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.
Highlights
Endometrial cancer (EC) is the most frequent gynecologic malignancy, which seriously threatens the health of women worldwide [1, 2]
Guangzhou Ribobio Biotechnology Co., Ltd (China) synthesized the biotinylated miR-139-5p (BiotinmiR-139-5p) and its negative control
Given that emerging evidence confirms that exosomes derived from M2-polarized macrophages (EXOs) derived from Tumor-associated macrophages (TAMs) play a central role in the communication between tumor cells and TAMs [25, 26], we explored whether TAM-derived EXOs mediated the radiosensitivity of EC cells
Summary
Endometrial cancer (EC) is the most frequent gynecologic malignancy, which seriously threatens the health of women worldwide [1, 2]. Radiotherapy, as one of the main adjuvant therapies for EC, successfully promotes the survival rate of patients with early-stage EC [4] and decreased loco-regional recurrence in patients with high-intermediate risk EC [5]. Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME present at all stages during tumor progression. Meng et al [9] depleted TAMs in xenograft implants of melanoma cells in mice through local injection of macrophage-depleting liposomal clodronate and found that TAM depletion reinforced the antitumor effect of irradiation. These previous studies suggest that the accumulated TAMs are involved in the radioresistance of EC cells
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