Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells
Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells
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DOI：
10.1016/j.yexcr.2016.04.012
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发表时间：
2016-06-10
影响因子：
3.7
通讯作者：
Chiu, Ing-Ming
中科院分区：
文献类型：
--
作者：
Hsu, Yi-Chao;Kao, Chien-Yu;Chiu, Ing-Ming
成纤维细胞生长因子1(FGF1)结合并激活成纤维细胞生长因子受体，从而调节细胞增殖和神经发生。人类FGF1基因1B启动子(-540到+31)驱动的SV40T抗原已被证明在转基因小鼠的大脑中导致肿瘤发生。FGF1B启动子(-540~+31)驱动的绿色荧光蛋白(F1BGFP)也被用于从发育中和成年小鼠脑中分离出具有自我更新和多潜能的神经干细胞(NSCs)。在这项研究中，我们提供了六条证据来证明FGF1/FGFR信号与Aurora A(AURA)的表达及其激活域(Thr288磷酸化)在维持胶质母细胞瘤(GBM)细胞和神经干细胞的维持中有关。首先，FGF1的处理增加了人GBM细胞系中AURA的表达。其次，利用荧光激活的细胞分选方法，我们观察到F1BGFP报告基因有助于分离FGFR和AURA高表达水平的F1BGFP(+)GBM细胞。第三，FGFR抑制剂(SU5402)和AURA抑制剂(VX680)均可下调F1BGFP依赖的AURA活性。第四，两种不同的AURA抑制剂(VX680和丙戊酸)对AURA活性的抑制不仅减少了神经球的形成，而且还诱导了F1BGFP(+)GBM细胞的神经元分化。第五，流式细胞仪分析显示F1BGFP(+)GBM细胞具有不同的NSC细胞表面标志。最后，VX680对Aura的抑制减少了不同类型NSCs的神经球形成。我们的结果表明，通过FGF1/FGFR信号轴激活Aura激酶维持了GBM细胞的干细胞特性。意义：本研究发现了GBM恶变的新机制，可能成为GBM的潜在治疗靶点。(C)2016 Elsevier Inc.保留所有权利。
Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven SV40 T antigen has been shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (-540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288 phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP (+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells.Implications: This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM. (C) 2016 Elsevier Inc. All rights reserved.