Study On Chemoprevention And Treatment Of Human Endometrioid Adenocarcinoma By Celecoxib, A Selective COX-2 Inhibitor

Objective:The aim of this study was to detect the expression of cyclooxygenase-2(COX-2) in tamoxifen-associated endometrial hyperplasia(tamoxifen-associated "high-risk endometrium") and investigate the effect of celecoxib,a selective COX-2 inhibitor on human endometrioid adenocarcinoma cells(HEC-1-B),thereby investigate the feasibility and mechanism of celecoxib on chemoprevention and treatment.,especially for the breast cancer patient who had to use tamoxifen and the patient with well-differentiated endometrial cancer in women 40 years old or younger.Methods:1.The endometrial tissue specimens were obtained froml0 cases with hysteromyoma,22 cases with tamoxifen-associated endometrial hyperplasia and 10 cases with endometrioid adenocarcinoma.Immunohistochemistry(with SP method) was utilized to measure levels of expression of COX-2 in endometrial tissue specimens.2.HEC-1-B cells were cultured in vitro and exposed to different concentrations of celecoxib(6.25,12.5,25,50,100 uM).The morphologic characters were viewed by inverted phase contrast microscope.Cell growth curve was made by cell count.CCK-8 assay was used to calculate the inhibiting rate of NS-398(celecoxib),on cell proliferation.RT-PCR was applied to detect the degree of COX-2 mRNA expression.All data was analyzed with stata 8.0 sol,ware.Results:1.Expression of COX-2 was detect in tissues of endometrioid adenocarcinoma, tamoxifen-associated endometrial hyperplasia(tamoxifen-associated "high-risk endometrium") and normal endometrum.COX-2 was mainly expressed in the endochylema of endometrial cells and some in caryotheca.The endometrial interstitiums were weak-expressed or no-expressed.The typical histopathologic morphous was polypoid hyperplasia of endometrum.The strong positive expression of COX-2 in tissues of tamoxifen-associated endometrial hyperplasia (tamoxifen-associated "high-risk endometrium")(54.2%) was significantly than normal endometrium(8.3%,P＜0.016),and so did the tissues of endometrioid adenocarcinoma (37.5%vs.8.3%,P＜0.016).So the evidence that upregulation of COX-2 in tamoxifen-associated endometrial hyperplasia and endometrioid adenocarcinoma might be an indication of an early step in carcinogenesis.While the strong positive expression of COX-2 in tamoxifen-associated endometrial hyperplasia(tamoxifen-associated "high-risk endometrium") was higher than that in endometrioid adenocarcinoma(54.2%vs.37.5%, P=0.1,P＜0.016),but there was no significant difference between the two groups.2.Celecoxib could inhibit the COX-2 expression of endometrial cancer cell HEC-1-B.2.Celecoxib could inhibitor HEC-1-B cell proliferation in a dose -and time-dependent manner.COX-2 mRNA expression was downregulated after the addition of celecoxib,50 uM celecoxib had stronger effect than 20 uM celecoxib.The inhibiting rate of them was 15.3%and 49.6%,respectively.The results showed that celecoxib exerted more inhibitive effect with higher concertration.Conclution:Expression of COX-2 showed an increasing tendency from normal endometrium to tamoxifen-associated endometrial hyperplasia and endometrioid adenocarcinoma.The results were similar with the former reports of no-tamoxifen-associated endometrial hyperplasia tissues,which suggested upregulation of COX-2 may be an early step in carcinogenesis of endometrial carcinoma.Celecoxib could inhibitor HEC-1-B cell proliferation in a dose -and time- dependent manner.COX-2 mRNA expression was downregulated after the addition of celecoxib.The sudy provided experimental evidence for celecoxib usage as an accessorial therapy drug of endometrial carcinoma, especially for the breast cancer patient who had to use tamoxifen and the patient with well-differentiated endometrial cancer in women 40 years old or younger.