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首页> 外文期刊>Molecular and Cellular Biology >MicroRNA-146a Inhibits Glioma Development by Targeting Notch1
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MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

机译：MicroRNA-146a通过靶向Notch1抑制胶质瘤的发展

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFRvIII), 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?/? EgfrvIII 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.
机译：通过基因组扩增或显性激活突变（EGFR vIII ）失调的表皮生长因子受体（EGFR）信号转导以及INK4A / ARF和PTEN的双重失活是胶质瘤发生的主要原因。我们对microRNA的整体表达分析表明，EGFR激活可诱导miR-146a表达，并通过PTEN失活进一步增强表达。出乎意料的是，miR-146a的过表达减弱了 Ink4a / Arf ？/？ Pten 的增殖，迁移和致瘤潜力。 em> ？/？ Egfr vIII 鼠星形胶质细胞。它的异位表达还抑制原位异种移植模型中人胶质母细胞瘤细胞系的神经胶质瘤发展。 miR-146a对神经胶质瘤的这种抑制功能主要是通过Notch1的下调来实现的，Notch1在神经干细胞维持中起关键作用，并且是miR-146a的直接靶标。因此，miR-146a调节神经干细胞的增殖和分化，并减少神经胶质瘤干样细胞的形成和迁移。相反，通过microRNA海绵敲低miR-146a会上调Notch1并促进恶性星形胶质细胞的肿瘤发生。这些发现表明，响应致癌线索，miR-146a被诱导为通过抑制Notch1来限制肿瘤生长的负反馈机制。我们的结果为将神经干细胞与神经胶质瘤形成联系起来的信号传导途径提供了新颖的见解，并可能导致治疗脑肿瘤的新策略。

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