Abstract
Ovarian cancer is a fatal gynecologic tumor, and conventional treatment is mainly limited by chemoresistance. The mechanism contributing to chemoresistance in ovarian cancer has yet to be established. This study aimed to investigate the specific role of circ_C20orf11 in regulating chemoresistance to cisplatin (DDP)in ovarian cancer. We first established two DDP-resistant ovarian cancer cell lines. Then, we identified the effect of circ_C20orf11 on specific cellular characteristics (proliferation, apoptosis, DDP resistance) via a series of experiments. The binding sites between circ_C20orf11 and miR-527 and between miR-527 and YWHAZ were predicted using a bioinformatics tool and confirmed with a dual-luciferase reporter assay. Furthermore, extracellular vesicles (EVs) derived from DDP-resistant cell lines were identified, and the effect of EVs on macrophage polarization was examined. circ_C20orf11 was upregulated in ovarian cancer. Increased circ_C20orf11 expression enhanced DDP resistance and cell proliferation and reduced cell apoptosis in DDP-resistant cell lines after DDP treatment by sponging miR-527 and promoting YWHAZ expression. In addition, we found that DDP-resistant cell-derived EVs can induce macrophage M2 polarization, whereas silencing of circ_C20orf11 inhibited EV-induced macrophage M2 polarization. Consistent with these results, silencing of circ_C20orf11 enhanced sensitivity to DDP in vivo. Importantly, we proved that circ_C20orf11 expression was upregulated in EVs extracted from the serum of DDP-resistant patients. Our study demonstrated that silencing circ_C20orf11 sensitizes ovarian cancer to DDP by promoting miR-527/YWHAZ signaling and EV-mediated macrophage M2 polarization.