miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis
miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis
复制标题
miRNA-124-3p/neuropilin-1(NRP-1)轴在介导胶质母细胞瘤生长和血管生成中发挥重要作用
DOI：
10.1002/ijc.31329
复制
发表时间：
2018-08-01
影响因子：
6.4
通讯作者：
Yan, Jianghua
中科院分区：
文献类型：
--
作者：
Zhang, Guilong;Chen, Lukui;Yan, Jianghua
多形性胶质母细胞瘤(GBM)是致命性最强的脑部恶性肿瘤，涉及多基因异常。不幸的是，针对GBM的有效治疗仍然缺乏。以前，我们发现NRP-1及其下游的NRP-1/GIPC1通路在GBM中起重要作用。在我们的研究中，我们进一步研究了NRP-1的上游信号，以了解它是如何调节的。首先，我们通过高通量测序证实hsa-miR-124-3p在GBM和正常脑组织中差异表达。然后，通过双荧光素酶报告基因，我们发现miR-124-3p可以与NRP-1的3UTR区特异性结合，从而抑制其表达。此外，miR-124-3p过表达显著抑制GBM细胞的增殖、迁移和肿瘤血管生成，从而导致GBM细胞凋亡和细胞周期停滞，这可能是通过NRP-1介导的PI3K/Akt/NFB信号通路在GBM细胞中激活的。同时，在PDX模型中，当以NRP-1为靶点时，miR-124-3p的过表达也抑制了肿瘤的生长，减少了肿瘤血管的生成。此外，NRP-1mAb与miR-124-3p在GBM中的高表达具有协同抑制作用。因此，我们发现miR-124-3p是NRP-1的上游抑制因子，通过PI3K/Akt/NFB途径促进GBM细胞的生长发育。MiR-124-3p/NRP-1/GIPC1通路作为一条新的通路，在胶质瘤的发生发展中起着至关重要的作用，有望成为未来恶性胶质瘤治疗的潜在靶点。多形性胶质母细胞瘤(GBM)与多种不同的基因改变和microRNAs(MiRNAs)表达的变化有关。在本研究中，miRNA miR-124-3p在GBM和正常脑组织中差异表达。分子分析进一步表明miR-124-3p特异性靶向NRP-1，结合NRP-1 3‘非编码区，miR-124-3p上调与抑制PI3K/Akt/NKB信号通路有关。在患者来源的异种移植胶质瘤模型中，miR-124-3p的过度表达与GBM肿瘤生长抑制和血管生成减少相关。提示miR-124-3p/NRP-1信号转导通路是GBM潜在的治疗靶点。
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.