miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis

Glioblastoma multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM remains lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In our study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. First, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124-3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124-3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future. What's new? Glioblastoma multiforme (GBM) is associated with a number of different genetic alterations and with changes in the expression of microRNAs (miRNAs). In this study, the miRNA miR-124-3p was found to be differentially expressed in GBM vs. normal brain tissue. Molecular analyses further revealed that miR-124-3p specifically targets neuropilin-1 (NRP-1), binding to the NRP-1 3'UTR region, and that miR-124-3p upregulation is associated with inhibition of the PI3K/Akt/NKB signaling pathway. In a patient-derived xenograft glioma model, overexpression of miR-124-3p was associated with suppressed GBM tumor growth and reduced angiogenesis. The findings suggest that miR-124-3p/NRP-1 signaling is a potential therapeutic target in GBM.