Department of Surgery I, Oita University Faculty of Medicine, 1-1 Hasama-machi, Yufu, Oita 879-5593, Japan.
J Hepatobiliary Pancreat Sci. 2011 Mar;18(2):147-53. doi: 10.1007/s00534-010-0318-9.
BACKGROUND/PURPOSE: 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.
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.
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.
PAR-2 may regulate COX-2 expression in human bile duct cancer via the MAPKs and NF-κB pathways.
背景/目的：最近的研究表明，蛋白酶激活受体-2（PAR-2）的活性与细胞增殖和肿瘤生长相关，其激活可诱导环氧化酶-2（COX-2）的表达。然而，以前没有研究过胆管癌中的 PAR-2 信号通路。本研究旨在确定 PAR-2 激活是否可以通过丝裂原活化蛋白激酶（MAPKs）和核因子 kappa B（NF-κB）调节人胆管癌细胞中的 COX-2 表达。
我们通过免疫组织化学方法检测了 104 例肝外胆管癌患者的 PAR-2 和 COX-2 表达。然后，我们确定了在 HuCCT1 和 TKKK 人胆管癌细胞系中，PAR-2 激活时 MAPK 和 NF-κB 信号通路抑制剂如何影响 COX-2 表达。
PAR-2 和 COX-2 蛋白在 63%和 57%的标本中通过免疫组织化学方法被识别，且具有显著相关性。PAR-2 激动肽在 HuCCT1 和 TKKK 中激活了 COX-2 的 mRNA 和蛋白表达。p44/42 或 p38 MAPK 的药理学阻断显著抑制了两种细胞中 PAR-2 激活的 COX-2 mRNA 和蛋白表达。两种细胞中 NF-κB 通路的阻断剂也抑制了 COX-2 蛋白的表达。
PAR-2 可能通过 MAPKs 和 NF-κB 通路调节人胆管癌细胞中的 COX-2 表达。
