全球 microRNA 分析鉴定 miR-10b-5p 是神经纤维瘤病 1（NF1）-神经胶质瘤迁移的调节剂。
Global microRNA profiling identified miR-10b-5p as a regulator of neurofibromatosis 1 (NF1)-glioma migration.
机构信息
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
出版信息
Neuropathol Appl Neurobiol. 2021 Feb;47(1):96-107. doi: 10.1111/nan.12641. Epub 2020 Jul 22.
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 noncoding 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, whereas miR-451a was increased 2.7-fold (adjusted P < 0.05) in NF1-PAs compared to non-neoplastic NF1 patient brain specimens (n = 2). As 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, whereas 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.
目的
神经纤维瘤病 1 型（NF1）是一种常染色体显性遗传的癌症易感性综合征，由涉及 17 号染色体 NF1 基因座的功能丧失改变引起。在受影响的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），尽管高级别胶质瘤的发生率也较高。虽然双等位基因 NF1 缺失特征是这些肿瘤，但先前的研究表明非编码 RNA 分子（microRNA，miR）可能在决定胶质瘤生物学方面发挥重要作用。
方法
为了探讨 miR 在 NF1 相关胶质瘤中的作用，我们使用基于 NanoString 的微阵列进行全基因组 microRNA 谱分析，分析了五例高级别胶质瘤（NF1-HGG）和五例 PA（NF1-PA），然后用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、miR-1247-5p 和 miR-320a（调整后的 P<0.05）在 NF1-HGG 中相对于 NF1-PA 肿瘤增加了>3 倍。此外，miR-378b 和 miR-1305 分别降低了 6.8 倍和 6 倍，而 miR-451a 在 NF1-PA 中相对于非肿瘤性 NF1 患者脑标本（n=2）增加了 2.7 倍（调整后的 P<0.05）。由于 miR-10b-5p 在 NF1 高级别胶质瘤中与 NF1 低级别胶质瘤相比表达最高（5.76 倍），我们检查了其在胶质瘤细胞系中的水平。miR-10b-5p 水平在成人胶质瘤细胞系中最高，在儿科低级别胶质瘤系中最低（P=0.02）。NF1 缺陷 LN229 高级别胶质瘤系中 miR-10b-5p 敲低导致侵袭性降低，而 NF1-PA 衍生系（JHH-NF1-PA1）中 miR-10b-5p 的过表达导致侵袭性增加。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-胶质瘤生物学中的作用。
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