Cyclooxygenase-2 is involved in the up-regulation of matrix metalloproteinase-9 in cholangiocarcinoma induced by tumor necrosis factor-alpha.
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.
Itatsu
Keita
K
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
Sasaki
Motoko
M
Yamaguchi
Junpei
J
Ohira
Shusaku
S
Ishikawa
Akira
A
Ikeda
Hiroko
H
Sato
Yasunori
Y
Harada
Kenichi
K
Zen
Yoh
Y
Sato
Hiroshi
H
Ohta
Tetsuo
T
Nagino
Masato
M
Nimura
Yuji
Y
Nakanuma
Yasuni
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology / Q000473:pathology; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D018078:Receptors, Prostaglandin E / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D015854:Up-Regulation
D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9