Background: The resistance of glioma patients to temozolomide (TMZ) treatment is a limiting factor in clinical treatment. Circular RNA HIPK3 (circ-HIPK3) was found to be highly expressed in glioma, however, the role and potential mechanism of exosomal circ-HIPK3 from TMZ-resistant cells remain poorly unclear. Methods: Exosomes were characterized by transmission electron microscopy. The levels of all protein were detected by Western blot. Expression levels of circ-HIPK3, microRNA-421 (miR-421), and zinc finger protein of the cerebellum 5 (ZIC5) were measured by quantitative real-time polymerase chain reaction. The cell's 50% inhibitory concentration (IC₅₀) of TMZ, apoptosis, and invasion were determined by methyl thiazolyl tetrazolium (MTT), flow cytometry, and Transwell assays, respectively. The correlation between miR-421 and circ-HIPK3 or ZIC5 was identified by dual-reporter luciferase and RNA immunoprecipitation (RIP) assays. The xenograft model was established to explore the effect of circ-HIPK3 in vivo. Results: circ-HIPK3 was obviously increased in TMZ-resistant glioma cells and their exosomes, miR-421, was downregulated in TMZ-resistant glioma. circ-HIPK3 directly targeted miR-421 and their expressions were negatively correlated in glioma tissues. Besides, circ-HIPK3 knockdown hampered the IC₅₀ of TMZ, cell invasion, TMZ resistance, and triggered cell apoptosis, whereas these effects were reversed by transfection of anti-miR-421. ZIC5 was the target of miR-421 and ZIC5 overexpression weakened the inhibition effects of miR-421 on cell progression and TMZ resistance. More importantly, circ-HIPK3 depletion inhibited tumor growth by decreasing ZIC5 through sponging miR-421 in vivo. Conclusion: Exosomal circ-HIPK3 could promote cell progression and TMZ resistance by regulating miR-421/ZIC5 axis in TMZ-resistant glioma.

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