Exosomal circWDR62 promotes temozolomide resistance and malignant progression through regulation of the miR-370-3p/MGMT axis in glioma

Exosome-mediated delivery of circular RNAs (circRNAs) is implicated in cancer progression. However, the role of exosomal circRNAs in the chemotherapy resistance of tumours remains poorly understood. Here we identified a novel circRNA, circWDR62. It was found that circWDR62 expression was upregulated in TMZ-resistant glioma cells and TMZ-resistant glioma cell-derived exosomes compared with their controls by using high-throughput microarray analysis and quantitative real-time polymerase chain reaction, and high circWDR62 expression was associated with poor prognosis of glioma. Functionally, downregulation of circWDR62 expression could significantly inhibit the TMZ-resistance and malignant progression of glioma. Further mechanistic studies showed that circWDR62 plays a role by sponging miR-370-3p as a competing endogenous RNA. Rescue experiments confirmed that MGMT is the downstream target of the circWDR62/miR-370-3p axis in glioma. In addition, circWDR62 could be transported between TMZ-resistant and TMZ-sensitive glioma cells via exosomes. Exosomal circWDR62 from TMZ-resistant cells conferred TMZ-resistance in recipient sensitive cells while also enhancing the proliferation, migration and invasion of these cells. A series of clinical and in vivo trials corroborated that exosomal circWDR62 could promote TMZ-chemoresistance and malignant progression of glioma. Our results demonstrate for the first time that exosome-mediated delivery of circWDR62 can promote TMZ-resistance and malignant progression via targeting of the miR-370-3p/MGMT axis in vitro and in vivo in glioma, providing a new therapeutic strategy. Moreover, exosomal circWDR62 in human serum may serve as a promising therapeutic target and prognostic marker for glioma therapy.

Automated summary

The delivery of circWDR62 through exosomes promotes TMZ-resistance and malignant progression in glioma by targeting the miR-370-3p/MGMT axis, providing a new therapeutic strategy. Exosomal circWDR62 in human serum may serve as a promising therapeutic target and prognostic marker for glioma therapy.