Abstract
Background: Radiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communications between hypoxic cells and aerobic cells via exosomes during radiation resistance remain unclear. Methods: We previously detected miR-340-5p is highly expressed in hypoxic OSCC exosomes by RNA-seq. The effects and mechanisms of hypoxic EVs and miR-340-5p on radiosensitivity were evaluated by qPCR, western blot IHC, flow cytometry, TUNEL assay, etc. Tumour xenografts and clinical samples were used for evaluating radiosensitivity and dissecting underlying mechanisms. Results: Hypoxic exosomes can alleviate radiation induced apoptosis and accelerate DNA damage repair. miR-340-5p is highly expressed in hypoxic exosomes and causes radioresistance. Knockdown miR-340-5p in hypoxic EVs reversed whose radioresistant effect, indicating miR-340-5p is critical for hypoxic EV-induced radioresistance. KLF10 is the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance radiosensitivity of OSCC. And higher levels of miR-340-5p in the plasma exosomes of OSCC patients are related to poor radiotherapy response and prognosis. Conclusions: Hypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Combined use of metformin and radiotherapy might benefit OSCC patients.