Brain Tumour Centre and Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong,; Department of Chemistry, The University of Hong Kong, Hong Kong,; Department of Surgery, Yijishan Hospital of Wannan Medical College, Sun Yat-Sen University, Guangzhou.
Department of Chemistry, The University of Hong Kong, Hong Kong.
J Biol Chem. 2012 Mar 23;287(13):9962-9971. doi: 10.1074/jbc.M111.332627. Epub 2012 Jan 17.
miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133(+) cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2.
miR-124 是一种丰富于大脑的 microRNA，在神经发育中发挥着关键作用，并且已被证明在神经胶质瘤和髓母细胞瘤中下调，表明其可能参与脑肿瘤的进展。在这里，我们显示 miR-124 在一系列不同分级的神经胶质瘤组织和我们检查的所有人类神经胶质瘤细胞系中都下调。通过综合生物信息学分析和实验验证，我们确定了 SNAI2，它在神经胶质瘤中经常上调，是 miR-124 的直接功能靶标。由于 SNAI2 已被证明调节干细胞功能，我们研究了 miR-124 和 SNAI2 在神经胶质瘤细胞干性特征中的作用。结果表明，miR-124 的过表达和 SNAI2 的敲低减少了神经球形成、CD133(+)细胞亚群和干细胞标记物（BMI1、Nanog 和 Nestin）的表达，并且这些效应可以通过 SNAI2 的重新表达得到挽救。此外，增强 miR-124 的表达显著抑制了神经胶质瘤细胞在体外的侵袭能力。最后，miR-124 的稳定过表达和 SNAI2 的敲低抑制了体内神经胶质瘤细胞的致瘤性和侵袭性。这些发现首次揭示，miR-124 的肿瘤抑制活性可能部分归因于其通过 SNAI2 对神经胶质瘤干性特征和侵袭性的抑制作用。
