Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Mol Cell Biol. 2011 Sep;31(17):3584-92. doi: 10.1128/MCB.05821-11. Epub 2011 Jul 5.
Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR(vIII)), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf(-/-) Pten(-/-) Egfr(vIII) murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.
表皮生长因子受体（EGFR）信号通路的失调，无论是通过基因组扩增还是显性激活突变（EGFR(vIII)），再加上 INK4A/ARF 和 PTEN 的双重失活，是导致神经胶质瘤发生的主要原因。我们对 microRNAs 的全基因组表达分析表明，EGFR 的激活诱导了 miR-146a 的表达，而 PTEN 的失活则进一步增强了 miR-146a 的表达。出乎意料的是，miR-146a 的过表达会减弱 Ink4a/Arf(-/-) Pten(-/-) Egfr(vIII) 小鼠星形胶质细胞的增殖、迁移和致瘤能力。其异位表达也会抑制人胶质母细胞瘤细胞系在原位异种移植模型中的胶质瘤发展。miR-146a 对神经胶质瘤的这种抑制作用主要是通过下调 Notch1 实现的，Notch1 在神经干细胞维持中起着关键作用，是 miR-146a 的直接靶标。因此，miR-146a 调节神经干细胞的增殖和分化，减少胶质瘤干细胞样细胞的形成和迁移。相反，miR-146a 通过 microRNA 海绵的敲低会上调 Notch1，并促进恶性星形胶质细胞瘤的肿瘤发生。这些发现表明，miR-146a 作为一种负反馈机制，在受到致癌信号刺激时被诱导，通过抑制 Notch1 来限制肿瘤生长。我们的研究结果为连接神经干细胞与神经胶质瘤发生的信号通路提供了新的见解，并可能为治疗脑肿瘤提供新的策略。
