The Effects And Mechanisms Of FOXQ1 Contributing To Paclitaxel Resistance In Serous Ovarian Cancer

BackgroundOvarian cancer is one of the most lethal malignancies of the reproductive system in women worldwide,and chemotherapy resistance is one of the most important causes of death in ovarian cancer patients.In recent years,there have been more and more reports about the regulation of transcription factor FOXQ1 on epithelial-mesenchymal transition to promote tumorigenesis and development,but there have been few reports on the related role and mechanism of FOXQ1 in the regulation of chemotherapy resistance.Paclitaxel,as the first-line drug for ovarian cancer treatment,has greatly improved the survival rate of patients,but with the emergence of drug resistance,the treatment effect of paclitaxel is in a bottleneck period.In recent years,more and more studies on the correlation between EMT and chemotherapy resistance have emerged,so our research group speculated whether FOXQ1 might mediate paclitaxel resistance of ovarian cancer through EMT,and whether FOXQ1 might become a new target for chemotherapy-sensitization therapy.Serous ovarian cancer(SOC)is the most common and highly malignant subtype of ovarian cancer,accounting for about 70%of ovarian cancer,so this study is mainly aimed at epithelial Serous ovarian cancer.The effect and possible mechanism of FOXQ1 on paclitaxel resistance in serous ovarian cancer were discussed in this study.Methods1.The expression of FOXQ1 in serous ovarian cancer and its clinical significance were verified by gene expression database GEO and TCGA and tissue specimen analysis2.We used paclitaxel-resistant ovarian cancer model A2780/Taxol,SKOV3/Taxol cells and its sensitive strain A2780,SKOV3 to compare FOXQ1 expression.FOXQ1 overexpression and down-expression cell lines were established,and the response of FOXQ1 to paclitaxel chemotherapy for SOC was evaluated by cytotoxicity test and gradient paclitaxel treated plate colony assay.3.The effect of FOXQ1 on invasion and migration of SOC cells was studied by Scratch and Transwell function experiments,and the effect of FOXQ1 on EMT molecular mechanisms was detected by western-blot.The possible target genes of FOXQ1 were predicted by TCGA database.Results1.Expression of FOXQ1 in serous ovarian cancer(SOC)and its clinical significanceGEO analysis showed that FOXQ1 expression was significantly higher in SOC than that in normal control tissues(*P<0.05).Subsequently,the expression of FOXQ1 in Fallopian tube(FT)and SOC tissues was detected by immunohistochemistry and real-time quantitative PCR.The expression of FOXQ1 in SOC was significantly higher than that in normal control tissues(*P<0.05).Survival analysis using The GEO and TCGA database showed that the progression-free survival of high expression FOXQ1 was significantly shortened in patients with ovarian Cancer(*P<0.05).2.FOXQ is associated with paclitaxel resistance in serous ovarian cancerFOXQ1 expression was significantly increased with the increase of paclitaxel concentration and was overexpressed in paclitaxel-resistant cell strains(*P<0.05),indicating that FOXQ1 was correlated with the resistance of SOC to paclitaxel chemotherapy.The higher the number of clones,the higher IC50 of the cytotoxic assay,whereas the lower the number of clones,the lower IC50 of FOXQ1,and the more sensitive to paclitaxel than the control group,suggesting that FOXQ1 overexpression promotes paclitaxel resistance to SOC.3.FOXQ1 mediates paclitaxel resistance through EMT and its down-stream target geneThe effect of FOXQ 1 on the invasion and migration of SOC cells was investigated by Scratch and Transwell function experiments.FOXQ1 overexpression promoted the invasion and migration of SOC.The effect of FOXQ1 on EMT related molecules was detected by Western-Blot.The increase of N-cadherin,Snail,andβ-catenin in the mesenchymal markers of EMT was overexpressed by FOXQ1,and vice versa,indicating that FOXQ1 promoted the occurrence of EMT.Using the TCGA database and JASPAR analysis of the target gene prediction software to predict the possible target gene of FOXQ1,we found that there was a significant co-expression correlation between matrix metalloproteinase 7(MMP7)and FOXQ1,and we speculated whether there was a direct regulatory relationship between FOXQ1 and MMP7?To further test our hypothesis,we used Luciferase reporter assay to verify whether FOXQ1 can directly regulate MMP7.Luciferase experiment indicated that the activity of a binding site was significantly increased in MMP7,suggesting that FOXQ1 may play a role in targeting MMP7 through this site.Conclusion1.FOXQ1 is highly expressed in SOC tissues,and its high expression indicates the worse prognosis.2.FOXQ1 is associated with paclitaxel resistance in SOC and promotes paclitaxel resistance in serous ovarian cancer.3.The potential mechanism of how FOXQ1 promotes SOC resistance may through mediating epithelial mesenchymal transformation targeted by MMP7.