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Originally published online as doi:10.2353/ajpath.2009.080012 on February 13, 2009

Published online before print February 13, 2009
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(American Journal of Pathology. 2009;174:829-841.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080012

Cyclooxygenase-2 Is Involved in the Up-Regulation of Matrix Metalloproteinase-9 in Cholangiocarcinoma Induced by Tumor Necrosis Factor-{alpha}

Keita Itatsu*{dagger}, Motoko Sasaki*, Junpei Yamaguchi*{dagger}, Shusaku Ohira{dagger}, Akira Ishikawa{dagger}, Hiroko Ikeda*, Yasunori Sato*, Kenichi Harada*, Yoh Zen{ddagger}, Hiroshi Sato§, Tetsuo Ohta, Masato Nagino{dagger}, Yuji Nimura{dagger} and Yasuni Nakanuma*

From the Departments of Human Pathology,* and Gastroenterologic Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medicine, Kanazawa; the Division of Surgical Oncology,{dagger} Nagoya University Graduate School of Medicine, Nagoya; the Division of Diagnostic Pathology,{ddagger} Kanazawa University Hospital, Kanazawa; and the Department of Molecular Virology and Oncology,§ Cancer Institute, Kanazawa University, Kanazawa, Japan

Matrix metalloproteinase-9 (MMP-9) is an important enzyme in tumor invasion and metastasis in malignant tumors, including cholangiocarcinoma (CC). Tumor necrosis factor-{alpha} (TNF-{alpha}), a proinflammatory cytokine, was recently reported to induce the up-regulation of MMP-9 in cultured CC cells. We examined whether cyclooxygenase-2 (COX-2) and prostaglandin-E2 (PGE2), another endogenous tumor promoter, are involved in the up-regulation of MMP-9 in CC using CC tissue specimens and a CC cell line, HuCCT-1. MMP-9 and COX-2 were immunohistochemically expressed in 58% and 89% of 110 CC cases, respectively; the expression of MMP-9 and COX-2 was correlated (r = 0.32, P = 0.00072). Using zymography, latent MMP-9 was detectable in all cases and active MMP-9 was detected in 24% of cases of the CC specimens. The TNF-{alpha}/TNF-receptor 1 (TNF-R1) interaction induced MMP-9 production and activation, as well as COX-2 overexpression and PGE2 production, and increased the migration of CC cells. MMP-9 up-regulation was inhibited by COX inhibitors, antagonists of EP2/4 (receptors of PGE2), and COX-1 and COX-2 siRNAs. Inhibitors of both MMP-9 and MMP-9 siRNA treatment abrogated the increase in the migration of CC cells induced by TNF-{alpha}. In conclusion, we propose a novel signaling pathway of MMP-9 up-regulation in CC cells such that TNF-{alpha} induces the activation of COX-2 and PGE2 via TNF-R1 followed by the up-regulation of MMP-9 via the PGE2 (EP2/4) receptor.






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