miR-484 sensitizes in IDH-wild and IDH-mutant glioblastoma cells to temozolomide by inhibiting oncogenic FOXM1 signaling

Glioblastoma (GBM) is the most diagnosed primary brain tumor with an extremely poor survival rate. Emerging evidence suggests that miRNAs are involved in GBM tumorigenesis. miR-484 was highly expressed in glioma cells and enhanced cell migration, and invasion. However, the role of miR-484 in GBM and its downstream targets are not well understood. We analyzed miR-484 expression in GBM patient tissue samples (IDH wild-type and IDH-mutant) and cell lines via Real-Time PCR. In GBM cells transfected with inhibitor- and mimic-miR-484, we investigated cell proliferation, migration, invasion, cell cycle, and apoptosis. Additionally, protein expression of FOXM1 and its downstream targets were investigated. RNA-seq analysis was performed on mimic-miR-484-transfected U87-MG and IDH1-mutant-U87 cells. miR-484 expression was higher in IDH-mutant patient tumors compared to IDH1-wild type patient tumors. Ectopic expression of miR-484 suppressed cell proliferation, colony formation, migration and invasion, and induced apoptosis in GBM cells. Furthermore, we found that miR-484 suppresses FOXM1 and its downstream targets including Integrin-β1/FAK/Src and Cyclin-D and PARP, all of which have been shown to be potential therapeutic targets in GBM cells. In addition, expression of miR-484 enhanced TMZ-induced FOXM1 downregulation in GBM. Our findings suggest for the first time that miR-484 act as a tumor suppressor in IDH1-wild type and mutant GBM cells by targeting FOXM1 oncogenic transcription factor and its downstream in GBM cells. Therefore, miR-484-based treatment may provide a new avenue for controlling GMB growth and progression and may enhance the therapeutic efficacy of TMZ. Trial registry: decision no: 2019/247.