Hsa_circ_0043949 reinforces temozolomide resistance via upregulating oncogene ITGA1 axis in glioblastoma

• Published in: Metabolic brain disease Vol. 37; no. 8; pp. 2979 - 2993
• Main Authors: Li, Xuzhao, Wang, Nianhua, Leng, Haibin, Yuan, Huichun, Xu, Lixin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2022; Springer Nature B.V
• Subjects: Apoptosis; Assaying; Biochemistry; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Brain cancer; Cell culture; Cell lines; Cell proliferation; Chemoresistance; Exosomes; Flow cytometry; Glioblastoma; Metabolic Diseases; Nanoparticles; Neurology; Neurosciences; Oncogenes; Oncology; Original Article; Polymerase chain reaction; Reverse transcription; Sequestering; Temozolomide; Transmission electron microscopy; Ultracentrifugation; Western blotting; Wound healing; Xenografts; Xenotransplantation; TMZ; GBM; circ_0043949; miR-876-3p; exosome
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-022-01069-3

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 (IC 50 ) 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 IC 50 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.