Cyclooxygenase-2 is involved in the up-regulation of matrix metalloproteinase-9 in cholangiocarcinoma induced by tumor necrosis factor-alpha.

Abstract

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.

• Authors: 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, Yasuni Nakanuma
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 3 Pg. 829-41 (Mar 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19218340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Prostaglandin E
• Tumor Necrosis Factor-alpha
• Cyclooxygenase 2
• Matrix Metalloproteinase 9

Topics

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms (chemically induced, enzymology, genetics)
• Bile Ducts, Intrahepatic (enzymology, pathology)
• Cholangiocarcinoma (chemically induced, enzymology, genetics, pathology)
• Cyclooxygenase 2 (genetics)
• Female
• Humans
• Immunohistochemistry
• Lymphatic Metastasis
• Male
• Matrix Metalloproteinase 9 (genetics)
• Middle Aged
• Neoplasm Staging
• Promoter Regions, Genetic
• Receptors, Prostaglandin E (physiology)
• Tumor Necrosis Factor-alpha (toxicity)
• Up-Regulation