Exosomal miR-590-3p derived from cancer-associated fibroblasts confers radioresistance in colorectal cancer

Abstract Radiotherapeutic resistance is a major obstacle for effective treatment of colorectal cancer (CRC). MicroRNAs (miRNAs) act critical role in chemoresistance and radioresistance. Here we aimed to investigate whether miR-590-3p participates to the radioresistance of CRC. High expression of miR-590-3p and low expression of CLCA4 was found in both CRC tissues and cell lines. CLCA4 was indicated as a target gene of miR-590-3p. CAF-derived exosomes were extracted and co-cultured with CRC cells which were then exposed to radiation. CRC cells were transfected with plasmids and injected into nude mice to detect in vivo effect of CAF-derived exosome. Treatment with CAF-derived exosomes decreased sensitivity of CRC cells to radiation. CAF-derived exosomes overexpressing miR-590-3p increased cell survival and the ratio of p-PI3K/PI3K and p-AKT/AKT while lowering the expressions of cleaved-PARP, cleaved-caspase 3 and γH2AX in cells. Furthermore, in vivo experimental results confirmed that CAF-derived exosomal miR-590-3p stimulated tumor growth in mice following radiotherapy. Our results demonstrate that miR-590-3p delivery via exosomes derived from CAFs enhances radioresistance in CRC through the positive regulation of CLCA4 dependent PI3K/Akt signaling pathway.