Published online before print February 13, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080012

Accepted for publication November 18, 2008.

Article

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

Keita Itatsu^*, Motoko Sasaki^*, Junpei Yamaguchi^*, Shusaku Ohira, Akira Ishikawa, Hiroko Ikeda^*, Yasunori Sato^*, Kenichi Harada^*, Yoh Zen, Hiroshi Sato, Tetsuo Ohta^¶, Masato Nagino, Yuji Nimura, and Yasuni Nakanuma^*@

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

^@ To whom correspondence should be addressed. E-mail: pbcpsc{at}kenroku.kanazawa-u.ac.jp.

	Abstract

Matrix metalloproteinase-9 (MMP-9) is an important enzyme in tumor invasion and metastasis in malignant tumors, including cholangiocarcinoma (CC). Tumor necrosis factor- (TNF-), 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-/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-. In conclusion, we propose a novel signaling pathway of MMP-9 up-regulation in CC cells such that TNF- 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.