Novel exosomal miR-46146 transfer oxaliplatin chemoresistance in colorectal cancer

Oxaliplatin (OX) is widely used for patients with advanced colorectal cancer (CRC). However, most of them will turn out to be OX resistant. Therefore, it is necessary to uncover the causes underlying this phenomenon. Emerging works have reported that exosomal miRNAs are linked to chemoresistance in many types of cancer. Hence, we separated exosomes from OX sensitive (Exo-S) and resistant CRC cells (Exo-R) by ultracentrifugation and characterized those exosomes by transmission electron microscope and Nanosight NS300. The differentiated miRNAs between Exo-S and Exo-R were identified by small RNA deep sequencing. The expression of miRNA was examined by quantitative real-time PCR (qRT-PCR). The effect of Exo-R and exosomal miR-46146 was determined by CCK-8 assay and flow cytometry (FCM). The target gene of miR-46146 was predicted by computational algorithms and validated by dual luciferase assay. We found that parental OX sensitive CRC cell acquired increased resistance to the cytotoxicity of OX when they were cocultured with exosomes secreted by OX-resistant CRC. Notably, a novel miRNA miR-46146 was identified and proved to be upregulated in the Exo-R which was internalized by its recipient cells and contributes to the chemoresistance transfer. Furthermore, we demonstrated that PDCD10 was the direct functional target of miR46146 and augmentation of the PDCD10 expression might reverse the effect of Exo-miR-46146-driven chemoresistance. These results indicate that exosomal miR-46146 functions as a vital mediator of OX resistance by targeting PDCD10 and could be a potential target to re-sensitize CRC cell to OX.