NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells
NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells
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NFAT1 介导的 NDEL1 调节促进胶质瘤干细胞样细胞的生长和侵袭
DOI：
10.1158/0008-5472.can-18-3297
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发表时间：
2019-05-15
期刊：
影响因子：
11.2
通讯作者：
Han, Sheng
中科院分区：
文献类型：
--
作者：
Jiang, Yang;Song, Yifu;Han, Sheng
胶质瘤干细胞（GSC）促进肿瘤的发生和发展。然而，GSC诱导或维持的机制在很大程度上是未知的。我们之前证明了活化T细胞的钙响应转录因子核因子-1 （NFAT1）在胶质母细胞瘤中被激活并调节肿瘤细胞的侵袭。在本研究中，我们进一步探讨了NFAT1在GSC中的作用。我们发现NFAT1表达与侵袭性表型相关，并预测胶质瘤的低存活率。与正常胶质瘤细胞相比，GSC中NFAT1表达上调。在体外，NFAT1敲低降低了GSC的活力、侵袭和自我更新，并抑制了体内的肿瘤发生，而NFAT1过表达增强了GSC的生长和侵袭。RNA测序显示，NFAT1缺失与神经发育蛋白1样1 （NDEL1， NFAT1的潜在下游靶点）表达减少有关，而NFAT1过表达诱导NDEL1表达。此外，NFAT1调节NDEL1的启动子活性，而NFAT1沉默的GSC中NDEL1的恢复部分恢复了肿瘤的生长和侵袭。NFAT1-NDEL1信号的上调上调了Erk的激活，增加了GSC中干细胞标志物的蛋白水平，导致正常神经元细胞和星形胶质细胞的去分化。我们的研究结果表明，NFAT1通过调控NDEL1部分控制GSC的生长和侵袭。因此，靶向NFAT1-NDEL1轴可能在治疗胶质瘤患者中具有潜在的益处。意义：NFAT1部分通过调控NDEL1调控GSCs的生长和侵袭。靶向NFAT1-NDEL1轴可能为治疗胶质瘤患者提供机会。
Glioma stem-like cells (GSC) promote tumor generation and progression. However, the mechanism of GSC induction or maintenance is largely unknown. We previously demonstrated that the calcium-responsive transcription factor nuclear factor of activated T cells-1 (NFAT1) is activated in glioblastomas and regulates the invasion of tumor cells. In this study, we further explored the role of NFAT1 in GSC. We found that NFAT1 expression was associated with an aggressive phenotype and predicted poor survival in gliomas. Compared with normal glioma cells, NFAT1 was upregulated in GSC. NFAT1 knockdown reduced GSC viability, invasion, and self-renewal in vitro and inhibited tumorigenesis in vivo, whereas NFAT1 overexpression enhanced the growth and invasion of GSCs. RNA sequencing showed that NFAT1 depletion was associated with reduced neurodevelopment protein 1-like 1 (NDEL1, a potential downstream target of NFAT1) expression, whereas NFAT1 overexpression induced NDEL1 expression. In addition, NFAT1 regulated the promoter activities of NDEL1, whereas rescue of NDEL1 in NFAT1-silenced GSC partially restored tumor growth and invasion. Upregulation of NFAT1-NDEL1 signaling elevated Erk activation, increased protein levels of stemness markers in GSC, and resulted in de-differentiation of normal neuronal cells and astrocytes. Our results indicate that NFAT1 controls the growth and invasion of GSC partially through regulation of NDEL1. Targeting the NFAT1-NDEL1 axis therefore might be of potential benefit in the treatment of patients with glioma.Significance: NFAT1 controls the growth and invasion of GSCs, partially by regulating NDEL1. Targeting the NFAT1-NDEL1 axis might provide opportunities in treating patients with glioma.