AIMS Neurofibromatosis 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by loss of function alterations involving the NF1 locus on chromosome 17. The most common brain tumours encountered in affected patients are low-grade gliomas (pilocytic astrocytomas), although high-grade gliomas are also observed at increased frequency. While bi-allelic NF1 loss characterizes these tumours, previous studies have suggested non-coding RNA molecules (microRNA, miR) may have important roles in dictating glioma biology. METHODS To explore the contributions of miRs in NF1-associated gliomas, we analysed five high-grade gliomas (NF1-HGG) and five PAs (NF1-PA) using global microRNA profiling with NanoString-based microarrays followed by functional experiments with glioma cell lines. RESULTS miR-10b-5p, miR-135b-5p, miR-196a-5p, miR-196b-5p, miR-1247-5p, and miR-320a (adjusted p<0.05) were increased >3-fold in NF1-HGG relative to NF1-PA tumours. In addition, miR-378b and miR-1305 were decreased 6.8- and 6-fold, respectively, while miR-451a was increased 2.7-fold (adjusted p<0.05) in NF1-PAs compared to non-neoplastic NF1 patient brain specimens (n=2). Since miR-10b-5p was the microRNA overexpressed the most in NF1-high-grade glioma compared to NF1-low grade glioma (5.76 fold), we examined its levels in glioma cell lines. miR-10b-5p levels were highest in adult glioma cell lines and lowest in paediatric low grade glioma lines (p=0.02). miR-10b-5p knockdown resulted in decreased invasion in NF1-deficient LN229 high-grade glioma line, while its overexpression in the NF1-PA derived line (JHH-NF1-PA1) led to increased invasion. There was no change in cell growth (viability and proliferation). CONCLUSIONS These proof-of-concept experiments support a role for microRNA regulation in NF1-glioma biology.

中文翻译：

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全球 microRNA 分析确定 miR-10b-5p 作为神经纤维瘤病 1 (NF1)-神经胶质瘤迁移的调节剂

AIMS 神经纤维瘤病 1 (NF1) 是一种常染色体显性遗传癌症易感综合征，由涉及 17 号染色体上 NF1 位点的功能改变丧失引起。受影响患者中最常见的脑肿瘤是低级别胶质瘤（毛细胞星形细胞瘤），尽管是高级别胶质瘤也以增加的频率观察到。虽然双等位基因 NF1 丢失是这些肿瘤的特征，但先前的研究表明，非编码 RNA 分子（microRNA、miR）可能在决定神经胶质瘤生物学方面具有重要作用。方法为了探索 miRs 在 NF1 相关神经胶质瘤中的贡献，我们使用基于 NanoString 的微阵列的全局 microRNA 分析分析了五个高级神经胶质瘤 (NF1-HGG) 和五个 PA (NF1-PA)，然后用神经胶质瘤细胞系进行功能实验. 结果 miR-10b-5p、miR-135b-5p、miR-196a-5p、miR-196b-5p、与 NF1-PA 肿瘤相比，NF1-HGG 中的 miR-1247-5p 和 miR-320a（调整后的 p<0.05）增加了 >3 倍。此外，与非肿瘤性 NF1 患者脑标本相比，NF1-PA 中的 miR-378b 和 miR-1305 分别降低了 6.8 倍和 6 倍，而 miR-451a 增加了 2.7 倍（调整后 p<0.05）。 n=2）。由于与 NF1 低级别神经胶质瘤相比，miR-10b-5p 是 NF1 高级别神经胶质瘤中过表达最多的 microRNA（5.76 倍），我们检查了它在神经胶质瘤细胞系中的水平。miR-10b-5p 水平在成人神经胶质瘤细胞系中最高，在儿童低级别神经胶质瘤细胞系中最低（p=0.02）。miR-10b-5p 敲低导致 NF1 缺陷型 LN229 高级别胶质瘤系的侵袭减少，而其在 NF1-PA 衍生系（JHH-NF1-PA1）中的过度表达导致侵袭增加。细胞生长（活力和增殖）没有变化。结论 这些概念验证实验支持 microRNA 调节在 NF1-神经胶质瘤生物学中的作用。