The Expression Of The LXRs In The Ovarian Tissue And The Effects Of T0901317 On The EOC Cell Lines

Background and objectiveEpithelial ovarian cancer(EOC)is the first leading cause of cancer-related death among the malignancies of female reproductive system.One reason for its high mortality is that the disease is widely metastatic within the abdomen when the presentation is obvious in most cases.Although a large proportion of EOC patients could obtain complete response after modern management,most of those who present with advanced disease will develop distant metastases ultimately.Optimal debulking surgery and adjuvant chemotherapy is the standard treatment option for most EOC patients.Despite most patients have good response to such treatment option initially,relapse and drug resistant will occur in most patients sooner or later.So it is very important to explore the pathogenesis of ovarian cancer and find out the molecular mechanism of the malignant transformation and develop new target-drug therapy.Liver X receptor is a transcription factor particularly expressed in the liver,intestine and adipocytes,belonging to a family of nuclear hormone receptors,which could be activated by multiple oxysterols endogennously.A few potent synthetic LXR agonists such as T0901317 and GW3965 have also been developed in recent years.The effects of the anticancer properties of the Liver X receptors have been validated in various types of cancer in the past ten years,which include lung cancer,colon cancer,pancreatic cancer,breast cancer and prostate cancer.However,the clinical potentials of nuclear hormone receptors have not been fully elucidated in other solid tumors especially those originating from female reproductive system.Scoles et al have reported that LXR pathway proteins are expressed in various ovarian cancer cell lines,and the LXR agonist T0901317 could inhibit the proliferation of the ovarian cancer cell lines.However,the expression of LXRs in human EOC samples has not been elucidated.And more importantly,the effects of LXR agonists on the apoptosis of EOC cells have not been reported.We therefore undertook to explore the expression status of LXR in EOC tissue samples as well as in EOC cell lines.Besides,we also sought to elucidate the effects of LXR agonists on the apoptosis of EOC cells.Materials and methods1.83 epithelial ovarian tissues(including 32 normal ovarian tissues and 51 epithelial type tumor samples)were obtained from the Qilu Hospital,Shandong University.Immunohistochemical staining was performed to detect the expression of LXRa and LXR? protein in ovarian tissues.2.We then used western blotting to explore the expression of LXRa in three cell lines including HOSEpiC,A2780 and SKOV3.3.CCK8 assays were used to determine whether the liver X receptor agonists T0901317 affected on the viability of ovarian cancer cell lines SKOV3 and A2780.4.A2780 and SKOV3 cell lines were cultured under various concentrations of T0901317 and flow cytometry was used to examine the cell apoptosis.Results1.The immunoreactive staining both of LXRa and LXR? were primarily localized to the nuclei and the expression of LXRa and LXR? were both higher in normal ovarian epithelium tissues compared to the ovarian epithelial tumors.The statistics were significant both in LXRa and LXR?(P<0.05).2.Although LXRa was expressed in all three cell lines,the expression levels of LXRa in A2780 and SKOV3 were lower than that in HOSEpiC(P<0.05).3.The result demonstrated that increasing doses of T0901317 did significantly inhibit the growth of each of the two cell lines(P<0.05).4.In A2780 and SKOV3,there was a positive relationship between the concentrations of the drug and the occurrence of cell apoptosis.The cell apoptosis ratio of A2780 and SKOV3 increased accompanied by the increase of drug concentration(P<0.05).ConclusionThe results of IHC demonstrated that the expression level of both LXR? and LXR? protein among normal ovarian specimens was higher compared to the ovarian tumor specimens.So we hypothesized that the LXRs pathway singling might be related to the occurrence,development,and prognosis in ovarian cancer.In summary,this study shows that LXRs,a type of nuclear hormone receptor,is downregulated in EOC cells and patient tissue samples.Furthermore,it is suggested that the activation of LXRs pathway may has antitumor activities.