Lab of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Lab of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Cancer Lett. 2017 Oct 10;406:12-21. doi: 10.1016/j.canlet.2017.07.022. Epub 2017 Aug 2.
The epidermal growth factor receptor (EGFR) frequently undergoes high-level genomic amplification and variant III (vIII) deletion in adult glioblastoma. MicroRNAs (miRNAs) are recognized to participate in gene expression regulation. We found that miR-524-3p and miR-524-5p were suppressed in the classical molecular subtype of glioblastoma (GBM) from Chinese Glioma Genome Atlas (CGGA) data, and the suppression was associated with EGFR overexpression and EGFRvIII mutation. These two miRNAs improved overall survival time of patients with glioma, and their overexpression could restrain glioma cell migration, proliferation, and cell cycle, and control tumor formation in vivo. Interestingly, both of the miRNAs had a synergistic inhibitory effect on glioma cells. Furthermore, we confirmed that EGFR amplification/EGFRvIII mutation can repress the expression of Pri-miR-524 by histone modification. MiR-524-3p and miR-524-5p inhibited TGF/β, Notch and the Hippo pathway by targeting Smad2, Hes1 and Tead1, respectively; these pathways repressed their common downstream transcription factor, C-myc. More interestingly, C-myc bound to the promoter region of EGFR/EGFRvIII and activated its expression. These findings indicate that miR-524 mediates the EGFR/EGFRvIII stimulating effect. It may serve as a potential therapeutic agent and classical-specific biomarker for the development of glioma.
表皮生长因子受体（EGFR）在成人胶质母细胞瘤中经常经历高水平的基因组扩增和变体 III（vIII）缺失。现已认识到 microRNAs（miRNAs）参与基因表达调控。我们发现，从中国脑胶质瘤基因组图谱（CGGA）数据中发现，miR-524-3p 和 miR-524-5p 在经典分子亚型的胶质母细胞瘤（GBM）中受到抑制，而这种抑制与 EGFR 过表达和 EGFRvIII 突变有关。这两种 miRNA 改善了胶质母细胞瘤患者的总生存时间，其过表达可以抑制神经胶质瘤细胞的迁移、增殖和细胞周期，并控制体内肿瘤的形成。有趣的是，这两种 miRNA 对神经胶质瘤细胞具有协同抑制作用。此外，我们证实 EGFR 扩增/EGFRvIII 突变可以通过组蛋白修饰抑制 Pri-miR-524 的表达。miR-524-3p 和 miR-524-5p 通过靶向 Smad2、Hes1 和 Tead1 分别抑制 TGF/β、Notch 和 Hippo 通路；这些通路抑制它们的共同下游转录因子 C-myc。更有趣的是，C-myc 结合到 EGFR/EGFRvIII 的启动子区域并激活其表达。这些发现表明，miR-524 介导了 EGFR/EGFRvIII 的刺激作用。它可能作为胶质母细胞瘤发展的潜在治疗剂和经典特异性生物标志物。
