Exosomal transfer of miR-1238 contributes to temozolomide-resistance in glioblastoma

Background: Although temozolomide (TMZ) resistance is a significant clinical problemin glioblastoma (GBM), its underlying molecular mechanisms are poorly understood. In this study, we identified the role of exosomal microRNAs (miRNAs) from TMZ-resistant cells as important mediators of chemoresistance in GBM cells. Methods: Exosomes were isolated fromTMZ-resistant GBM cells and characterized via scanning electron microscopy (SEM). Expression levels of miR-1238 in GBM cell lines and their exosomes, clinical tissues, and sera were evaluated by RT-qPCR. In vitro and in vivo experiments were performed to elucidate the function of exosomal miR-1238 in TMZ resistance in GBM cells. Co-immunoprecipitation assays and western blot analysis were used to investigate the potential mechanisms of miR-1238/CAV1 that contribute to TMZ resistance. Findings: MiR-1238 levels were higher in TMZ-resistant GBM cells and their exosomes than in sensitive cells. Higher levels of miR-1238 were found in the sera of GBM patients than in healthy people. The loss of miR1238 may sensitize resistant GBM cells by directly targeting the CAV1/EGFR pathway. Furthermore, bioactive miR-1238 may be incorporated into the exosomes shed by TMZ-resistant cells and taken up by TMZ-sensitive cells, thus disseminating TMZ resistance. Interpretation: Our findings establish that miR-1238 plays an important role in mediating the acquired chemoresistance of GBMand that exosomalmiR-1238may confer chemoresistance in the tumour microenvironment. These results suggest that circulatingmiR-1238 serves as a clinical biomarker and a promising therapeutic target for TMZ resistance in GBM.