Exosome-derived miR-339-5p mediates radiosensitivity by targeting Cdc25A in locally advanced esophageal squamous cell carcinoma.

Cancer cells associated with radioresistance are likely to give rise to local recurrence and distant metastatic relapse. However, it remains unclear whether specific miRNAs have direct roles in radioresistance and/or prognosis. In this study, we find that miR-339-5p promotes radiosensitivity, and is downregulated in radioresistant subpopulations of esophageal cancer cells. Notably, miR-339-5p was selectively secreted into blood via exosomes, and that higher serum miR-339-5p levels were positively associated with radiotherapy sensitivity and good survival. Moreover, miR-339-5p expression was downregulated in the T3/T4 stage compared with T1/T2 stage in esophageal squamous cell carcinoma (ESCC) patients (P = 0.04), and low miR-339-5p expression in tissue was significantly associated with poor overall survival (P = 0.036) and disease-free survival (P = 0.037). Overexpression of miR-339-5p enhanced radiosensitivity in vitro and in vivo. Mechanistically, miR-339-5p enhances radiosensitivity by targeting Cdc25A, and is transcriptionally regulated by Runx3. Correlations were observed between miR-339-5p levels and Cdc25A/Runx3 levels in tissue samples. Intriguingly, combined analysis of miR-339-5p expression with Runx3 increased the separation of the survival curves obtained for either gene alone in the TCGA datasets (P = 0.009). Overall, exosome-derived miR-339-5p mediates radiosensitivity through downregulation of Cdc25A, and predicts pathological response to preoperative radiotherapy in locally advanced ESCC, suggesting it could be a promising non-invasive biomarker for facilitating personalized treatments.