Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.