Cyclooxygenase 2 Enhances The Malignant Biological Behavior Of Ovarian Cancer Cells And Related Mechanism

Background and objectives:Ovarian cancer is the leading cause of death among gynecological malignant tumors.The incidence of recurrence and drug resistance is high.Ovarian cancer lacks specific diagnostic indicators and effective therapeutic targets.At present,the molecular mechanism of the occurrence and development of ovarian cancer is still unclear.In-depth study of the pathogenesis of ovarian cancer and the discovery of key therapeutic targets are of great significance for improving the treatment and prognosis of ovarian cancer.Cyclooxygenase 2(COX2)regulates a variety of downstream signaling pathways and is involved in the development and progression of tumors.However,the role and molecular mechanism of COX2 in the progression of ovarian cancer remains unclear.The aim of this study was to analyze the relationship between COX2 and different grades of ovarian tumors,to determine the effect of COX2 on the malignant biological behavior of ovarian cancer cells,and to explore its regulatory mechanisms in order to provide clues for identifying new therapeutic targets.Methods:The expression of COX2,nuclear factor-kappa B(NF-?B)and CYP19 in ovarian cancer tissues was detected by immunohistochemistry,and the correlation between the three and the degree of lesions was analyzed.CCK8,Transwell and FACS were used to detect cell proliferation,invasion and IC50 of cisplatin.Apoptosis and its molecular basis were analyzed by qPCR,immunofluorescence and Western blot.The concentration of prostaglandin E2(PGE2)in the culture supernatant and the expression of cell surface receptor PTGER2 were detected.The specific inhibitors celecoxib,AH6809 and BAY11-7082 inhibited the activation of COX2,PTGER2 and NF-?B,respectively.These inhibitors were used to investigate the regulation mechanism of COX2 on the malignant biological behavior of ovarian cancer.The tumor-bearing mouse model was used to verify the signaling pathway and anti-tumor effect evaluation.Results:COX2 is highly expressed in ovarian cancer tissues.The expression level of COX2 is positively correlated with the malignant degree of ovarian tumors(r=0.757,P<0.01).COX2 can promote the proliferation,invasion and drug resistance of ovarian cancer cells,and up-regulated the level of proteins related to proliferation,invasion and drug resistance in ovarian cancer cells,including Ki67,CYP19,C-MYC,MMP2,MMP9,ABCG2 and p-STAT3.But COX2 has no obvious inhibitory effects on apoptosis in ovarian cancer cells.The COX2 inhibitor celecoxib blocks the effect of COX2 on ovarian cancer cells,inhibits the proliferation and invasion,and enhances sensitivity to cisplatin in COX2 high-expression ovarian cancer cells.Meanwhile,in animal experiments,celecoxib also inhibits the growth of ovarian cancer xenografts and enhances the anti-tumor effect of cisplatin.COX2 promotes the synthesis and secretion of PGE2 and phosphorylation of NF-?B,up-regulating the expression of downstream genes related to proliferation,invasion and drug resistance in ovarian cancer cells.But COX2 has no significantly effects on the expression level of PGE2 receptor PTGER2.After specifically inhibiting PTGER2 or NF-?B,COX2 inhibited the proliferation,invasion and drug resistance and down-regulated the level of proteins related to proliferation,invasion and drug resistance in ovarian cancer cells.Conclusions:COX2 enhances the malignant biological behavior,promotes proliferation,invasion and drug resistance in ovarian cancer cells via the PGE2/NF-?B pathway.The key nodes in the COX2/PGE2/NF-?B pathway can play a certain role in anti-cancer effect of ovarian cancer.