circNEIL3 Stabilizes SPI1 mRNA and Promotes Glioma Progression and Temozolomide Resistance by Binding to U2AF2.

UNLABELLED: Temozolomide (TMZ) resistance is an urgent problem in the treatment of glioma. circNEIL3 is related to the malignant progression of glioma. Nevertheless, the function of circNEIL3 in TMZ resistance is still unclear. In this study, we found that circNEIL3 is overexpressed in glioma tissues and cells and is related to TMZ resistance. Cell experiments and mouse experiments have shown that inhibiting the expression of circNEIL3 can enhance the sensitivity of glioma cells to TMZ. RNA immunoprecipitation and other molecular experiments demonstrated that circNEIL3 and the RNA-binding protein U2 small nuclear RNA auxiliary factor 2 (U2AF2) interact with each other and partially colocalize in cells. SPI1 was highly expressed in glioma, more significantly in TMZ-resistant tissues, and correlated with circNEIL3 expression. Furthermore, we discovered that U2AF2 interacts with SPI1 mRNA as well, and circNEIL3 and U2AF2 together regulate the expression and mRNA stability of SPI1. More importantly, SPI1 silencing inhibited the malignant progression of cells and partially reversed the effects of circNEIL3 on glioma cell proliferation and apoptosis. In conclusion, circNEIL3 stabilizes SPI1 mRNA expression by binding to U2AF2, thereby promoting glioma progression and TMZ resistance.

IMPLICATIONS: Our findings offer new mechanistic insights into glioma drug resistance, and targeting the circNEIL3/U2AF2/SPI1 axis represents a promising approach to counteract TMZ resistance in gliomas.