Circ-VPS18 Knockdown Enhances TMZ Sensitivity and Inhibits Glioma Progression by MiR-370/RUNX1 Axis

Abstract

Glioma is a prevalent primary brain tumor. Temozolomide (TMZ) has been used to treat glioma. However, the resistance of TMZ to glioma poses heavy burden to glioma treatment. In this study, the effects of glioma resistance to TMZ and underlying mechanism were revealed. The expression levels of circ-VPS18, microRNA-370 (miR-370) and runt-related transcription factor 1 (RUNX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of RUNX1, multidrug resistance-associated protein 1 (MRP1), and multi-drug resistance gene-1 (MDR1) was determined by western blot. The functional effects of circ-VPS18 knockdown on TMZ sensitivity and glioma progression were revealed by cell counting kit-8 proliferation (CCK-8), flow cytometry, and transwell assays. The impacts of circ-VPS18 deletion on TMZ sensitivity in vivo were illustrated by in vivo tumor formation assay. The binding relationship between miR-370 and circ-VPS18 or RUNX1 was predicted by starBase v2.0 online database and identified by dual-luciferase reporter assay. Circ-VPS18 expression and the mRNA and protein levels of RUNX1 were dramatically upregulated, and miR-370 expression was significantly downregulated in glioma cells, TMZ-resistant glioma tissues, or tissue compared with control groups. Functionally, circ-VPS18 knockdown improved TMZ sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in U251/TR and LN229/TR cells, which was reversed by miR-370 inhibitor. Additionally, RUNX1 overexpression hindered the effects of miR-370 on TMZ sensitivity and glioma progression. Circ-VPS18 knockdown enhanced TMZ sensitivity in vivo. Mechanistically, circ-VPS18 functioned as a sponge of miR-370 and miR-370 targeted RUNX1. Circ-VPS18 knockdown improved TMZ sensitivity and repressed glioma progression by sponging miR-370 to downregulate RUNX1 expression, which provided a new insight in further studying glioma resistance to TMZ.