Exosomal transfer of tumor-associated macrophage-derived hsa_circ_0001610 reduces radiosensitivity in endometrial cancer

Abstract

The occurrence of radioresistance is a clinical obstacle to endometrial cancer (EC) treatment and induces tumor relapse. In this study, we found that tumor-associated macrophages (TAMs) enriched in EC specimens were determined to present an M2-like phenotype. In vitro, the coculture of M2-polarized macrophages significantly downregulated the radiosensitivity of EC cells by releasing exosomes. Hsa_circ_0001610 was found to be abundant in exosomes derived from M2-polarized macrophages (EXOs), and hsa_circ_0001610 knockdown eliminated the reduction effect of EXOs on the radiosensitivity of EC cells. The following mechanism research revealed that hsa_circ_0001610 functioned as the competing endogenous RNA of miR-139-5p, thereby upregulating cyclin B1 expression, which is a vital pusher of radioresistance in several types of cancer by regulating the cell cycle. Hsa_circ_0001610 overexpression reduced the radiosensitivity of EC cells, which was then reversed by miR-139-5p overexpression. In vivo, the promotion effect of EXOs on xenograft tumor growth in nude mice treated with irradiation was further reinforced after hsa_circ_0001610 overexpression. In conclusion, TAM-derived exosomes transferred hsa_circ_0001610 to EC cells, and the overexpressed hsa_circ_0001610 in EC cells released cyclin B1 expression through adsorbing miR-139-5p, thereby weakening the radiosensitivity of EC cells.

The Role of miRNA in Regulating the Fate of Monocytes in Health and Cancer

“…The knockdown of has_circ_0001610 in in vitro and in vivo results in the increased radiosensitivity of EC. This study showed that knowledge about complicated miRs machinery in macrophages could help to increase cancer sensitivity to therapies, e.g., radiotherapy [ 135 ].…”

Exosomes on Endometrial Cancer: A Biomarkers Treasure Trove?

“…The administration of exosomes in a xenograft EC model caused a post-irradiation increase in tumor growth and promoted EMT. These effects were augmented with the administration of exosomes that overexpressed hsa_circ_0001610, whereas the silencing of hsa_circ_0001610 abolished the ability of the delivered exosomes to weaken the radiosensitivity of EC cells [ 59 ]. Another recent study provided additional evidence demonstrating that TAMs promote the proliferation of EC cells and EMT via exosome transfer.…”

Macrophage-Derived Small Extracellular Vesicles in Multiple Diseases: Biogenesis, Function, and Therapeutic Applications

“…Cyclin B1, a key mitotic cyclin, is a downstream target of hsa_circ_0001610/miRNA-139-5p axis. After the transfer of hsa_circ_0001610 by M2-sEVs to endometrial cancer cells, cyclin B1 expression is upregulated through miRNA-139-5p, which affects the G2/M phase of the cell cycle, when the cells are the most sensitive to radiation, reduces the radiosensitivity of endometrial cancer cells, and affects prognosis ( Gu et al, 2021 ) (see Table 2 ). This will provide new targets for enhancing the radiosensitivity of EC cells in clinical settings.…”