title: Claudin-18 is an early-stage marker of pancreatic carcinogenesis.
abstract: Pancreatic ductal neoplasms exhibit gastric epithelium-like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium-associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinal-type IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12-myristate 13-acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis.
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Fukushima
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Umeda
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kokudo
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D057167:Claudins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D014408:Biomarkers, Tumor; C486683:CLDN18 protein, human; D057167:Claudins; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate