M2 Macrophages Crosstalk with Ovarian Cancer Cells by Regulating Cell Ferroptosis via the miR-1228-3p/GPX4 Pathway

Background: Presently, the occurrence and development mechanisms of ovarian cancer (OC) remain unclear. This study explored the potential mechanisms of M2 macrophages in the occurrence and development of OC. Methods The effect and potential mechanisms of M2 macrophages in OC cells were investigated by constructing a cell co-culture system. The differentially expressed microRNAs in OC patients were analyzed using bioinformatics, and their role in the occurrence and development of OC was further studied in vivo and in vitro through gene overexpression or knockdown. Results Interleukin (IL)-6 was highly expressed in the M2 macrophages. IL-6 secreted by M2 macrophages promoted glutathione peroxidase 4 (GPX4) expression, caused ferroptosis resistance, and promoted the proliferation and migration of OC cells, which was reversed by the ferroptosis inducer erastin. Bioinformatics analysis showed that miR-1228-3p was highly expressed in OC patients, further confirming that IL-6 promoted miR-1228-3p expression in OC cells and the secretion of exosomes rich in miR-1228-3p. This promotes the secretion of IL-6 by M2 macrophages and GPX4 expression in OC cells, leading to ferroptosis resistance and stimulating proliferation and migration. We found that IL-6R on the OC cell membrane, in fact, promoted GPX4 expression by mediating the miR-1228-3p/IL-6 dialogue, causing ferroptosis resistance and promoting the proliferation and migration of OC cells. In vivo nude mice subcutaneous tumor formation experiments further showed that OV-GPX4 and miR-1228-3p accelerated tumor volume and weight increase, while si-GPX4 miR-1228-3p inhibitor and si-IL-6R slowed down the increase in tumor volume and weight. IL-6 secreted by M2 macrophages induced OC cell ferroptosis resistance and promoted proliferation and migration through the miR-1228-3p/GPX4 pathway, thereby accelerating tumor growth in nude mice. Conclusions Our study may provide a possible therapeutic target for the development of OC.