Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor gamma in epithelial ovarian tumours.
Expression of cyclooxygenase (COX)-2 plays a key role in tumorigenesis and development and peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in the control of COX-2 expression in some tissues. The aim of this study is to investigate (1) whether expression of COX-2 and PPARgamma is associated with ovarian carcinogenesis and progression of ovarian tumours and (2) whether COX-2 expression is controlled through ligand-mediated activation of PPARgamma in ovarian carcinoma cells. For this purpose, the presence of COX-2 and PPARgamma was immunohistochemically examined in 71 epithelial ovarian carcinomas, 18 borderline tumours and 23 benign tumours and the levels of COX-2 and PPARgamma proteins were determined by enzyme immunoassay in four benign tumours, three borderline tumours and 12 carcinomas. The frequency of COX-2 and PPARgamma detection was significantly increased and decreased as lesions progressed to carcinoma, respectively. The COX-2 protein was not detected in the three borderline tumours, whereas PPARgamma protein was detected in all of them. COX-2 protein was detected in eight of the 12 carcinomas, whereas PPARgamma protein was detected in only two cases. In addition, PPARgamma protein was not detected in all of the eight carcinomas in which COX-2 protein was detected, suggesting that expression of PPARgamma and COX-2 was in a reciprocal relationship. Furthermore, in cultured ovarian carcinoma cells, Western blot revealed that PPARgamma and COX-2 expression was regulated conversely as a result of stimulation by 15-deoxy-Delta(12, 14) PGJ(2) (15-PGJ(2)), a PPARgamma activator. In addition, 15d-PGJ(2) suppressed tumour necrosis factor-alpha-induced-COX-2 expression, confirming the reciprocal correlation between COX-2 and PPARgamma. From these results, it was suggested that PPARgamma activation might suppress COX-2 expression via the nuclear factor-kappaB pathway in the ovarian carcinoma cells and that low expression of PPARgamma and high expression of COX-2 might be involved in carcinogenesis and progression of ovarian tumours.
Sakamoto
A
A
Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan.
Yokoyama
Y
Y
Umemoto
M
M
Futagami
M
M
Sakamoto
T
T
Bing
X
X
Mizunuma
H
H
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2; D018282:Cystadenocarcinoma, Mucinous / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008024:Ligands; D008565:Membrane Proteins; D008830:Microbodies; D008875:Middle Aged; D016328:NF-kappa B / Q000494:pharmacology; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011230:Precancerous Conditions; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D012189:Retrospective Studies; D014157:Transcription Factors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases