CAFs exosomal circFOXO1 promotes TNBC autophagy and radioresistance via miR-27a-3p/BNIP3 axis.

Cancer-associated fibroblasts (CAFs) are related to tumor treatment tolerance. Therefore, this study investigated the molecular mechanisms and tumor microenvironment-influencing factors of CAFs in promoting triple-negative breast cancer (TNBC) radiotherapy tolerance. Transwell assays were used to detect cell invasion capacity, and wound-healing assays were used to detect cell migration capacity. CCK-8 was used to assess cell proliferation, and flow cytometry was used to assess apoptosis. Western blotting was used to detect the expression levels of epithelial‒mesenchymal transition (EMT)-related and autophagy marker proteins. Transmission electron microscopy was performed to observe the number of autophagosomes. A nude mouse model of TNBC xenograft tumor was established, and the expression levels of circRNA-FOXO1, miR-27a-3p and BNIP3 in the tumor tissues of the nude mice were detected using RT‒qPCR. The results revealed that circRNA-FOXO1 was highly expressed in CAFs exosomes subjected to radiotherapy. The overexpression of circRNA-FOXO1 in TNBC cells promoted proliferation, migration and invasion; reduced the cell apoptosis rate; and promoted the occurrence of EMT and autophagy. However, the knockdown of circRNA-FOXO1 resulted in the opposite outcome. Transfection of the miR-27a-3p mimic reversed the promoting influence of FOXO1 on the malignant biological behavior of TNBC cells. BNIP3 overexpression effectively reversed the inhibitory influence of miR-27a-3p on the malignant biological behavior of TNBC cells. In addition, in vivo animal experiments have shown that CAFs exosomes or overexpression of FOXO1 can promote the growth of tumors in nude mice, while further treatment with the autophagy inhibitor 3-MA weakens the effects of exosome or FOXO1 overexpression to a certain extent. In conclusion, exosomal circRNA-FOXO1 in CAFs promotes TNBC cell autophagy and reduces radiosensitivity by regulating the miR-27a-3p/BNIP3 axis.