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.
Highlights
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,† Nagoya University Graduate School of Medicine, Nagoya; the Division of Diagnostic Pathology,‡ Kanazawa University Hospital, Kanazawa; and the Department of Molecular Virology and Oncology,§ Cancer Institute, Kanazawa University, Kanazawa, Japan
As for the roles of Tumor necrosis factor (TNF)-␣ in CC, we previously showed, using a cell culture study and human CC tissue specimens, that TNF-␣ in proximity to the invasive front of CC is at least partly responsible for the increased migration of CC cells[28]; that is, the interaction of stromal cell-derived factor (SDF)-1 released from fibroblasts and CXCR4 expressed on intrahepatic cholangiocarcinoma (ICC) cells may be actively involved in ICC migration, and TNF-␣ may enhance ICC cell migration by increasing the CXCR4 expression on the CC cells
Matrix metalloproteinase-9 (MMP-9) and COX-1 were expressed in the cytoplasm of the CC cells as a diffuse and granular pattern (Figure 1A, a– c), whereas COX-2 was expressed in the CC cells as granular cytoplasmic and membrane patterns (Figure 1Ad)
Summary
MMP-9 plays an important and necessary role in the catalytic activity of tumor cell invasion and metastasis.[11,12] Latent MMP-9 (92 kDa) is a proenzyme form, and the active form of MMP-9 (82 kDa) has full catalytic activity for the extracellular matrix.[8,9,10,11] COX is a ratelimiting enzyme that catalyzes the conversion from arachidonic acid to prostaglandins, including PGE2.13–15 In contrast to COX-1, which is constitutively expressed in various organ tissues, COX-2 is induced by a variety of stimuli.[13,14,15] COX-2 expression in many malignant tumors is associated with tumor growth and invasion.[13,16,17] PGE2 has many biological activities such as cell prolifer-. Supported in part by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports and Science and Technology of Japan (19390098)
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