COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma.
The expression of cyclooxygenase (COX)-2 is induced by growth factors, tumor promoters and cytokines, and is correlated with carcinogenesis, tumor progression and inhibition of apoptosis. To clarify the pathological significance of COX-2, we examined the effect of a selective COX-2 inhibitor, NS398, on two human gastric carcinoma cell lines, MKN-45 and KATO-III, and the expression of Skp2, P27/Kip1 and COX-2 protein in human gastric carcinomas. NS398 inhibited cell growth in a time- and dose-dependent manner and exerted cell cycle arrest in the G0/G1 phase without induction of apoptosis in MKN-45, but had no effect in KATO-III. In MKN-45, NS398 induced up-regulation of P27/Kip1 and down-regulation of COX-2, cyclin D1 and Skp2. Immunohistochemistry using 63 surgically resected gastric carcinomas disclosed that COX-2 expression was correlated with Skp2 expression and that P27/Kip1 expression was inversely correlated with COX-2 and Skp2 expression. High levels of COX-2 or Skp2 were significantly correlated with poor survival (P=0.02 and P=0.004). Our results suggested that: a) NS398 induced inhibition of cell proliferation through cell cycle arrest and suppressed the expression of Skp2 in COX-2-expressing gastric carcinoma cells, and b) COX-2 contributes to the expression of Skp2 and poor survival in human gastric carcinomas.
Honjo
Soichiro
S
Division of Organ Pathology, Department of Microbiology and Pathology, Faculty of Medicine, Tottori University, Tottori 683-8503, Japan. honjo@grape.med.tottori-u.ac.jp
Kase
Satoru
S
Osaki
Mitsuhiko
M
Ardyanto
Tonang Dwi
TD
Kaibara
Nobuaki
N
Ito
Hisao
H
D017209:Apoptosis; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D044783:F-Box Proteins / Q000096:biosynthesis*; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D044783:F-Box Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D009578:Nitrobenzenes; D044786:S-Phase Kinase-Associated Proteins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases