circCELSR1 (hsa_circ_0063809) Contributes to Paclitaxel Resistance of Ovarian Cancer Cells by Regulating FOXR2 Expression via miR-1252

Abstract Ovarian cancer is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance of chemotherapeutic drugs like paclitaxel (PTX) occurring in very early stage is one of the important factors of the poor prognosis of ovarian cancer. Here we aim to study the dysregulation of a particular circular RNA (circRNA), circCELSR1 (hsa_circ_0063809), and its role in in progression and PTX resistance of ovarian cancer. The high expression of circCELSR1 in PTX resistant tissues of ovarian cancer and PTX-resistant ovarian cancer cells (SKOV3/PTX and HeyA-8/PTX) were determined by microarray analyses and Real-Time qPCR. CCK8 assay were performed to investigate the effect of circCELSR1 on PTX sensitivity of ovarian cancer cells. Flow cytometer assays were used to detect cell cycle and apoptosis of ovarian cancer cells. The effect of circCELSR1 on ovarian cancer cells was assessed in vitro and in vivo. The microRNA (miRNA) sponge mechanism of circRNAs was demonstrated using dual-luciferase reporter and RNA immunoprecipitation assays. By microarray (5 PTX-resistant ovarian cancer tissues νs. 5 PTX-sensitive ovarian cancer tissues) and RT- qPCR (36 normal ovarian tissues and ovarian cancer tissues) we identified circCELSR1 to be dramatically high expressed in ovarian cancer samples and correlated with PTX resistance. Compared with sensitive cell lines, circCELSR1 was also high expressed in PTX resistant ovarian cancer cell lines, and circCELSR1 silencing enhanced PTX-induced cytotoxicity in ovarian cancer cells. Meanwhile the inhibition of circCELSR1 also caused ovarian cancer cells G0/G1 arrest and apoptosis increase. In vivo studies revealed that circCELSR1 was stably inhibited in a xenograft mouse model and inhibited the growth of ovarian cancer. Furthermore, we demonstrated that circCELSR1 acts as a sponge for miR-1252 and verified that Forkhead box 2 (FOXR2) is a novel target of miR-1252. Here we explored the specific mechanisms of PTX resistance and tumor progress of ovarian cancer due to circCELSR1, presented the circCELSR1-miR-1252-FOXR2 axis and its role in ovarian cancer drug-sensitivity and progression, and the results may provide experimental basis for clinical application.