title: Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas.
abstract: The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Lódi
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Szabó
authors.forename: Agnes
authors.initials: A
authors.lastname: Holczbauer
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Batmunkh
authors.forename: Attila
authors.initials: A
authors.lastname: Szíjártó
authors.forename: Péter
authors.initials: P
authors.lastname: Kupcsulik
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Sándor
authors.initials: S
authors.lastname: Paku
authors.forename: György
authors.initials: G
authors.lastname: Illyés
authors.forename: András
authors.initials: A
authors.lastname: Kiss
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Schaff
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001661:Biliary Tract Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D062506:Claudin-4; D003937:Diagnosis, Differential; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053552:Keratin-7; D007633:Keratins / Q000032:analysis; D007797:Laminin / Q000032:analysis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis / Q000379:methods
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; C507497:KRT7 protein, human; D053552:Keratin-7; D007797:Laminin; D008565:Membrane Proteins; D012333:RNA, Messenger; D007633:Keratins