Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
Cell Rep. 2019 Aug 20;28(8):2064-2079.e11. doi: 10.1016/j.celrep.2019.07.071.
Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.
确定导致癌症具有干细胞样和治疗抗性的细胞程序对于改善患者的预后至关重要。在这里，我们证明了组成型细胞外信号调节激酶 1/2（ERK1/2）的激活在胶质母细胞瘤（GBM）中维持了干细胞样状态，GBM 是最常见的原发性恶性脑肿瘤。ERK1/2 激活的药理学抑制在小鼠星形细胞瘤形成过程中恢复神经发生，诱导肿瘤球中的神经元分化。组成型 ERK1/2 激活在小鼠和人类 GBM 中全局调节 miRNA 表达，而 ERK1/2 激活抑制后 GBM 肿瘤球的神经元分化需要 miR-124 的功能表达和其靶基因 SOX9 的耗竭。miR124 的过表达在体内耗尽 SOX9 并促进干细胞样到神经元的转变，降低致瘤性并提高辐射敏感性。为报告表明 miR-124 诱导的 GBM 侵袭性消除提供了理论依据，我们得出结论，逆转 ERK1/2-miR-124-SOX9 轴诱导神经元表型，并且强制神经元分化代表改善 GBM 预后的治疗策略。
