1 1428 136 DIFFERENTIAL EXPRESSION OF LONG NONCODING RNA IN HEPATOCELLULAR CARCINOMA ON TOP OF CHRONIC HCV AND HBV INFECTIONS. AIM OF THE STUDY: THE TASK OF LONG NONCODING RNAS (LNCRNAS) AS A PROSPECTIVE GOAL FOR HEPATOCELLULAR CARCINOMA (HCC) IS A CANDIDATE FOR RESEARCH. SEVERAL LNCRNAS ARE INVOLVED IN SIGNAL TRANSDUCTION, DIRECTING GENE EXPRESSION AND EPIGENETIC ALTERATION IN NORMAL AND CANCER CELLS. DYSREGULATION OF DIVERSE LNCRNAS HAS BEEN INVOLVED IN THE PATHOGENESIS AND PROGRESSION OF DIFFERENT CANCERS INCLUDING HCC. WE AIMED TO INVESTIGATE THE DIFFERENTIAL EXPRESSION OF LNCRNAS (AHIF, HPVT1, ANRIL) IN HCC ON TOP OF CHRONIC HEPATITIS C VIRUS (HCV) AND HEPATITIS B VIRUS (HBV) INFECTIONS. MATERIAL AND METHODS: 182 PARTICIPANTS WERE INCLUDED: 85 PATIENTS WITH HCC IN ADDITION TO 50 PATIENTS WITH CIRRHOSIS ON TOP OF CHRONIC HCV OR HBV, AND 47 HEALTHY SUBJECTS AS CONTROLS. HCC WAS DIAGNOSED BY TRIPHASIC COMPUTED TOMOGRAPHY (CT). DETECTION OF ALPHA-FETOPROTEIN (AFP) AND SEROLOGICAL MARKERS OF HCVAB AND HBSAG BY ENZYME-LINKED FLUORESCENT IMMUNOASSAY (ELFA) AND QUANTITATION OF LNCRNAS BY REAL TIME PCR WERE APPLIED. RESULTS: UPREGULATION OF ANRIL AND HPVT1 AND DOWNREGULATION OF AHIF WERE OBSERVED IN PATIENTS WITH HCC ON TOP OF HCV AND HBV VS. CONTROLS. CIRCULATING AHIF COULD BE OF MAJOR DIAGNOSTIC IMPORTANCE TO DISCRIMINATE HCC ON TOP OF HCV FROM CIRRHOTIC PATIENTS WITH SENSITIVITY 86.67% AND SPECIFICITY 91.89% WHEREAS CIRCULATING HPVT1 HAD SENSITIVITY 85.0% AND SPECIFICITY 84.62%; MOREOVER ANRIL HAD AUC 0.902 AND COULD DISCRIMINATE HCC ON TOP OF HBV FROM CIRRHOTIC PATIENTS. CONCLUSIONS: THE DIFFERENTIAL EXPRESSION OF LNCRNAS (ANRIL, HPVT1 AND AHIF) MIGHT BE OF MAJOR WORTH IN PREDICTING THE OCCURRENCE OF HCC IN CIRRHOTIC PATIENTS RELATED TO CHRONIC VIRAL HEPATITIS AND COULD BE BENEFICIAL IN THE EARLY MANAGEMENT. 2021 2 4225 37 METHYLATION DEGREE OF METALLOPROTEINASE INHIBITOR RECK GENE: LINKS TO RECK PROTEIN LEVEL AND HEPATOCELLULAR CARCINOMA IN CHRONIC HCV INFECTION PATIENTS. THE RECK GENE, A TUMOR SUPPRESSOR GENE, INHIBITS ANGIOGENESIS, INVASION, AND TUMOR METASTASIS. EPIGENETIC REGULATION OF THE RECK GENE CONSTITUTES A POTENT APPROACH TO THE MOLECULAR BASIS OF LIVER MALIGNANCY. THIS STUDY AIMS TO EVALUATE THE PROMOTER METHYLATION STATUS OF THE RECK GENE AND ITS SERUM LEVEL IN PATIENTS WITH HEPATITIS C VIRUS (HCV)-RELATED HEPATOCELLULAR CARCINOMA (HCC) AND THE POTENTIAL ASSOCIATION OF RECK GENE METHYLATION WITH CLINICAL CRITERIA OF HCC. ONE HUNDRED AND FIFTY-FIVE SUBJECTS WERE INCLUDED (HEALTHY CONTROL [55], CHRONIC HCV PATIENTS [55], HCV-RELATED HCC PATIENTS [45]). THE METHYLATION STATUS OF THE RECK GENE PROMOTER AND SERUM RECK LEVEL WERE INVESTIGATED BY METHYLATION-SPECIFIC PCR AND ENZYME-LINKED IMMUNOSORBENT ASSAY TECHNIQUES, RESPECTIVELY. RECK GENE PROMOTER HYPERMETHYLATION WAS RECORDED IN 46.7% OF HCC PATIENTS, AND 10.9% OF HCV PATIENTS, BUT NOT IN CONTROL SUBJECTS (0%). IT WAS RELATED TO RECK PROTEIN LEVEL, VARICES, EDEMA, ASCITES, LYMPH NODE METASTASIS, VASCULAR INVASION, AND THE LARGEST DIAMETER OF FOCAL LESIONS. MEANWHILE, IT WAS NOT ASSOCIATED WITH FOCAL LESION NUMBER NOR DISTANT METASTASIS OF HCC. IN CONCLUSION, RECK GENE PROMOTER HYPERMETHYLATION IS LINKED TO HCV GENOTYPE-4-RELATED HCC. MOREOVER, DIFFERENT DEGREES OF RECK GENE PROMOTER METHYLATION ARE ASSOCIATED WITH SERUM RECK LEVEL, LYMPH NODE METASTASIS, AND VASCULAR INVASION, WHICH COULD PROVE ITS PATHOGENIC ROLE IN HEPATOCARCINOGENESIS IN CHRONIC HCV-INFECTED PATIENTS. 2021 3 3307 37 HIGH-RESOLUTION GENOMIC PROFILING OF LIVER CANCER LINKS ETIOLOGY WITH MUTATION AND EPIGENETIC SIGNATURES. BACKGROUND & AIMS: HEPATOCELLULAR CARCINOMA (HCC) IS A MODEL OF A DIVERSE SPECTRUM OF CANCERS BECAUSE IT IS INDUCED BY WELL-KNOWN ETIOLOGIES, MAINLY HEPATITIS C VIRUS (HCV) AND HEPATITIS B VIRUS. HERE, WE AIMED TO IDENTIFY HCV-SPECIFIC MUTATIONAL SIGNATURES AND EXPLORED THE LINK BETWEEN THE HCV-RELATED REGIONAL VARIATION IN MUTATIONS RATES AND HCV-INDUCED ALTERATIONS IN GENOME-WIDE CHROMATIN ORGANIZATION. METHODS: TO IDENTIFY AN HCV-SPECIFIC MUTATIONAL SIGNATURE IN HCC, WE PERFORMED HIGH-RESOLUTION TARGETED SEQUENCING TO DETECT PASSENGER MUTATIONS ON 64 HCC SAMPLES FROM 3 ETIOLOGY GROUPS: HEPATITIS B VIRUS, HCV, OR OTHER. TO EXPLORE THE LINK BETWEEN THE GENOMIC SIGNATURE AND GENOME-WIDE CHROMATIN ORGANIZATION WE PERFORMED CHROMATIN IMMUNOPRECIPITATION SEQUENCING FOR THE TRANSCRIPTIONALLY PERMISSIVE H3K4ME3, H3K9AC, AND SUPPRESSIVE H3K9ME3 MODIFICATIONS AFTER HCV INFECTION. RESULTS: REGIONAL VARIATION IN MUTATION RATE ANALYSIS SHOWED SIGNIFICANT ETIOLOGY-DEPENDENT REGIONAL MUTATION RATES IN 12 GENES: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, AND ARSD. WE FOUND AN ENRICHMENT OF C->T TRANSVERSION MUTATIONS IN THE HCV-ASSOCIATED HCC CASES. FURTHERMORE, THESE CASES SHOWED REGIONAL VARIATION IN MUTATION RATES ASSOCIATED WITH GENOMIC INTERVALS IN WHICH HCV INFECTION DICTATED EPIGENETIC ALTERATIONS. THIS SIGNATURE MAY BE RELATED TO THE HCV-INDUCED DECREASED EXPRESSION OF GENES ENCODING KEY ENZYMES IN THE BASE EXCISION REPAIR PATHWAY. CONCLUSIONS: WE IDENTIFIED NOVEL DISTINCT HCV ETIOLOGY-DEPENDENT MUTATION SIGNATURES IN HCC ASSOCIATED WITH HCV-INDUCED ALTERATIONS IN HISTONE MODIFICATION. THIS STUDY PRESENTS A LINK BETWEEN CANCER-CAUSING MUTAGENESIS AND THE INCREASED PREDISPOSITION TO LIVER CANCER IN CHRONIC HCV-INFECTED INDIVIDUALS, AND UNVEILS NOVEL ETIOLOGY-SPECIFIC MECHANISMS LEADING TO HCC AND CANCER IN GENERAL. 2023 4 3476 39 IDENTIFICATION OF A TRANSMEMBRANE PROTEIN INVOLVED IN SHEAR STRESS SIGNALING AND HEPATOCARCINOGENESIS AFTER A SUSTAINED VIROLOGICAL RESPONSE TO HEPATITIS C VIRUS. BACKGROUND & AIMS: THE RISK OF HEPATOCELLULAR CARCINOMA (HCC) REMAINS AFTER ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE (SVR) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC). EPIGENETIC ABNORMALITIES MIGHT BE KEY REGULATORS IN THE DEVELOPMENT OF HCC. THIS STUDY AIMED TO IDENTIFY THE GENES INVOLVED IN HEPATOCARCINOGENESIS AFTER AN SVR. METHODS: DNA METHYLATION IN LIVER TISSUE WAS COMPARED BETWEEN 21 CHC PATIENTS WITHOUT HCC AND 28 CHC PATIENTS WITH HCC, ALL OF WHOM HAD ACHIEVED AN SVR. ADDITIONAL COMPARISONS WITH 23 CHC PATIENTS BEFORE TREATMENT AND 10 NORMAL LIVERS WERE PERFORMED. THE CHARACTERISTICS OF A NEWLY IDENTIFIED GENE WERE EXPLORED IN VITRO AND IN VIVO. RESULTS: WE FOUND THAT THE TRANSMEMBRANE PROTEIN NO. 164 (TMEM164) GENE WAS DEMETHYLATED BY HEPATITIS C VIRUS INFECTION AND HCC DEVELOPMENT AFTER ACHIEVING AN SVR. TMEM164 WAS EXPRESSED MAINLY IN ENDOTHELIAL CELLS, ALPHA SMOOTH MUSCLE ACTIN-POSITIVE CELLS, AND SOME CAPILLARIZED LIVER SINUSOIDAL ENDOTHELIAL CELLS. TMEM164 EXPRESSION WAS SIGNIFICANTLY CORRELATED WITH LIVER FIBROSIS AND RELAPSE-FREE SURVIVAL IN HCC PATIENTS. TMEM164 WAS INDUCED BY SHEAR STRESS, INTERACTED WITH GRP78/BIP, ACCELERATED ATF6 (ACTIVATING TRANSCRIPTION FACTOR 6)-MEDIATED ENDOPLASMIC RETICULUM (ER) STRESS SIGNALING, AND ACTIVATED INTERLEUKIN-6/STAT3 (SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3) SIGNALING IN THE TMNK1 LIVER ENDOTHELIAL CELL LINE. THEREFORE, WE TERMED TMEM164 "SHEAR STRESS-INDUCED TRANSMEMBRANE PROTEIN ASSOCIATED WITH ER STRESS SIGNALING" (SHERMER). SHERMER KNOCKOUT MICE WERE PROTECTED AGAINST CCL4-INDUCED LIVER FIBROSIS. SHERMER OVEREXPRESSION IN TMNK1 CELLS ACCELERATED HCC GROWTH IN A XENOGRAFT MODEL. CONCLUSIONS: WE IDENTIFIED A NEW TRANSMEMBRANE PROTEIN, SHERMER, IN CHC PATIENTS WITH HCC AFTER ACHIEVING AN SVR. SHERMER WAS INDUCED BY SHEAR STRESS AND ACCELERATED ATF6-MEDIATED ER STRESS SIGNALING IN ENDOTHELIAL CELLS. THUS, SHERMER IS A NOVEL ENDOTHELIAL MARKER ASSOCIATED WITH LIVER FIBROSIS, HEPATOCARCINOGENESIS, AND PROGRESSION OF HCC. 2023 5 1190 36 CORRELATION BETWEEN HEPATIC HUMAN MALES ABSENT ON THE FIRST (HMOF) AND VIRAL PERSISTENCE IN CHRONIC HEPATITIS B PATIENTS. BACKGROUND: CHRONIC HEPATITIS B (CHB) REMAINS A GLOBAL HEALTH DILEMMA WITH HIGH MORBIDITY AND MORTALITY. HUMAN MALES ABSENT ON THE FIRST (HMOF) (A HISTONE ACETYLTRANSFERASE) IS RESPONSIBLE FOR DNA DAMAGE REPAIR, TUMORIGENESIS AND CELL CYCLE REGULATION. PERSISTENCE OF HBV DNA CONTRIBUTES TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC) IN CHB PATIENTS. HISTONE ACETYLTRANSFERASE ENHANCES HBV REPLICATION, HOWEVER THE PRECISE UNDERLYING MECHANISM OF HMOF IN HBV REPLICATION IN CHB PATIENTS REMAINS TO BE EXPLORED. THIS STUDY AIMS TO INVESTIGATE THE CORRELATION BETWEEN HEPATIC HMOF AND HBV DNA REPLICATION IN CHB PATIENTS, AND MAY PROVIDE NEW INSIGHTS TOWARDS THE TREATMENT OF CHB PATIENTS. METHODS: HMOF IN LIVER BIOPSY (CHB, N = 33 HBEAG(+); N = 20 HBEAG(-), AND THREE HEALTHY CONTROLS) WAS DETERMINED, USING IMMUNOHISTOCHEMISTRY, QPCR AND WESTERN BLOT. THE CORRELATION BETWEEN HMOF AND HBSAG, AS WELL AS, HBEAG WERE DETERMINED. RESULTS: A POSITIVE CORRELATION BETWEEN HMOF AND HBV DNA IN OVERALL CHB PATIENTS WAS OBSERVED. A DISTINCT POSITIVE CORRELATION BETWEEN HMOF AND HBSAG AND/OR HBEAG IN HBEAG(+) CHB PATIENTS WAS ALSO DETECTED, HOWEVER NOT OBSERVED BETWEEN HMOF AND HBSAG IN HBEAG(-) CHB PATIENTS. NO CORRELATION WAS OBSERVED BETWEEN HMOF AND HEPATIC INFLAMMATION SEVERITY AND FIBROTIC STAGE IN CHB PATIENTS. CONCLUSIONS: HEPATIC HMOF MIGHT CONTRIBUTE TO HOST HBV CLEARANCE IN CHB PATIENTS AND POSSIBLE PATHOGENESIS. 2018 6 155 29 ABERRANT METHYLATION OF POLO-LIKE KINASE CPG ISLANDS IN PLK4 HETEROZYGOUS MICE. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC), ONE OF THE MOST COMMON CANCERS WORLD-WIDE OCCURS TWICE AS OFTEN IN MEN COMPARED TO WOMEN. PREDISPOSING CONDITIONS SUCH AS ALCOHOLISM, CHRONIC VIRAL HEPATITIS, AFLATOXIN B1 INGESTION, AND CIRRHOSIS ALL CONTRIBUTE TO THE DEVELOPMENT OF HCC. METHODS: WE USED A COMBINATION OF METHYLATION SPECIFIC PCR AND BISULFITE SEQUENCING, QREAL-TIME PCR (QPCR), AND WESTERN BLOT ANALYSIS TO EXAMINE EPIGENETIC CHANGES FOR THE POLO-LIKE KINASES (PLKS) DURING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IN PLK4 HETEROZYGOUS MICE AND MURINE EMBRYONIC FIBROBLASTS (MEFS). RESULTS: HERE WE REPORT THAT THE PROMOTER METHYLATION OF PLK4 CPG ISLANDS INCREASES WITH AGE, WAS MORE PREVALENT IN MALES AND THAT PLK4 EPIGENETIC MODIFICATION AND SUBSEQUENT DOWNREGULATION OF EXPRESSION WAS ASSOCIATED WITH THE DEVELOPMENT OF HCC IN PLK4 MUTANT MICE. INTERESTINGLY, THE OPPOSITE OCCURS WITH ANOTHER PLK FAMILY MEMBER, PLK1 WHICH WAS TYPICALLY HYPERMETHYLATED IN NORMAL LIVER TISSUE BUT BECAME HYPOMETHYLATED AND UPREGULATED IN LIVER TUMOURS. FURTHERMORE, UPON ALCOHOL EXPOSURE MURINE EMBRYONIC FIBROBLASTS EXHIBITED INCREASED PLK4 HYPERMETHYLATION AND DOWNREGULATION ALONG WITH INCREASED CENTROSOME NUMBERS AND MULTINUCLEATION. CONCLUSIONS: THESE RESULTS SUGGEST THAT ABERRANT PLK METHYLATION IS CORRELATED WITH THE DEVELOPMENT OF HCC IN MICE. 2011 7 4220 35 METHYLATED CYSTEINE DIOXYGENASE-1 GENE PROMOTER IN THE SERUM IS A POTENTIAL BIOMARKER FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. EPIGENETIC ANALYSIS HAS ATTRACTED INCREASING ATTENTION IN THE MOLECULAR DIAGNOSIS OF HCC. CYSTEINE DIOXYGENASE 1 (CDO1) IS A KEY ENZYME IN THE TAURINE BIOSYNTHETIC PATHWAY AND CONVERTS CYSTEINE TO CYSTEINE SULFINATE. THE CDO1 GENE IS A TUMOR SUPPRESSOR GENE AND IS USUALLY SILENCED BY THE METHYLATION OF ITS PROMOTER IN CARCINOGENESIS. IN THIS STUDY, WE EVALUATED WHETHER THE METHYLATION STATUS OF CDO1 GENE PROMOTER IS OF DIAGNOSTIC VALUE FOR HEPATITIS B VIRUS (HBV)-RELATED HCC. THE CDO1 PROMOTER METHYLATION STATUS WAS DETERMINED IN SERUM SAMPLES USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN A COHORT OF 123 PATIENTS WITH HBV-RELATED HCC, 28 WITH LIVER CIRRHOSIS (LC), 29 WITH CHRONIC HEPATITIS B (CHB) AND 20 HEALTHY CONTROLS. THE FREQUENCY OF THE CDO1 PROMOTER METHYLATION IN HBV-RELATED HCC (42.3%) WAS SIGNIFICANTLY HIGHER THAN THAT IN LC (14.3%), CHB (6.9%) AND HEALTHY CONTROLS (0%) (P = 0.006; P < 0.0001; P < 0.0001; RESPECTIVELY). FURTHERMORE, IN HCC PATIENTS, THE FREQUENCY OF CDO1 PROMOTER METHYLATION WAS HIGHER IN ADVANCED STAGES (III-IV) (53%) THAN THE EARLY STAGES (I-II) (20%) (P = 0.001). EVALUATION OF THE CDO1 PROMOTER METHYLATION STATUS IN SERUM, IN COMBINATION WITH AFP (> 20 NG/ML), SIGNIFICANTLY IMPROVED THE DIAGNOSTIC VALUE, WITH SENSITIVITY AND SPECIFICITY OF 82.9% AND 75.4%, RESPECTIVELY IN DISTINGUISHING HCC FROM LC AND CHB. IN CONCLUSION, METHYLATION STATUS OF SERUM CDO1 GENE PROMOTER MAY BE HELPFUL IN THE DIAGNOSIS OF HCC AND THE ESTIMATION OF THE HCC STAGES. 2014 8 5004 30 PERIPHERAL B CELLS FROM PATIENTS WITH HEPATITIS C VIRUS-ASSOCIATED LYMPHOMA EXHIBIT CLONAL EXPANSION AND AN ANERGIC-LIKE TRANSCRIPTIONAL PROFILE. CHRONIC HCV INFECTION REMAINS A GLOBAL HEALTH CONCERN DUE TO ITS INVOLVEMENT IN HEPATIC AND EXTRAHEPATIC DISEASES, INCLUDING B CELL NON-HODGKIN LYMPHOMA (BNHL). CLINICAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A CAUSAL ROLE FOR HCV IN BNHL DEVELOPMENT, ALTHOUGH MECHANISTIC INSIGHT IS LACKING. WE PERFORMED RNA-SEQUENCING ON PERIPHERAL B CELLS FROM PATIENTS WITH HCV ALONE, BNHL ALONE, AND HCV-ASSOCIATED BNHL TO IDENTIFY UNIQUE AND SHARED TRANSCRIPTIONAL PROFILES ASSOCIATED WITH TRANSFORMATION. IN PATIENTS WITH HCV-ASSOCIATED BNHL, WE OBSERVED THE ENRICHMENT OF AN ANERGIC-LIKE GENE SIGNATURE AND EVIDENCE OF CLONAL EXPANSION THAT WAS CORRELATED WITH THE EXPRESSION OF EPIGENETIC REGULATORY GENES. OUR DATA SUPPORT A ROLE FOR VIRAL-MEDIATED CLONAL EXPANSION OF ANERGIC-LIKE B CELLS IN HCV-ASSOCIATED BNHL DEVELOPMENT AND SUGGEST EPIGENETIC DYSREGULATION AS A POTENTIAL MECHANISM DRIVING EXPANSION. WE PROPOSE EPIGENETIC MECHANISMS MAY BE INVOLVED IN BOTH HCV-ASSOCIATED LYMPHOMA AND REGULATION OF B CELL ANERGY, REPRESENTING AN ATTRACTIVE TARGET FOR CLINICAL INTERVENTIONS. 2023 9 5349 42 RASSF1A AND DOK1 PROMOTER METHYLATION LEVELS IN HEPATOCELLULAR CARCINOMA, CIRRHOTIC AND NON-CIRRHOTIC LIVER, AND CORRELATION WITH LIVER CANCER IN BRAZILIAN PATIENTS. HEPATOCELLULAR CARCINOMA (HCC) IS THE SECOND MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. MOST CASES OF HCC ARE ASSOCIATED WITH CIRRHOSIS RELATED TO CHRONIC HEPATITIS B VIRUS OR HEPATITIS C VIRUS INFECTIONS. HYPERMETHYLATION OF PROMOTER REGIONS IS THE MAIN EPIGENETIC MECHANISM OF GENE SILENCING AND HAS BEEN INVOLVED IN HCC DEVELOPMENT. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER ABERRANT METHYLATION OF RASSF1A AND DOK1 GENE PROMOTERS IS ASSOCIATED WITH THE PROGRESSION OF LIVER DISEASE IN BRAZILIAN PATIENTS. METHYLATION LEVELS WERE MEASURED BY PYROSEQUENCING IN 41 (20 HCC, 9 CIRRHOTIC, AND 12 NON-CIRRHOTIC) LIVER TISSUE SAMPLES. MEAN RATES OF METHYLATION IN RASSF1A AND DOK1 WERE 16.2% AND 12.0% IN NON-CIRRHOTIC, 26.1% AND 19.6% IN CIRRHOTIC, AND 59.1% AND 56.0% IN HCC TISSUES, RESPECTIVELY, SHOWING A GRADUAL INCREASE ACCORDING TO THE PROGRESSION OF THE DISEASE, WITH SIGNIFICANTLY HIGHER LEVELS IN TUMOR TISSUES. IN ADDITION, HYPERMETHYLATION OF RASSF1A AND DOK1 WAS FOUND IN THE VAST MAJORITY (88%) OF THE HCC CASES. INTERESTINGLY, DOK1 METHYLATION LEVELS IN HCC SAMPLES WERE SIGNIFICANTLY HIGHER IN THE GROUP OF YOUNGER (<40 YEARS) PATIENTS, AND HIGHER IN MODERATELY DIFFERENTIATED THAN IN POORLY DIFFERENTIATED TUMORS (P < 0.05). OUR RESULTS REINFORCE THE HYPOTHESIS THAT HYPERMETHYLATION OF RASSF1A AND DOK1 CONTRIBUTES TO HEPATOCARCINOGENESIS AND IS ASSOCIATED TO CLINICOPATHOLOGICAL CHARACTERISTICS. RASSF1A AND DOK1 PROMOTER HYPERMETHYLATION MAY BE A VALUABLE BIOMARKER FOR EARLY DIAGNOSIS OF HCC AND A POTENTIAL MOLECULAR TARGET FOR EPIGENETIC-BASED THERAPY. 2016 10 3354 34 HISTONE DEMETHYLATION PROFILES IN NONALCOHOLIC FATTY LIVER DISEASE AND PROGNOSTIC VALUES IN HEPATOCELLULAR CARCINOMA: A BIOINFORMATIC ANALYSIS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WITH MULTIFACTORIAL PATHOGENESIS; HISTONE DEMETHYLASES (HDMS) ARE EMERGING AS ATTRACTIVE TARGETS. WE IDENTIFIED HDM GENES (INCLUDING KDM5C, KDM6B, KDM8, KDM4A, AND JMJD7) THAT WERE DIFFERENTIALLY EXPRESSED IN NAFLD AND NORMAL SAMPLES BY EXPLORING GENE EXPRESSION PROFILING DATASETS. THERE WAS NO SIGNIFICANT DIFFERENCE IN THE EXPRESSION OF GENES RELATED TO HISTONE DEMETHYLATION BETWEEN MILD AND ADVANCED NAFLD. IN VITRO AND IN VIVO STUDIES INDICATED THAT KDM6B AND JMJD7 WERE UPREGULATED AT THE MRNA LEVEL IN NAFLD. WE EXPLORED THE EXPRESSION LEVELS AND PROGNOSTIC VALUES OF THE IDENTIFIED HDM GENES IN HEPATOCELLULAR CARCINOMA (HCC). KDM5C AND KDM4A WERE UPREGULATED IN HCC COMPARED TO NORMAL TISSUE, WHILE KDM8 SHOWED DOWNREGULATION. THE ABNORMAL EXPRESSION LEVELS OF THESE HDMS COULD PROVIDE PROGNOSTIC VALUES. FURTHERMORE, KDM5C AND KDM4A WERE ASSOCIATED WITH IMMUNE CELL INFILTRATION IN HCC. HDMS WERE ASSOCIATED WITH CELLULAR AND METABOLIC PROCESSES AND MAY BE INVOLVED IN THE REGULATION OF GENE EXPRESSION. DIFFERENTIALLY EXPRESSED HDM GENES IDENTIFIED IN NAFLD MAY PROVIDE VALUE TO UNDERSTANDING PATHOGENESIS AND IN THE DEVELOPMENT OF EPIGENETIC THERAPEUTIC TARGETS. HOWEVER, ON THE BASIS OF THE INCONSISTENT RESULTS OF IN VITRO STUDIES, FUTURE IN VIVO EXPERIMENTS COMBINED WITH TRANSCRIPTOMIC ANALYSIS ARE NEEDED FOR FURTHER VALIDATION. 2023 11 6421 31 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES. 2018 12 1067 27 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC. 2014 13 6645 38 UP-REGULATION OF DBPA MRNA IN HEPATOCELLULAR CARCINOMA ASSOCIATED WITH METABOLIC SYNDROME. PURPOSE: METABOLIC SYNDROME (MS) IS A GROUP OF RECOGNIZED RISK FACTORS FOR THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IN PATIENTS WITH CHRONIC LIVER DISEASE. THE AIM OF THIS STUDY WAS TO ANALYZE THE CLINICOPATHOLOGICAL CHARACTERISTICS OF HCC PATIENTS WITH MS AND THE RISK FACTORS FOR RECURRENCE. ALSO, THE AIM WAS TO INVESTIGATE THE COLD SHOCK PROTEIN: DNA-BINDING PROTEIN A (DBPA) EXPRESSION IN HCC PATIENTS WITH MS. METHODS: A TOTAL OF 243 PATIENTS WHO UNDERWENT CURATIVE RESECTIONS FOR HCC WERE CLASSIFIED INTO TWO GROUPS. DBPA EXPRESSION WAS INVESTIGATED IN 66 HCC PATIENTS WITH MS AND IN 30 PATIENTS WITHOUT MS BY USING REAL-TIME RT-PCR. PROMOTER METHYLATION STATUS WAS EXAMINED BY USING MS-PCR. RESULTS: THE INCIDENCE OF METABOLIC FACTORS AFFECT THE HCC SIGNIFICANTLY HIGHER IN NON-B NON-C PATIENTS THAN IN HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) PATIENTS (P < 0.001). UNIVARIATE ANALYSIS OF HCC PATIENTS WITH MS RECURRENCE REVEALED ASPARTATE AMINO TRANSFERASE (AST), MULTIPLE TUMORS, LIVER DAMAGE, HEPATIC VEIN INVASION, ADVANCED CANCER STAGES (P < 0.01), ALPHA-FETOPROTEIN (AFP) AND DIABETES MELLITUS TYPE II (P < 0.05) AS RISK FACTORS. MULTIVARIATE ANALYSIS, AST, MULTIPLE TUMORS, AND HEPATIC VEIN INVASION (P < 0.01) WERE IDENTIFIED AS INDEPENDENT FACTORS FOR THE RECURRENCE. DBPA MRNA WAS HIGHER IN PATIENTS WITH MS THAN IN THOSE WITHOUT MS (P = 0.016), AND IT WAS MOSTLY UPREGULATED IN NON-B NON-C HCC PATIENTS WITH MS THAN IN NON-B NON-C HCC PATIENTS WITHOUT HBV OR HCV. ESPECIALLY, IN HCC PATIENTS WITH DIABETES MELLITUS TYPE II, THE MRNA AND PROTEIN LEVELS WERE HIGHLY UPREGULATED. THE DBPA EXPRESSION WAS REGULATED BY PROMOTER METHYLATION STATUS (P < 0.05). CONCLUSIONS: THIS STUDY IDENTIFIES THAT DBPA MAY ACCELERATE THE HEPATOCARCINOGENESIS IN HCC PATIENTS WITH MS VIA INFLAMMATION-INDUCED AND OXIDATIVE STRESS PATHWAYS. THE DEMETHYLATION-RELATED EPIGENETIC ACTIVATION MAY BE ONE OF THE REGULATING FACTORS FOR HCC PATIENTS WITH MS. 2013 14 3296 36 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT. 2013 15 6849 24 [MOLECULAR MECHANISM OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IN JAPAN IS CLOSELY ASSOCIATED WITH THE CHRONIC LIVER DISEASES OF INFECTION WITH THE HEPATITIS B OR C VIRUSES. ANALYSIS OF HCC TISSUES FREQUENTLY DETECTS LOSS OF HETEROZYGOSITY AT CHROMOSOMES 1P, 4, 6Q, 8P, 10Q, 13Q, 16Q, 17P, AND MANY GENOMIC AND EPIGENOMIC ABNORMALITIES HAVE BEEN FOUND IN P53, BETA-CATENIN, P16CDKI, DNA MISMATCH REPAIR GENES, AND OTHERS. HOWEVER, NO SPECIFIC ABNORMAL GENETIC OR EPIGENETIC CHANGES FOR HCC HAVE BEEN FOUND SO FAR. THE DEVELOPMENT OF HCC HAS BEEN REPORTED IN MICE TRANSGENIC FOR THE HEPATITIS B VIRUS X GENE OR THE HEPATITIS C VIRUS CORE GENE, AND THESE VIRAL PROTEINS MIGHT PLAY ESSENTIAL ROLES IN HEPATOCARCINOGENESIS. CHRONIC HEPATITIS AND FIBROSIS DUE TO PERSISTENT VIRAL INFECTION MIGHT ALSO INFLUENCE THE GENOMIC INSTABILITY OF HEPATOCYTES, LEADING TO ACCUMULATION OF GENOMIC CHANGES. 1999 16 2316 36 EPIGENETIC REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 BY HOST TRANSCRIPTION FACTOR SPECKLED 110 KDA DURING HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV) IS THE LEADING CAUSE OF LIVER DISEASE RANGING FROM ACUTE AND CHRONIC HEPATITIS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). STUDIES HAVE REVEALED THAT HBV INFECTION BROADLY REPROGRAMMES THE HOST CELLULAR METABOLIC PROCESSES FOR VIRAL PATHOGENESIS. PREVIOUS REPORTS HAVE SHOWN THAT GLYCOLYSIS AND GLUCONEOGENESIS ARE AMONG THE MOST DEREGULATED PATHWAYS DURING HBV INFECTION. WE NOTED THAT DESPITE BEING ONE OF THE RATE-LIMITING ENZYMES OF GLUCONEOGENESIS, THE ROLE AND REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 (FBP1) DURING HBV INFECTION IS NOT MUCH EXPLORED. IN THIS STUDY, WE REPORT FBP1 UPREGULATION UPON HBV INFECTION AND UNRAVEL A NOVEL MECHANISM OF EPIGENETIC REPROGRAMMING OF FBP1 BY HBV VIA UTILIZING HOST FACTOR SPECKLED 110 KDA (SP110). HERE, WE IDENTIFIED ACETYLATED LYSINE 18 OF HISTONE H3 (H3K18AC) AS A SELECTIVE INTERACTOR OF SP110 BROMODOMAIN. FURTHERMORE, WE FOUND THAT SP110 GETS RECRUITED ON H3K18AC-ENRICHED FBP1 PROMOTER, AND FACILITATES RECRUITMENT OF DEACETYLASE SIRTUIN 2 (SIRT2) ON THAT SITE IN THE PRESENCE OF HBV. SIRT2 IN TURN BRINGS ITS INTERACTOR AND TRANSCRIPTIONAL ACTIVATOR HEPATOCYTE NUCLEAR FACTOR 4-ALPHA TO THE PROMOTER, WHICH ULTIMATELY LEADS TO A LOSS OF DNA METHYLATION NEAR THE COGNATE SITE. INTERESTINGLY, THIS SP110 DRIVEN FBP1 REGULATION DURING INFECTION WAS FOUND TO PROMOTE VIRAL-BORNE HCC PROGRESSION. MOREOVER, SP110 CAN BE USED AS A PROGNOSTIC MARKER FOR THE HEPATITIS-MEDIATED HCC PATIENTS, WHERE HIGH SP110 EXPRESSION SIGNIFICANTLY LOWERED THEIR SURVIVAL. THUS, THE EPIGENETIC READER PROTEIN SP110 HAS POTENTIAL TO BE A THERAPEUTIC TARGET TO CHALLENGE HBV-INDUCED HCCS. 2022 17 758 40 CAS9-TARGETED NANOPORE SEQUENCING REVEALS EPIGENETIC HETEROGENEITY AFTER DE NOVO ASSEMBLY OF NATIVE FULL-LENGTH HEPATITIS B VIRUS GENOMES. HEPATITIS B VIRUS (HBV) CONTAINS A 3.2 KB DNA GENOME AND CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A GLOBAL HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). METHYLATION OF HBV DNA IN A CPG CONTEXT (5MCPG) CAN ALTER THE EXPRESSION PATTERNS OF VIRAL GENES RELATED TO INFECTION AND CELLULAR TRANSFORMATION. MOREOVER, IT MAY ALSO PROVIDE CLUES AS TO WHY CERTAIN INFECTIONS ARE CLEARED OR PERSIST WITH OR WITHOUT PROGRESSION TO CANCER. THE DETECTION OF 5MCPG OFTEN REQUIRES TECHNIQUES THAT DAMAGE DNA OR INTRODUCE BIAS THROUGH A MYRIAD OF LIMITATIONS. THEREFORE, WE DEVELOPED A METHOD FOR THE DETECTION OF 5MCPG ON THE HBV GENOME THAT DOES NOT RELY ON BISULFITE CONVERSION OR PCR. WITH CAS9-GUIDED RNPS TO SPECIFICALLY TARGET THE HBV GENOME, WE ENRICHED IN HBV DNA FROM PRIMARY HUMAN HEPATOCYTES (PHHS) INFECTED WITH DIFFERENT HBV GENOTYPES, AS WELL AS ENRICHING IN HBV FROM INFECTED PATIENT LIVER TISSUE, FOLLOWED BY SEQUENCING WITH OXFORD NANOPORE TECHNOLOGIES MINION. DETECTION OF 5MCPG BY NANOPORE SEQUENCING WAS BENCHMARKED WITH BISULFITE-QUANTITATIVE METHYL-SPECIFIC QPCR (BS-QMSP). THE 5MCPG LEVELS IN HBV DETERMINED BY BS-QMSP AND NANOPORE SEQUENCING WERE HIGHLY CORRELATED. OUR NANOPORE SEQUENCING APPROACH ACHIEVED A COVERAGE OF ~2000X OF HBV DEPENDING ON INFECTION EFFICIENCY, SUFFICIENT COVERAGE TO PERFORM A DE NOVO ASSEMBLY AND DETECT SMALL FLUCTUATIONS IN HBV METHYLATION, PROVIDING THE FIRST DE NOVO ASSEMBLY OF NATIVE HBV DNA, AS WELL AS THE FIRST LANDSCAPE OF 5MCPG FROM NATIVE HBV SEQUENCES. MOREOVER, BY CAPTURING ENTIRE HBV GENOMES, WE EXPLORED THE EPIGENETIC HETEROGENEITY OF HBV IN INFECTED PATIENTS AND IDENTIFIED FOUR EPIGENETICALLY DISTINCT CLUSTERS BASED ON METHYLATION PROFILES. THIS METHOD IS A NOVEL APPROACH THAT ENABLES THE ENRICHMENT OF VIRAL DNA IN A MIXTURE OF NUCLEIC ACID MATERIAL FROM DIFFERENT SPECIES AND WILL SERVE AS A VALUABLE TOOL FOR INFECTIOUS DISEASE MONITORING. 2021 18 3198 31 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES. 2018 19 2761 36 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY. 2012 20 3959 35 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS. 2019