUMOR TISSUES AND ASSESSED THEIR CORRELATION WITH THE SERUM LEVEL OF THIS PANEL. RESULTS: THE FOUR RIBONUCLEIC ACID (RNA)-BASED BIOMARKER PANEL [LONG NON-CODING RNA-C TERMINAL BINDING PROTEIN, ANDROGEN RESPONSIVE (LNCRNA-CTBP), MICRORNA-16-2 (MIR-16-2), MICRORNA-21-5-P (MIR-21-5P) AND LAMP2], HAD HIGH SENSITIVITY AND SPECIFICITY FOR DISCRIMINATING HCC FROM HEALTHY CONTROLS AND ALSO FROM CHC PATIENTS. AMONG THESE FOUR RNAS, SERUM MIR-16-2 AND MIR-21-5P WERE INDEPENDENT PROGNOSTIC FACTORS. CONCLUSION: THE CIRCULATORY RNA-BASED BIOMARKER PANEL CAN SERVE AS A POTENTIAL BIOMARKER FOR HCC DIAGNOSIS AND PROGNOSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  5274  14 PROMOTER METHYLATION OF P16 AND EDNRB GENE IN LEUKEMIA PATIENTS IN TAIWAN. BOTH EPIGENETIC AND GENETIC ALTERNATIONS ARE INVOLVED IN CANCER FORMATION. IN THIS STUDY, WE HAVE IDENTIFIED THE METHYLATION FREQUENCY OF P16 AND ENDOTHELIN RECEPTOR TYPE B (EDNRB) OF 26 LEUKEMIA PATIENTS AND 8 RANDOMLY SELECTED NORMAL BLOOD DONORS IN TAIWAN. PROMOTER METHYLATION OF P16 WAS DETECTED IN 85% OF ACUTE LYMPHOCYTIC LEUKEMIA (ALL), 83% IN ACUTE MYELOID LEUKEMIA (AML) WHEREAS NO METHYLATION WAS DETECTED IN CHRONIC MYELOID LEUKEMIA (CML) IN BLAST CRISIS. HYPERMETHYLATION OF EDNRB WAS OBSERVED IN 92% OF ALL, 75% AML AND 100% IN CML IN BLAST CRISIS. NO ABERRANT METHYLATION OF P16 AND EDNRB WAS FOUND IN 8 NORMAL BLOOD DONORS. TAKEN TOGETHER, ABERRANT METHYLATION OF P16 AND EDNRB WAS HIGHLY PREVALENT IN LEUKEMIA PATIENTS IN TAIWAN.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  1022  34 CIRCULAR RNA HSA_CIRC_0098181 INHIBITS METASTASIS IN HEPATOCELLULAR CARCINOMA BY ACTIVATING THE HIPPO SIGNALING PATHWAY VIA INTERACTION WITH EEF2. INTRODUCTION AND OBJECTIVES: THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTI-STEP PROCESS THAT ACCUMULATES GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING CHANGES IN CIRCULAR RNA (CIRCRNA). THIS STUDY AIMED TO UNDERSTAND THE ALTERATIONS IN CIRCRNA EXPRESSION IN HCC DEVELOPMENT AND METASTASIS AND TO EXPLORE THE BIOLOGICAL FUNCTIONS OF CIRCRNA. MATERIALS AND METHODS: TEN PAIRS OF ADJACENT CHRONIC HEPATITIS TISSUES AND HCC TISSUES FROM PATIENTS WITHOUT VENOUS METASTASES, AND TEN HCC TISSUES FROM PATIENTS WITH VENOUS METASTASES WERE ANALYZED USING HUMAN CIRCRNA MICROARRAYS. DIFFERENTIALLY EXPRESSED CIRCRNAS WERE THEN VALIDATED BY QUANTITATIVE REAL-TIME PCR. IN VITRO AND IN VIVO ASSAYS WERE PERFORMED TO ASSESS THE ROLES OF THE CIRCRNA IN HCC PROGRESSION. RNA PULL-DOWN ASSAY, MASS SPECTROMETRY ANALYSIS, AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION WERE CONDUCTED TO EXPLORE THE PROTEIN PARTNERS OF THE CIRCRNA. RESULTS: CIRCRNA MICROARRAYS REVEALED THAT THE EXPRESSION PATTERNS OF CIRCRNAS ACROSS THE THREE GROUPS WERE SIGNIFICANTLY DIFFERENT. AMONG THESE, HSA_CIRC_0098181 WAS VALIDATED TO BE LOWLY EXPRESSED AND ASSOCIATED WITH POOR PROGNOSIS IN HCC PATIENTS. ECTOPIC EXPRESSION OF HSA_CIRC_0098181 DELAYED HCC METASTASIS IN VITRO AND IN VIVO. MECHANISTICALLY, HSA_CIRC_0098181 SEQUESTERED EUKARYOTIC TRANSLATION ELONGATION FACTOR 2 (EEF2) AND DISSOCIATED EEF2 FROM FILAMENTOUS ACTIN (F-ACTIN) TO PREVENT F-ACTIN FORMATION, WHICH BLOCKED ACTIVATION OF THE HIPPO SIGNALING PATHWAY. IN ADDITION, THE RNA BINDING PROTEIN QUAKING-5 BOUND DIRECTLY TO HSA_CIRC_0098181 AND INDUCED ITS BIOGENESIS. CONCLUSIONS: OUR STUDY REVEALS CHANGES IN CIRCRNA EXPRESSION FROM CHRONIC HEPATITIS, PRIMARY HCC, TO METASTATIC HCC. FURTHER, THE QKI5-HSA_CIRC_0098181-EEF2-HIPPO SIGNALING PATHWAY EXERTS A REGULATORY ROLE IN HCC.	2023	
                                                                                                                                                                                                                         
18  1342  33 DETECTING ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES GSTP1, P16, RIZ1, AND RASSF1A IN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL SIGNIFICANCE. HEPATOCELLULAR CARCINOMA (HCC) HAS A HIGH RATE OF MORTALITY. FURTHER STUDIES INTO EPIGENETIC CHANGES IN HCC, PARTICULARLY THE ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES (TSGS), ARE REQUIRED, SINCE THESE CHANGES MAY PROVIDE NOVEL BIOMARKERS FOR EARLY SCREENING AND DIAGNOSIS OF HCC. BY USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), THE PRESENT STUDY DETECTED THE METHYLATION STATUS IN THE PROMOTER REGION OF 4 CANDIDATE TSGS, GSTP1, P16, RIZ1, AND RASSF1A, RESPECTIVELY, IN 35 PAIRED HCC AND TUMOR-ADJACENT LIVER TISSUES IN ADDITION TO 20 NORMAL LIVER TISSUES. THEIR EFFECT ON THE INITIATION AND PROGRESSION OF HCC WAS ALSO INVESTIGATED BY ANALYZING THE CLINICOPATHOLOGICAL DATA. THE RESULTS OF THE PRESENT STUDY REVEALED THAT THE METHYLATION LEVEL OF RIZ1 AND GSTP1 GENES IN HCC WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN THE ADJACENT TISSUES (P<0.01) AND THE NORMAL LIVER TISSUES (P<0.01). THE METHYLATION FREQUENCY OF P16 AND RASSF1A GENES WAS NOT SIGNIFICANTLY INCREASED COMPARED WITH THAT OBSERVED IN THE ADJACENT TISSUES (P>0.05) BUT WAS SIGNIFICANTLY INCREASED COMPARED WITH THE NORMAL TISSUES (P<0.01). IN HCC TISSUES, THE METHYLATION FREQUENCY OF THE GSTP1 GENE IN TUMORS WITH CAPSULAR INVASION WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN TUMORS WITHOUT CAPSULAR INVASION (P<0.05). THE METHYLATION FREQUENCY OF P16 GENE IN HEPATITIS B SURFACE ANTIGEN (HBSAG)-POSITIVE HCC PATIENTS WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN HBSAG-NEGATIVE PATIENTS (P<0.05). THE METHYLATION STATUS OF RIZ1 AND RASSF1A GENES WAS NOT SIGNIFICANTLY CORRELATED WITH THE CLINICOPATHOLOGICAL DATA (P>0.05). PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE METHYLATION STATUS OF RIZ1 AND GSTP1 GENES IS HCC-SPECIFIC, AND THUS MAY BE USED AS A BIOMARKER TO ASSIST THE CLINICAL DIAGNOSIS OF HCC. WHILE THE METHYLATION OF GSTP1 GENE PROMOTER MAY ASSOCIATE WITH THE INVASIVENESS OF HCC, CHRONIC HEPATITIS B VIRUS INFECTION MAY BE THE CAUSE OF METHYLATION-INDUCED P16 INACTIVATION.	2015	
                                               
19  2202  38 EPIGENETIC MODIFICATION OF MIR-10A REGULATES RENAL DAMAGE BY TARGETING CREB1 IN TYPE 2 DIABETES MELLITUS. EMERGING EVIDENCE HAS SHOWN THAT MICRORNA-MEDIATED GENE EXPRESSION MODULATION PLAYS A CRUCIAL ROLE IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS, BUT THE NOVEL MIRNAS INVOLVED IN TYPE 2 DIABETES AND ITS FUNCTIONAL REGULATORY MECHANISMS STILL NEED TO BE DETERMINED. IN THIS STUDY, WE ASSESSED THE ROLE OF MIR-10A IN EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY OF DIABETIC MELLITUS INDUCED BY COMBINING ADMINISTRATION OF CHRONIC HIGH FAT DIET (HFD) AND LOW DOSAGE OF STREPTOZOTOCIN (STZ, 35MG/KG). HERE, WE FOUND THAT HFD/STZ ADMINISTRATION DECREASED THE LEVEL OF MICRORNA (MIR-10A) EXPRESSION IN ICR STRAIN MICE. OVEREXPRESSION OF MIR-10A ALLEVIATED THE INCREASED RATIO OF URINE ALBUMIN-TO-CREATININE (ACR) RATIO OF HFD/STZ MICE. IN CONTRAST, KNOCKDOWN OF MIR-10A INCREASED THE RATIO OF KIDNEY ACR IN NAIVE MICE. FURTHERMORE, CAMP RESPONSE ELEMENT BINDING PROTEIN 1 (CREB1) WAS VALIDATED AS A TARGET OF MIR-10A IN VITRO AND IN VIVO. CREB1 AND ITS DOWNSTREAM FIBRONECTIN (FN, EXTRACELLULAR MATRIX) WERE INCREASED IN HFD/STZ-TREATED MICE, WHICH WAS REVERSED BY KIDNEY MIR-10A OVEREXPRESSION. THE CONTENT OF CREB1 AND FN WAS INCREASED BY MIR-10A KNOCKDOWN IN KIDNEY OF NAIVE MICE. FURTHERMORE, HISTONE DEACETYLASE 3 (HDAC3) WAS REVEALED TO BE INCREASED IN KIDNEY OF HFD/STZ MICE, ACCOMPANIED WITH THE AUGMENTATION OF ACR RATIO AND FN LEVEL. KNOCKDOWN OF HDAC3 WITH SIRNA SIGNIFICANTLY CAUSED THE INCREASE OF MIR-10A, RESULTING IN THE DECREASE IN CREB1 AND FN EXPRESSION IN KIDNEY OF HFD/STZ MICE. CONTRARILY, HDAC3 OVEREXPRESSION MEDIATED BY LENTIVIRUS DECREASED MIR-10A CONTENT, AND ENHANCED ACR VALUE, CREB1 AND FN FORMATION IN NAIVE MICE. COLLECTIVELY, THESE RESULTS ELUCIDATE THAT HDAC3/MIR-10A/CREB1 SERVES AS A NEW MECHANISM UNDERLYING KIDNEY INJURY, PROVIDING POTENTIAL THERAPEUTIC TARGETS IN TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                      
20  5777  24 SPINAL CIRCKCNK9 REGULATES CHRONIC VISCERAL HYPERSENSITIVITY OF IRRITABLE BOWEL SYNDROME. DYSREGULATION OF CIRCULAR RNAS (CIRCRNAS) HAS BEEN REPORTED TO BE FUNCTIONALLY ASSOCIATED WITH CHRONIC PAIN, BUT IT IS UNKNOWN WHETHER AND HOW CIRCRNAS PARTICIPATE IN VISCERAL HYPERSENSITIVITY. THE EXPRESSION OF CIRCKCNK9 WAS INCREASED IN SPINAL NEURONS OF IRRITABLE BOWEL SYNDROME (IBS)-LIKE RATS. SHCIRCKCNK9 ATTENUATED VISCERAL HYPERSENSITIVITY AND INHIBITED C-FOS EXPRESSION IN IBS-LIKE RATS, WHEREAS OVEREXPRESSION OF SPINAL CIRCKCNK9 INDUCED VISCERAL HYPERSENSITIVITY AND INCREASED C-FOS EXPRESSION IN CONTROL RATS. FURTHERMORE, CIRCKCNK9 WAS FOUND TO ACT AS A MIR-124-3P SPONGE. MIR-124-3P ANTAGOMIR RESTORED PAIN RESPONSES DOWNREGULATED BY SHCIRCKCNK9 IN IBS-LIKE RATS. FINALLY, THE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3), VALIDATED AS A TARGET OF MIR-124-3P, COULD PLAY A CRITICAL ROLE IN VISCERAL HYPERSENSITIVITY BY REGULATING NSF/GLUR2. PERSPECTIVE: SPINAL CIRCKCNK9 FUNCTIONS AS A MIR-124-3P SPONGE TO PROMOTE VISCERAL HYPERSENSITIVITY BY REGULATING THE STAT3/NSF/GLUR2 PATHWAY. THIS PATHWAY MIGHT PROVIDE A NOVEL EPIGENETIC MECHANISM OF VISCERAL HYPERSENSITIVITY AND A POTENTIAL CIRCRNA THERAPEUTIC TARGET FOR IBS.	2023