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 3′UTR 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/NFκB 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/NFκB 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/NKκB 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.