1   852 176 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  3030  30 GENETICS OF OPISTHORCHIS VIVERRINI-RELATED CHOLANGIOCARCINOMA. PURPOSE OF REVIEW: WE REVIEW THE GENETIC, EPIGENETIC AND TRANSCRIPTIONAL LANDSCAPE OF LIVER FLUKE (OPISTHORCHIS VIVERRINI, OV)-RELATED CHOLANGIOCARCINOMA (CCA). ITS DISTINCT ALTERATIONS, AS COMPARED WITH NON-OV-RELATED CCA MAY HELP SHED LIGHT ON ITS UNDERLYING MOLECULAR MECHANISMS. RECENT FINDINGS: RECENT WHOLE-EXOME AND TARGETED SEQUENCING NOT ONLY CONFIRMED FREQUENT MUTATIONS IN KNOWN CCA-RELATED GENES INCLUDING TP53 (44%), KRAS (16.7%) AND SMAD4 (16.7%), BUT ALSO REVEALED MUTATIONS IN NOVEL CCA-RELATED GENES ASSOCIATED WITH CHROMATIN REMODELING [BAP1 (2.8%), ARID1A (17.6%), MLL3 (13%) AND IDH1/2 (2.8%)], WNT SIGNALING [RNF43 (9.3%) AND PEG3 (5.6%)] AND KRAS/G PROTEIN SIGNALING [GNAS (9.3%) AND ROBO2 (9.3%)]. INTERESTINGLY, THERE IS A SIGNIFICANT DIFFERENCE IN THE FREQUENCY OF MUTATED GENES BETWEEN OV-RELATED CCA AND NON-OV-RELATED CCA, SUCH AS P53 AND IDH1/2, REFLECTING THE IMPACT OF CAUSE ON PATHOGENESIS. ALTERED DNA METHYLATION AND TRANSCRIPTIONAL PROFILES ASSOCIATED WITH XENOBIOTIC METABOLISM AND PRO-INFLAMMATORY RESPONSES WERE ALSO FOUND IN OV-RELATED CCA. SUMMARY: LIVER FLUKE-INDUCED CHRONIC INFLAMMATION PLAYS A CRUCIAL ROLE IN CHOLANGIOCARCINOGENESIS, RESULTING IN DISTINCT SIGNATURES OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL ALTERATIONS. THESE ALTERATIONS, WHEN CONTRASTED WITH NON-OV-RELATED CCA, INDICATE A UNIQUE PATHOGENIC PROCESS IN OV-RELATED CCA AND MAY HAVE POTENTIAL CLINICAL IMPLICATIONS ON DIAGNOSTICS, THERAPEUTICS AND PREVENTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  1978  39 EPIGENETIC ALTERATIONS IN CHOLANGIOCARCINOMA-SUSTAINED IL-6/STAT3 SIGNALING IN CHOLANGIO- CARCINOMA DUE TO SOCS3 EPIGENETIC SILENCING. CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM, CHARACTERIZED BY ITS TYPICALLY LATE CLINICAL PRESENTATION AND LACK OF EFFECTIVE THERAPEUTIC MODALITIES. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION AND HEPATOLITHIASIS, ARE LISTED IN THE RISK FACTORS, BUT FOR MOST CASES OF CCA THE CAUSE IS UNKNOWN. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION IN ADDITION TO GENETIC CHANGES IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES HYPERMETHYLATED IN CCA TO DATE AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. AMONG GENES HYPERMETHYLATED, WE FOUND THE CPG ISLAND HYPERMETHYLATION IN SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3) GENE PROMOTER IN CCA. INTERLEUKIN-6 (IL-6)-MEDIATED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION ARE ABERRANTLY SUSTAINED IN CCA CELLS, RESULTING IN RESISTANCE TO APOPTOSIS. SOCS3 CONTROLS THE IL-6/STAT3 SIGNALING PATHWAY BY A CLASSIC FEEDBACK LOOP. INDEED, SOCS3 EPIGENETIC SILENCING IS RESPONSIBLE FOR SUSTAINED IL-6/STAT3 SIGNALING IN CCA. THESE FINDINGS PROVIDE NEW PERSPECTIVES FOR EPIGENETIC THERAPY TO RESTORE SOCS3 IN THIS CANCER.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  4951  32 PATHOGENESIS OF CHOLANGIOCARCINOMA: FROM GENETICS TO SIGNALLING PATHWAYS. CHOLANGIOCARCINOMA (CCA) IS A MALIGNANT TUMOUR OF BILE DUCT EPITHELIAL CELLS WITH DISMAL PROGNOSIS AND RISING INCIDENCE. CHRONIC INFLAMMATION RESULTING FROM LIVER FLUKE INFECTION, HEPATITIS AND OTHER INFLAMMATORY BOWEL DISEASES IS A MAJOR CONTRIBUTING FACTOR TO CHOLANGIOCARCINOGENESIS, LIKELY THROUGH ACCUMULATION OF SERIAL GENETIC AND EPIGENETIC ALTERATIONS RESULTING IN ABERRATION OF ONCOGENES AND TUMOUR SUPPRESSORS. RECENT STUDIES MAKING USE OF ADVANCES IN HIGH-THROUGHPUT GENOMICS HAVE REVEALED THE GENETIC LANDSCAPE OF CCA, GREATLY INCREASING OUR UNDERSTANDING OF ITS UNDERLYING BIOLOGY. A SERIES OF HIGHLY RECURRENT MUTATIONS IN GENES SUCH AS TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 AND BAP1, WHICH ARE KNOWN TO BE INVOLVED IN CELL CYCLE CONTROL, CELL SIGNALLING PATHWAYS AND CHROMATIN DYNAMICS, HAVE LED TO INVESTIGATIONS OF THEIR ROLES, THROUGH MOLECULAR TO MOUSE MODELLING STUDIES, IN CHOLANGIOCARCINOGENESIS. THIS REVIEW FOCUSES ON THE LANDSCAPE GENETIC ALTERATIONS IN CCA AND ITS FUNCTIONAL RELEVANCE TO THE FORMATION AND PROGRESSION OF CCA.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  2936  52 GENETIC AND EPIGENETIC ABNORMALITIES IN PRIMARY SCLEROSING CHOLANGITIS-ASSOCIATED CHOLANGIOCARCINOMA. PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHOLESTATIC LIVER DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE BILIARY TREE WITH SUBSEQUENT FIBROSIS AND CIRRHOSIS OF THE LIVER. PATIENTS WITH PSC ARE AT INCREASED RISK FOR THE DEVELOPMENT OF CHOLANGIOCARCINOMA (CCA), A HIGHLY MALIGNANT EPITHELIAL TUMOR ARISING FROM THE INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS. CURRENTLY, ORTHOTOPIC LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT. THE LACK OF EFFICIENT DIAGNOSTIC METHODS FOR EARLY DETECTION AND THE LIMITED THERAPEUTIC OPTIONS FOR CCA ARE MAJOR PROBLEMS AND ARE ASSOCIATED WITH POOR SURVIVAL. THE PATHOGENESIS OF PSC-ASSOCIATED CCA IS COMPLEX AND POORLY UNDERSTOOD. IT SEEMS THAT PRO-INFLAMMATORY CYTOKINES PLAY AN IMPORTANT ROLE IN GENETIC AND EPIGENETIC CHANGES THAT CONTRIBUTE TO THE CARCINOGENIC PROCESS. THE MAPPING OF GENETIC ALTERATIONS MAY ELUCIDATE MOLECULAR TARGETS THAT MAY BE APPLIED AS BIOMARKERS TO FACILITATE EARLY DIAGNOSIS OF MALIGNANT DEGENERATION TO IMPROVE PATIENT OUTCOME. IN THE LAST DECADE, THE INTRODUCTION OF SEVERAL NOVEL MOLECULAR TECHNIQUES AVAILABLE FOR GENOME-WIDE SCREENING HAS ADVANCED OUR KNOWLEDGE ON MANY OF THE GENETIC ABNORMALITIES THAT ARE PREVALENT IN CCA AND PSC-ASSOCIATED CCA. THIS REVIEW SUMMARIZES GENETIC AND EPIGENETIC ABNORMALITIES, WHICH HAVE IMPORTANT POTENTIAL FOR CLINICAL APPLICATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  1972  38 EPIGENETIC ALTERATIONS ASSOCIATED WITH CHOLANGIOCARCINOMA (REVIEW). CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION, AND HEPATOLITHIASIS, ARE CONSIDERED RISK FACTORS, BUT THE CAUSE IS STILL UNKNOWN IN MOST CASES. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS, INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION, IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. MORE RECENTLY, RESEARCH INTEREST HAS BEEN FOCUSING ON MICRORNA (MIR), A MAJOR SUBTYPE OF NON-CODING RNA. MIR IS HIGHLY CONSERVED AMONG SPECIES AND REGULATES THE EXPRESSION OF SPECIFIC TARGET GENES BY BINDING TO THE 3'-UNTRANSLATED REGIONS OF MESSENGER RNA. THE NUMBER OF STUDIES ON A POSSIBLE LINK BETWEEN MIR AND VARIOUS CANCERS IS GROWING. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES CURRENTLY KNOWN TO BE HYPERMETHYLATED IN CCA AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. THE EPIGENETIC ROLE OF MIR IN THE PATHOGENESIS OF CCA IS ALSO DISCUSSED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  6778  40 [BILIARY TRACT CANCERS : MOLECULAR CHARACTERIZATION AND IDENTIFICATION OF NOVEL PROGNOSTIC MARKERS]. BACKGROUND: BILE DUCT CANCERS (BTCS) ARE HIGHLY AGGRESSIVE TUMORS WITH A DISMAL PROGNOSIS AND AN INCREASING INCIDENCE. BTC IS A TUMORBIOLOGICALLY AND CLINICALLY HETEROGENEOUS TUMOR GROUP AND CAN BE SUBDIVIDED ACCORDING TO ANATOMICAL ASPECTS INTO INTRAHEPATIC CHOLANGIOCARCINOMAS (ICCA), EXTRAHEPATIC CHOLANGIOCARCINOMAS (ECCA) AND GALLBLADDER CARCINOMAS (GBC). NEW THERAPY OPTIONS: CHRONIC INFLAMMATORY PROCESSES OF THE BILIARY SYSTEM SEEM TO PLAY A ROLE IN THE DEVELOPMENT OF THESE TUMORS. INSIGHTS INTO MOLECULAR CHOLANGIOCARCINOGENESIS COULD MAKE AN IMPORTANT CONTRIBUTION TO NOVEL AND MORE PRECISE CLASSIFICATION ATTEMPTS AND TO THE DEVELOPMENT OF NEW, TARGETED THERAPIES FOR BTC. EPIGENETIC AND GENETIC ALTERATIONS IN CHOLANGIOCARCINOMAS: THE FIRST DESCRIPTION OF GENOME-WIDE DNA METHYLATION PATTERNS IN CCA SHOWED DRASTIC GLOBAL METHYLATION DIFFERENCES BETWEEN CCA AND CORRESPONDING NON-NEOPLASTIC TISSUE (MATCHED-PAIR ANALYSES). MOREOVER, SIGNIFICANT METHYLATION DIFFERENCES BETWEEN THE CCA SUBTYPES (ECCA AND ICCA) COULD BE FOUND. USING IMMUNOHISTOCHEMISTRY AND SANGER SEQUENCING, IT WAS SHOWN THAT THE ACTUAL BRAF V600E MUTATION RATE SEEMS TO BE SIGNIFICANTLY LOWER (1.3%) THAN PREVIOUSLY DESCRIBED IN THE LITERATURE. IMMUNEPHENOTYPING IN BILIARY TRACT CANCERS: A COMPREHENSIVE, SUBTYPE-SPECIFIC CHARACTERIZATION OF TUMOR-INFILTRATING IMMUNE CELLS AS WELL AS AN EXPRESSION ANALYSIS OF MAJOR HISTOCOMPATIBILITY COMPLEX I WAS PERFORMED IN A LARGE AND WELL-CHARACTERIZED BTC COHORT. FOR FURTHER STUDIES ON THE EFFICACY OF IMMUNOMODULATORY THERAPY APPROACHES FOR BTC, THE PRESENTED RESULTS PROVIDE A SOLID BASIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  5220  31 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  4472  46 MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA. BACKGROUND: CHOLANGIOCARCINOMAS ARE A HETEROGENEOUS GROUP OF MALIGNANCIES ARISING FROM A NUMBER OF CELLS OF ORIGIN ALONG THE BILIARY TREE. ALTHOUGH MOST CASES IN WESTERN COUNTRIES ARE SPORADIC, LARGE POPULATION-BASED STUDIES HAVE IDENTIFIED A NUMBER OF RISK FACTORS. THIS REVIEW SUMMARISES THE EVIDENCE BEHIND REPORTED RISK FACTORS AND CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA, WITH A FOCUS ON INFLAMMATION AND CHOLESTASIS AS THE DRIVING FORCES IN CHOLANGIOCARCINOMA DEVELOPMENT. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: CHOLESTATIC LIVER DISEASES (E.G. PRIMARY SCLEROSING CHOLANGITIS AND FIBROPOLYCYSTIC LIVER DISEASES), LIVER CIRRHOSIS, AND BILIARY STONE DISEASE ALL INCREASE THE RISK OF CHOLANGIOCARCINOMA. CERTAIN BACTERIAL, VIRAL OR PARASITIC INFECTIONS SUCH AS HEPATITIS B AND C AND LIVER FLUKES ALSO INCREASE CHOLANGIOCARCINOMA RISK. OTHER RISK FACTORS INCLUDE INFLAMMATORY DISORDERS (SUCH AS INFLAMMATORY BOWEL DISEASE AND CHRONIC PANCREATITIS), TOXINS (E.G. ALCOHOL AND TOBACCO), METABOLIC CONDITIONS (DIABETES, OBESITY AND NON-ALCOHOLIC FATTY LIVER DISEASE) AND A NUMBER OF GENETIC DISORDERS. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS CAUSE CHRONIC INFLAMMATION OR CHOLESTASIS. CHRONIC INFLAMMATION LEADS TO INCREASED EXPOSURE OF CHOLANGIOCYTES TO THE INFLAMMATORY MEDIATORS INTERLEUKIN-6, TUMOUR NECROSIS FACTOR-A, CYCLO-OXYGENASE-2 AND WNT, RESULTING IN PROGRESSIVE MUTATIONS IN TUMOUR SUPPRESSOR GENES, PROTO-ONCOGENES AND DNA MISMATCH-REPAIR GENES. ACCUMULATING BILE ACIDS FROM CHOLESTASIS LEAD TO REDUCED PH, INCREASED APOPTOSIS AND ACTIVATION OF ERK1/2, AKT AND NF-KAPPAB PATHWAYS THAT ENCOURAGE CELL PROLIFERATION, MIGRATION AND SURVIVAL. OTHER MEDIATORS UPREGULATED IN CHOLANGIOCARCINOMA INCLUDE TRANSFORMING GROWTH FACTOR-BETA, VASCULAR ENDOTHELIAL GROWTH FACTOR, HEPATOCYTE GROWTH FACTOR AND SEVERAL MICRORNAS. INCREASED EXPRESSION OF THE CELL SURFACE RECEPTOR C-MET, THE GLUCOSE TRANSPORTER GLUT-1 AND THE SODIUM IODIDE SYMPORTER LEAD TO TUMOUR GROWTH, ANGIOGENESIS AND CELL MIGRATION. STROMAL CHANGES ARE ALSO OBSERVED, RESULTING IN ALTERATIONS TO THE EXTRACELLULAR MATRIX COMPOSITION AND RECRUITMENT OF FIBROBLASTS AND MACROPHAGES THAT CREATE A MICROENVIRONMENT PROMOTING CELL SURVIVAL, INVASION AND METASTASIS. CONCLUSION: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS FOR CHOLANGIOCARCINOMA CAUSE CHRONIC INFLAMMATION AND/OR CHOLESTASIS, LEADING TO THE ACTIVATION OF COMMON INTRACELLULAR PATHWAYS THAT RESULT IN REACTIVE CELL PROLIFERATION, GENETIC/EPIGENETIC MUTATIONS AND CHOLANGIOCARCINOGENESIS. AN UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA IS VITAL WHEN DEVELOPING NEW DIAGNOSTIC BIOMARKERS AND TARGETED THERAPIES FOR THIS DISEASE.	2019	

10  4952  30 PATHOGENESIS OF CHRONIC CHIKUNGUNYA ARTHRITIS: RESEMBLANCES AND LINKS WITH RHEUMATOID ARTHRITIS. CHIKUNGUNYA VIRUS (CHIKV) INFECTION RESULTS FROM TRANSMISSION BY THE MOSQUITO VECTOR. FOLLOWING AN INCUBATION PERIOD OF 5-7 DAYS, PATIENTS DEVELOP AN ACUTE FEBRILE ILLNESS, CHIKUNGUNYA FEVER (CHIKF), CHARACTERIZED BY HIGH FEVERS, MACULOPAPULAR RASH, HEADACHES, POLYARTHRITIS/ARTHRALGIAS, MYALGIAS, NAUSEA, VOMITING, AND DIARRHEA. JOINT PAIN IS OFTEN SEVERE, AND MOST OFTEN INVOLVES THE HANDS, THE WRISTS, THE ANKLES, AND THE METATARSAL-PHALANGEAL JOINTS OF THE FEET. MANY PATIENTS RECOVER WITHIN SEVERAL WEEKS, BUT UP TO 50% DEVELOP CHRONIC JOINT PAIN AND SWELLING FOR MORE THAN 12 WEEKS, THEN WE REFER TO THESE SYMPTOMS AS CHRONIC CHIKUNGUNYA ARTHRITIS (CCA). THE PATHOGENESIS OF CCA IS NOT WELL UNDERSTOOD. IN THIS ARTICLE, WE SUGGEST THAT MESENCHYMAL STEM CELLS (MSCS) MAY PLAY AN IMPORTANT ROLE IN THIS PATHOGENESIS. THIS HETEROGENEOUS GROUP OF MULTIPOTENT CELLS, MORPHOLOGICALLY SIMILAR TO FIBROBLASTS, MAY UNDERGO EPIGENETIC CHANGES CAPABLE OF GENERATING ABERRANT PROGENIES. HOWEVER, WE BELIEVE THAT THERE IS NO NEED FOR A LATENT INFECTION. IN OUR PATHOGENIC HYPOTHESIS, CHIKV INFECTION OF MSCS WOULD CAUSE EPIGENETIC CHANGES BOTH IN MSCS THEMSELVES AND IN THEIR PROGENIES, WITHOUT THE NEED FOR REACTIVATION OF DORMANT VIRUSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  3251  28 HEPATITIS B VIRUS INFECTION: AN INSIGHT INTO THE CLINICAL CONNECTION AND MOLECULAR INTERACTION BETWEEN HEPATITIS B VIRUS AND HOST EXTRAHEPATIC CANCER RISK. THE EVIDENCE FOR CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND HEPATOCELLULAR CARCINOMA (HCC) OCCURRENCE IS WELL ESTABLISHED. THE HEPATOCYTE EPITHELIUM CARCINOGENESIS CAUSED BY HBV HAS BEEN INVESTIGATED AND REVIEWED IN DEPTH. NEVERTHELESS, RECENT FINDINGS FROM PRECLINICAL AND OBSERVATIONAL STUDIES SUGGESTED THAT CHRONIC HBV INFECTION IS EQUALLY IMPORTANT IN EXTRAHEPATIC CANCER OCCURRENCE AND SURVIVAL, SPECIFICALLY GASTROINTESTINAL SYSTEM-DERIVED CANCERS. IMMUNE MICROENVIRONMENT CHANGES (IMMUNE-SUPPRESSIVE CYTOKINE INFILTRATION), EPIGENETIC MODIFICATION (N6-METHYLADENOSINE), MOLECULAR SIGNALING PATHWAYS (PI3K-AKT AND WNT), AND SERUM BIOMARKERS SUCH AS HEPATITIS B VIRUS X (HBX) PROTEIN ARE POTENTIAL UNDERLYING MECHANISMS IN CHRONIC HBV INFECTION-INDUCED EXTRAHEPATIC CANCERS. THIS NARRATIVE REVIEW AIMED TO COMPREHENSIVELY SUMMARIZE THE MOST RECENT ADVANCES IN EVALUATING THE ASSOCIATION BETWEEN CHRONIC HBV INFECTION AND EXTRAHEPATIC CANCER RISK AND EXPLORE THE POTENTIAL UNDERLYING MOLECULAR MECHANISMS IN THE CARCINOGENESIS INDUCTION OF EXTRAHEPATIC CANCERS IN CHRONIC HBV CONDITIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  5731  34 SMAD3 PHOSPHO-ISOFORM SIGNALING IN HEPATITIS C VIRUS-RELATED CHRONIC LIVER DISEASES. THE RISK OF HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT INCREASES AS HEPATITIS VIRUS C (HCV)-RELATED LIVER DISEASES PROGRESS, ESPECIALLY IN PATIENTS WITH ACTIVE INFLAMMATION. INSIGHT INTO HEPATIC CARCINOGENESIS HAVE EMERGED FROM RECENT DETAILED ANALYSES OF TRANSFORMING GROWTH FACTOR-BETA AND C-JUN-N-TERMINAL KINASE SIGNALING PROCESSES DIRECTED BY MULTIPLE PHOSPHORYLATED (PHOSPHO)-ISOFORMS OF A SMAD3 MEDIATOR. IN THE COURSE OF HCV-RELATED CHRONIC LIVER DISEASES, CHRONIC INFLAMMATION AND HOST GENETIC/EPIGENETIC ALTERATIONS ADDITIVELY SHIFT THE HEPATOCYTIC SMAD3 PHOSPHO-ISOFORM SIGNALING FROM TUMOR SUPPRESSION TO CARCINOGENESIS, INCREASING THE RISK OF HCC. CHRONIC INFLAMMATION REPRESENTS AN EARLY CARCINOGENIC STEP THAT PROVIDES A NONMUTAGENIC TUMOR-PROMOTING STIMULUS. AFTER UNDERGOING SUCCESSFUL ANTIVIRAL THERAPY, PATIENTS WITH CHRONIC HEPATITIS C COULD EXPERIENCE A LOWER RISK OF HCC AS SMAD3 PHOSPHO-ISOFORM SIGNALING REVERSES FROM POTENTIAL CARCINOGENESIS TO TUMOR SUPPRESSION. EVEN AFTER HCV CLEARANCE, HOWEVER, PATIENTS WITH CIRRHOSIS COULD STILL DEVELOP HCC BECAUSE OF SUSTAINED, INTENSE CARCINOGENIC SMAD3 PHOSPHO-ISOFORM SIGNALING THAT IS POSSIBLY CAUSED BY GENETIC OR EPIGENETIC ALTERATIONS. SMAD3 PHOSPHO-ISOFORMS SHOULD ASSIST WITH EVALUATING THE EFFECTIVENESS OF INTERVENTIONS AIMED AT REDUCING HUMAN HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  4454  30 MOLECULAR MECHANISMS DRIVING PROGRESSION OF LIVER CIRRHOSIS TOWARDS HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B AND C INFECTIONS: A REVIEW. ALMOST ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC), A MAJOR TYPE OF PRIMARY LIVER CANCER, ALSO HAVE LIVER CIRRHOSIS, THE SEVERITY OF WHICH HAMPERS EFFECTIVE TREATMENT FOR HCC DESPITE RECENT PROGRESS IN THE EFFICACY OF ANTICANCER DRUGS FOR ADVANCED STAGES OF HCC. HERE, WE REVIEW RECENT KNOWLEDGE CONCERNING THE MOLECULAR MECHANISMS OF LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC FROM GENETIC AND EPIGENOMIC POINTS OF VIEW. BECAUSE ~70% OF PATIENTS WITH HCC HAVE HEPATITIS B VIRUS (HBV) AND/OR HEPATITIS C VIRUS (HCV) INFECTION, WE FOCUSED ON HBV- AND HCV-ASSOCIATED HCC. THE LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC FACTORS, SUCH AS MICRORNAS, PLAY A ROLE IN LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC, AND THAT HBV- AND HCV-ENCODED PROTEINS APPEAR TO BE INVOLVED IN HEPATOCARCINOGENESIS. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE MECHANISMS, INCLUDING IMMUNE CHECKPOINTS AND MOLECULAR TARGETS OF KINASE INHIBITORS, ASSOCIATED WITH LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1543  25 DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. AS FOR MANY OTHER TUMORS, DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES, LEADING TO ACTIVATION OF ONCOGENES AND INACTIVATION OR LOSS OF TUMOR SUPPRESSOR GENES (TSG). IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC INACTIVATION OF (TUMOR SUPPRESSOR) GENES BY PROMOTER HYPERMETHYLATION HAS BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMORIGENESIS. IN HCC, ABERRANT METHYLATION OF PROMOTER SEQUENCES OCCURS NOT ONLY IN ADVANCED TUMORS, IT HAS BEEN ALSO OBSERVED IN PREMALIGNANT CONDITIONS JUST AS CHRONIC VIRAL HEPATITIS B OR C AND CIRRHOTIC LIVER. THIS REVIEW DISCUSSES THE EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FOCUSING DNA METHYLATION.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  5969  37 TERT PROMOTER MUTATIONS IN PRIMARY LIVER TUMORS. NEXT-GENERATION SEQUENCING HAS DRAWN THE GENETIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA AND SEVERAL SIGNALING PATHWAYS ARE ALTERED AT THE DNA LEVEL IN TUMORS: WNT/BETA-CATENIN, CELL CYCLE REGULATOR, EPIGENETIC MODIFIER, HISTONE METHYLTRANSFERASE, OXIDATIVE STRESS, RAS/RAF/MAP KINASE AND AKT/MTOR PATHWAYS. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS STARTING WITH THE EXPOSURE TO DIFFERENT RISK FACTORS, FOLLOWED BY THE DEVELOPMENT OF A CHRONIC LIVER DISEASE AND CIRRHOSIS PRECEDE IN THE VAST MAJORITY OF THE CASES THE DEVELOPMENT OF HCC. SEVERAL LINES OF EVIDENCE HAVE UNDERLINED THE PIVOTAL ROLE OF TELOMERE MAINTENANCE IN BOTH CIRRHOSIS AND HCC PATHOGENESIS. TERT PROMOTER MUTATIONS WERE IDENTIFIED AS THE MOST FREQUENT GENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH AN OVERALL FREQUENCY AROUND 60%. MOREOVER, IN CIRRHOSIS, TERT PROMOTER MUTATIONS ARE OBSERVED AT THE EARLY STEPS OF HEPATOCARCINOGENESIS SINCE THEY ARE RECURRENTLY IDENTIFIED IN LOW-GRADE AND HIGH-GRADE DYSPLASTIC NODULES. IN CONTRAST, ACQUISITION OF GENOMIC DIVERSITY THROUGH MUTATIONS OF CLASSICAL ONCOGENES AND TUMOR SUPPRESSOR GENES (TP53, CTNNB1, ARID1A...) OCCURRED ONLY IN PROGRESSED HCC. IN NORMAL LIVER, A SUBSET OF HCC CAN DERIVED FROM THE MALIGNANT TRANSFORMATION OF HEPATOCELLULAR ADENOMA (HCA). IN HCA, CTNNB1 MUTATIONS PREDISPOSE TO TRANSFORMATION OF HCA IN HCC AND TERT PROMOTER MUTATIONS ARE REQUIRED IN MOST OF THE CASES AS A SECOND HIT FOR A FULL MALIGNANT TRANSFORMATION. ALL THESE FINDINGS HAVE REFINED OUR KNOWLEDGE OF HCC PATHOGENESIS AND HAVE POINTED TELOMERASE AS A TARGET FOR TAILORED THERAPY IN THE FUTURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  4248  26 METHYLATION STATUS, MRNA AND PROTEIN EXPRESSION OF THE SMAD4 GENE IN PATIENTS WITH NON-MELANOCYTIC SKIN CANCERS. BACKGROUND: SMAD4 IS A POTENT TUMOR SUPPRESSOR. SMAD4 LOSS INCREASES GENOMIC INSTABILITY AND PLAYS A CRITICAL ROLE IN THE DNA DAMAGE RESPONSE THAT LEADS TO SKIN CANCER DEVELOPMENT. WE AIMED TO INVESTIGATE SMAD4 METHYLATION EFFECTS ON MRNA AND PROTEIN EXPRESSION OF SMAD4 IN CANCER AND HEALTHY TISSUES FROM PATIENTS WITH BASAL CELL CARCINOMA (BCC), CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC), AND BASOSQUAMOUS SKIN CANCER (BSC). METHODS AND RESULTS: THE STUDY INCLUDED 17 BCC, 24 CSCC AND NINE BSC PATIENTS. DNA AND RNA WERE ISOLATED FROM CANCEROUS AND HEALTHY TISSUES FOLLOWING PUNCH BIOPSY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) AND REAL-TIME QUANTITATIVE PCR METHODS WERE USED TO EXAMINE SMAD4 PROMOTER METHYLATION AND SMAD4 MRNA LEVELS, RESPECTIVELY. THE PERCENTAGE AND INTENSITY OF STAINING OF THE SMAD4 PROTEIN WERE DETERMINED BY IMMUNOHISTOCHEMISTRY. THE PERCENTAGE OF SMAD4 METHYLATION WAS INCREASED IN THE PATIENTS WITH BCC (P = 0.007), CSCC (P = 0.004), AND BSC (P = 0.018) COMPARED TO THE HEALTHY TISSUE. SMAD4 MRNA EXPRESSION WAS DECREASED IN THE PATIENTS WITH BCC (P<0.001), CSCC (P<0.001), AND BSC (P = 0.008). THE STAINING CHARACTERISTIC OF SMAD4 PROTEIN WAS NEGATIVE IN THE CANCER TISSUES OF THE PATIENTS WITH CSCC (P = 0.00). LOWER SMAD4 MRNA LEVELS WERE OBSERVED IN THE POORLY DIFFERENTIATED CSCC PATIENTS (P = 0.001). THE STAINING CHARACTERISTICS OF THE SMAD4 PROTEIN WERE RELATED TO AGE AND CHRONIC SUN EXPOSURE. CONCLUSIONS: HYPERMETHYLATION OF SMAD4 AND REDUCED SMAD4 MRNA EXPRESSION WERE FOUND TO PLAY A ROLE IN THE PATHOGENESIS OF BCC, CSCC, AND BSC. A DECREASE IN SMAD4 PROTEIN EXPRESSION LEVEL WAS OBSERVED ONLY IN CSCC PATIENTS. THIS SUGGESTS THAT EPIGENETIC ALTERATIONS TO THE SMAD4 GENE ARE ASSOCIATED WITH CSCC. TRIAL REGISTRATION: THE NAME OF THE TRIAL REGISTER: SMAD4 METHYLATION AND EXPRESSION LEVELS IN NON-MELANOCYTIC SKIN CANCERS; SMAD4 PROTEIN POSITIVITY. THE REGISTRATION NUMBER: NCT04759261 ( HTTPS://CLINICALTRIALS.GOV/CT2/RESULTS?TERM=NCT04759261 ).	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  6650  33 UPDATE ON ETIOLOGY AND PATHOGENESIS OF BILIARY ATRESIA. BILIARY ATRESIA IS A RARE INFLAMMATORY SCLEROSING OBSTRUCTIVE CHOLANGIOPATHY THAT INITIATES IN INFANCY AS COMPLETE CHOLEDOCHAL BLOCKAGE AND PROGRESSES TO THE INVOLVEMENT OF INTRAHEPATIC BILIARY EPITHELIUM. GROWING EVIDENCE SHOWS THAT BILIARY ATRESIA IS NOT A SINGLE ENTITY WITH A SINGLE ETIOLOGY BUT A PHENOTYPE RESULTING FROM MULTIFACTORIAL EVENTS WHOSE COMMON PATH IS OBLITERATIVE CHOLANGIOPATHY. THE ETIOLOGY OF BILIARY ATRESIA HAS BEEN EXPLAINED AS RESULTING FROM GENETIC VARIANTS, TOXINS, VIRAL INFECTION, CHRONIC INFLAMMATION OR BILE DUCT LESIONS MEDIATED BY AUTOIMMUNITY, ABNORMALITIES IN THE DEVELOPMENT OF THE BILE DUCTS, AND DEFECTS IN EMBRYOGENESIS, ABNORMAL FETAL OR PRENATAL CIRCULATION AND SUSCEPTIBILITY FACTORS. IT IS INCREASINGLY EVIDENT THAT THE GENETIC AND EPIGENETIC PREDISPOSITION COMBINED WITH THE ENVIRONMENTAL FACTORS TO WHICH THE MOTHER IS EXPOSED ARE POTENTIAL TRIGGERS FOR BILIARY ATRESIA. THERE IS ALSO AN INDICATION THAT A PROGRESSIVE THICKENING OF THE ARTERIAL MIDDLE LAYER OCCURS IN THIS DISEASE, SUGGESTIVE OF VASCULAR REMODELING AND DISAPPEARANCE OF THE INTERLOBULAR BILE DUCTS. IT IS SUGGESTED THAT THE HYPOXIA/ISCHEMIA PROCESS CAN AFFECT PORTAL STRUCTURES IN BILIARY ATRESIA AND IS ASSOCIATED WITH BOTH THE EXTENT OF BILIARY PROLIFERATION AND THE THICKENING OF THE MEDIAL LAYER.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  6868  27 [PATHOGENESIS OF HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCER WORLDWIDE. MOST OF THE HCC OCCUR IN DEVELOPING COUNTRIES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HCC DEVELOPMENT. HBV INDUCES IMMUNE-MEDIATED CHRONIC HEPATITIS, LIVER INJURY, REGENERATION AND SCAR FORMING RESPONSES, LEADING TO AN INFLAMMATORY, FIBROTIC AND IMMUNE DEFICIENT MICROENVIRONMENT. HBV MAY INTEGRATE INTO HOST GENOME, INDUCING GENETIC ABNORMALITY AND ALTERING THE EXPRESSION OF HCC-RELATED GENES. HBV ALSO EXPRESSES ACTIVE PROTEINS SUCH AS X (HBX) AND S PROTEINS, WHICH MAY TRANS-ACTIVATE HCC-RELATED PROTEINS EXPRESSION, INTERACT WITH INTRACELLULAR SPECIFIC PROTEINS, ACTIVATE A VARIETY OF SIGNALING PATHWAYS, AND INDUCE ABERRANT EPIGENETIC MODIFICATIONS. HBV MUTATION ALSO HAS IMPACT ON HBV RELATED HCC DEVELOPMENT.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  6798  36 [EPIDEMIOLOGY, RISK FACTORS AND MOLECULAR PATHOGENESIS OF PRIMARY LIVER CANCER]. PRIMARY LIVER CANCER IS THE FIFTH MOST COMMON CANCER WORLDWIDE. HEPATOCELLULAR CARCINOMA ACCOUNTS FOR 85-90% OF PRIMARY LIVER CANCERS. DISTRIBUTION OF HEPATOCELLULAR CARCINOMA SHOWS VARIATIONS AMONG GEOGRAPHIC REGIONS AND ETHNIC GROUPS. MALES HAVE HIGHER LIVER CANCER RATES THAN FEMALES. HEPATOCELLULAR CARCINOMA OCCURS WITHIN AN ESTABLISHED BACKGROUND OF CHRONIC LIVER DISEASE AND CIRRHOSIS (70-90%). MAJOR CAUSES (80%) OF HEPATOCELLULAR CARCINOMA ARE HEPATITIS B, C VIRUS INFECTION, AND AFLATOXIN EXPOSITION. ITS DEVELOPMENT IS A MULTISTEP PROCESS. WE HAVE A GROWING UNDERSTANDING ON THE MOLECULAR PATHOGENESIS. GENETIC AND EPIGENETIC CHANGES ACTIVATE ONCOGENES, INHIBIT TUMORSUPPRESSOR GENES, WHICH RESULT IN AUTONOMOUS CELL PROLIFERATION. THE CHROMOSOMAL INSTABILITY CAUSED BY TELOMERE DYSFUNCTION, THE GROWTH-RETRAINED ENVIRONMENT AND THE ALTERATIONS OF THE MICRO- AND MACROENVIRONMENT HELP THE EXPANSION OF THE MALIGNANT CELLS. UNDERSTANDING THE MOLECULAR MECHANISMS COULD IMPROVE THE SCREENING OF PATIENTS WITH CHRONIC LIVER DISEASE, OR CIRRHOSIS, AND THE PREVENTION AS WELL AS TREATMENT OF HEPATOCELLULAR CARCINOMA.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  5590  32 ROLE OF THE BICARBONATE-RESPONSIVE SOLUBLE ADENYLYL CYCLASE IN CHOLANGIOCYTE APOPTOSIS IN PRIMARY BILIARY CHOLANGITIS; A NEW HYPOTHESIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC FIBROSING CHOLANGIOPATHY CHARACTERIZED BY AN AUTOIMMUNE STEREOTYPE AND DEFECTIVE BILIARY BICARBONATE SECRETION DUE TO DOWN-REGULATION OF ANION EXCHANGER 2 (AE2). DESPITE THE AUTOIMMUNE FEATURES, IMMUNOSUPPRESSANTS ARE INEFFECTIVE WHILE TWO BILE ACID-BASED THERAPIES (URSODEOXYCHOLIC ACID AND OBETICHOLIC ACID) HAVE BEEN SHOWN TO IMPROVE BIOCHEMICAL AND HISTOLOGICAL FEATURES OF CHOLESTASIS AND LONG-TERM PROGNOSIS. HOWEVER, THE ETIOLOGY AND PATHOGENESIS OF PBC IS LARGELY UNKNOWN. RECENTLY, IT HAS BEEN SHOWN THAT MICRORNA-506 (MIR-506) ON CHROMOSOME X IS UP-REGULATED IN PBC CHOLANGIOCYTES AND SUPPRESSES AE2 EXPRESSION, WHICH SENSITIZES CHOLANGIOCYTES TO BILE SALT-INDUCED APOPTOSIS BY ACTIVATING SOLUBLE ADENYLYL CYCLASE (SAC), AN EVOLUTIONARILY CONSERVED BICARBONATE SENSOR. IN THIS REVIEW, WE DISCUSS THE EXPERIMENTAL EVIDENCE FOR THE EMERGING ROLE OF THE MIR-506-AE2-SAC AXIS IN PBC PATHOGENESIS. WE FURTHER HYPOTHESIZE THAT THE INITIAL DISEASE TRIGGER INDUCES AN X-LINKED EPIGENETIC CHANGE, LEADING TO A FEMALE-BIASED ACTIVATION OF THE MIR-506-AE2-SAC AXIS. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: CHOLANGIOCYTES IN HEALTH AND DISEASEEDITED BY JESUS BANALES, MARCO MARZIONI AND PETER JANSEN.	2018