title: Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activation.
abstract: Increased cyclooxygenase (COX-2) expression in tumors is known to be correlated with tumor invasion, angiogenesis, resistance to apoptosis, and suppression of host immunity. We previously reported that the invasiveness of human oral squamous cell carcinoma (OSCC) cell lines NA and HSC-4 was suppressed by treatment with either NS-398, a selective COX-2 inhibitor, or COX-2 antisense oligonucleotide (AS). In the present study, to explore the effects of COX-2 inhibition on the interaction between cancer cells and fibroblasts, we examined the effects of these anti-COX-2 reagents on the expression of matrix metalloproteinases (MMPs) in fibroblast cell lines WI-38 and MRC-5. Western blotting and enzyme-linked immunosorbent assay revealed that NS-398 and COX-2 AS down-regulated the expression and secretion of MMP-2 and the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human fibroblast cell lines. Furthermore, invasion activity of OSCC cells was down-regulated by the addition of culture supernatant from fibroblasts treated with anti-COX-2 reagents in a Matrigel invasion assay. These results suggest that selective COX-2 inhibition suppresses the invasion activity of OSCC cells via down-regulation of an MMP-2-activating mechanism involving TIMP-2 and production of the MMP-2 protein by an interaction between cancer cells and stromal fibroblasts. Genetic or pharmacological inhibition of COX-2 may therefore be a beneficial strategy in the treatment of OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota-ku, Tokyo, 145-8515, Japan. yujikuri@senzoku.showa-u.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kurihara
authors.forename: Masashi
authors.initials: M
authors.lastname: Hatori
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Ando
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Takahiko
authors.initials: T
authors.lastname: Toyoshima
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Shintani
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D004338:Drug Combinations; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D013778:Tetrazolium Salts; D013844:Thiazoles; C059485:matrigel; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C022616:thiazolyl blue