Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Neurosurgery, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, China.
Neuro Oncol. 2017 Sep 1;19(9):1195-1205. doi: 10.1093/neuonc/nox017.
MIR155 host gene (MIR155HG) is a long noncoding RNA that has been considered as the primary micro (mi)RNA of miR-155. MIR155HG plays an essential role in hematopoiesis, inflammation, and tumorigenesis. Our study investigated the clinical significance, biological function, mechanisms, and small-molecule inhibitors of the MIR155HG/miR-155 axis in glioma.
We analyzed the expression of the MIR155HG/miR-155 axis and the correlation with glioma grade and patient survival using 2 different glioma gene expression datasets. Biological significance was elucidated through a series of in vitro and in vivo experiments. Furthermore, we conducted a high-throughput screening for small molecules to identify a potential inhibitor of the MIR155HG/miR-155 axis.
Increased MIR155HG was associated with glioma grade, mesenchymal transition, and poor prognosis. Functionally, MIR155HG reduction by small interfering RNA inhibited cell proliferation, migration, invasion, and orthotopic glioma growth by repressing the generation of its derivatives miR-155-5p and miR-155-3p. Bioinformatics and luciferase reporter assays revealed that protocadherin 9 and protocadherin 7, which act as tumor suppressors by inhibiting the Wnt/β-catenin pathway, were direct targets of miR-155-5p and miR-155-3p, respectively. Finally, we identified NSC141562 as a potent small-molecule inhibitor of the MIR155HG/miR-155 axis.
Our results demonstrate that the MIR155HG/miR-155 axis plays a critical role in facilitating glioma progression and serves as a prognostic factor for patient survival in glioblastoma. High-throughput screening indicated that the MIR155HG/miR-155 axis inhibitor NSC141562 may be a useful candidate anti-glioma drug.
miR155 宿主基因（MIR155HG）是一种长链非编码 RNA，被认为是 miR-155 的主要微（mi）RNA。MIR155HG 在造血、炎症和肿瘤发生中发挥重要作用。我们的研究调查了 MIR155HG/miR-155 轴在神经胶质瘤中的临床意义、生物学功能、机制和小分子抑制剂。
我们使用 2 种不同的神经胶质瘤基因表达数据集分析了 MIR155HG/miR-155 轴的表达及其与神经胶质瘤分级和患者生存的相关性。通过一系列体外和体内实验阐明了生物学意义。此外，我们进行了高通量筛选小分子，以鉴定 MIR155HG/miR-155 轴的潜在抑制剂。
MIR155HG 的增加与神经胶质瘤分级、间质转化和预后不良有关。功能上，通过小干扰 RNA 降低 MIR155HG 抑制了细胞增殖、迁移、侵袭和原位神经胶质瘤生长，抑制了其衍生物 miR-155-5p 和 miR-155-3p 的产生。生物信息学和荧光素酶报告基因测定表明，原钙粘蛋白 9 和原钙粘蛋白 7 通过抑制 Wnt/β-catenin 通路发挥肿瘤抑制作用，分别是 miR-155-5p 和 miR-155-3p 的直接靶标。最后，我们确定 NSC141562 是 MIR155HG/miR-155 轴的有效小分子抑制剂。
我们的结果表明，MIR155HG/miR-155 轴在促进神经胶质瘤进展中起关键作用，并作为胶质母细胞瘤患者生存的预后因素。高通量筛选表明，MIR155HG/miR-155 轴抑制剂 NSC141562 可能是一种有用的抗神经胶质瘤药物候选物。
