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

Abstract

Background Although temozolomide (TMZ) resistance is a significant clinical problem in 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 from TMZ-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 miR-1238 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 GBM and that exosomal miR-1238 may confer chemoresistance in the tumour microenvironment. These results suggest that circulating miR-1238 serves as a clinical biomarker and a promising therapeutic target for TMZ resistance in GBM. Fund This study was supported by the National Natural Science Foundation of China (No·81402056, 81472362, and 81772951) and the National High Technology Research and Development Program of China (863) (No·2012AA02A508).

Functions and clinical significance of circular RNAs in glioma

“…For example, miR-181b regulated the chemosensitivity of glioma to temozolomide by targeting Bcl-2 and EGFR [123,124]. Also, exosomal miR-1238 may confer chemoresistance in the tumor microenvironment, indicating that circulating miR-1238 acted as a promising therapeutic target for TMZ resistance in GBM [125]. Lei et al demonstrated that down-regulated hsa_circ_ 0076248 could remarkably promote the TMZ chemotherapy sensitivity via sponge miR-181a, which could suppress the expression of silent information regulator 1 (SIRT1) [52].…”

Exosomal circular RNA sorting mechanisms and their function in promoting or inhibiting cancer (Review)

“…Exosomes containing mRNA and miRNA were first reported by Valadi et al (54). Numerous studies have since demonstrated the existence of various small ncRNA species (in addition to miRNA, lncRNA and mRNA) in exosomes (55)(56)(57)(58). Subsequently, Li et al (6) reported the existence of a large quantity of circRNAs in exosomes.…”

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

“…Similarly, it has been elucidated that hypoxia-induced autophagy can affect cell mobility, tumor progression and chemosensitivity in GBM, via modulating the HIF-1α/ miR-224-3p/ATG5 axis [123]. While, miR-1238 is upregulated in TMZ-resistant GBM cells, and the silencing of miR-1238 can improve chemosensitivity through directly targeting the CAV1/epidermal growth factor receptor (EGFR) pathway [124]. And for DDP treatment, miR-501-3p can sensitize GBM to DDP-induced proliferation arrest and apoptosis by targeting N-myc (MYCN) [125].…”