title: Protease-activated receptor-2 regulates cyclooxygenase-2 expression in human bile duct cancer via the pathways of mitogen-activated protein kinases and nuclear factor kappa B.
abstract: OBJECTIVE
  Recent studies have suggested that protease-activated receptor-2 (PAR-2) activity correlates with cell proliferation and tumor growth, and its activation induces expression of cyclooxygenase-2 (COX-2). However, no previous reports have investigated PAR-2 signaling pathways in bile duct cancer. The aim of this study was to determine whether PAR-2 activation can regulate COX-2 expression via mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) in human bile duct cancer cells.
  
  
  METHODS
  We immunohistochemically examined PAR-2 and COX-2 expression in 104 resected human specimens of extrahepatic bile duct cancer. We then determined how inhibitors of MAPKs and NF-κB signaling pathways influence COX-2 expression under PAR-2 activation in HuCCT1 and TKKK, human bile duct cancer cell lines.
  
  
  RESULTS
  PAR-2 and COX-2 proteins were immunohistochemically recognized in 63 and 57% of specimens and were significantly correlated. PAR-2 agonist peptide activated mRNA and protein expression of COX-2 in HuCCT1 and TKKK. Pharmacologic blockade of p44/42 or p38 MAPK significantly inhibited PAR-2-activated mRNA and protein expression of COX-2 in both cells. COX-2 protein expression was also inhibited by the blocker of NF-κB pathway in both cells.
  
  
  CONCLUSIONS
  PAR-2 may regulate COX-2 expression in human bile duct cancer via the MAPKs and NF-κB pathways.
authors.affiliation: Department of Surgery I, Oita University Faculty of Medicine, 1-1 Hasama-machi, Yufu, Oita 879-5593, Japan. heguchi@med.oita-u.ac.jp
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Iwaki
authors.forename: Kohei
authors.initials: K
authors.lastname: Shibata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohta
authors.forename: Seigo
authors.initials: S
authors.lastname: Kitano
mesh_terms: D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases