Abstract

Temozolomide (TMZ) resistance limits its use in glioblastoma (GBM). Exosomes can carry circular RNAs (circRNAs) to regulate chemoresistance. To date, the role of exosomal hsa_circ_0043949 (circ_0043949) in GBM resistance to TMZ is unclear. Relative expression of circ_0043949 in clinical samples, GBM cell lines, and exosomes was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The half-maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, invasion, and migration were analyzed via MTT, EdU, flow cytometry, transwell, and wound-healing assays. Relative protein levels were evaluated by western blotting. Target relationship was predicted by bioinformatics analysis and validated by dual-luciferase reporter and RNA pull-down assays. Exosomes were isolated by ultracentrifugation and verified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The effect of exosomal circ_0043949 on TMZ resistance was validated by xenograft assay. Higher expression of circ_0043949 was gained in TMZ-resistant GBM samples and cells. Inhibition of circ_0043949 reduced TMZ resistance via decreasing IC50 of TMZ, repressing proliferation, invasion, migration, and inducing apoptosis in TMZ-resistant GBM cells. Circ_0043949 mediated integrinalpha1 (ITGA1) expression via function as a miR-876-3p sponge. Circ_0043949 was also upregulated in TMZ-resistant GBM cells-derived exosomes, and exosomal circ_0043949 increased the resistance of TMZ-resistant GBM cells to TMZ in xenograft models. TMZ-resistant GBM cells-derived exosomal circ_0043949 promoted TMZ resistance via upregulating ITGA1 expression via sequestering miR-876-3p, offering a potential target for the treatment of TMZ resistance in GBM.

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