The Neuronal Differentiation Factor NeuroD1 Downregulates the Neuronal Repellent Factor Slit2 Expression and Promotes Cell Motility and Tumor Formation of Neuroblastoma
The Neuronal Differentiation Factor NeuroD1 Downregulates the Neuronal Repellent Factor Slit2 Expression and Promotes Cell Motility and Tumor Formation of Neuroblastoma
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DOI：
10.1158/0008-5472.can-10-3524
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Kadomatsu, Kenji
中科院分区：
文献类型：
--
作者：
Huang, Peng;Kishida, Satoshi;Kadomatsu, Kenji
碱性螺旋-环-螺旋转录因子NeuroD1参与了胰腺内分泌细胞的神经发生和早期分化。然而，它与癌症相关的功能还没有得到很好的研究。在本研究中，我们发现NeuroD1参与了神经母细胞瘤的发生。在2周龄MYCN转基因(TG)小鼠的腹腔交感神经节中，NeuroD1在由神经母细胞组成的增生区强烈表达，并在随后产生的神经母细胞瘤组织中持续表达。短发夹状RNA(ShRNA)敲除NeuroD1可抑制人神经母细胞瘤细胞系的运动能力，这种作用可被shRNA抗性的NeuroD1逆转。NeuroD1基因敲除对细胞运动的抑制作用与诱导Slit2表达有关，Slit2基因敲除可恢复细胞运动。与这一发现一致的是，shRNA抗性的NeuroD1抑制了Slit2的表达。NeuroD1直接与Slit2启动子区域的第一和第二个E-box结合。此外，我们还发现，从MYCN TG小鼠神经母细胞瘤细胞系建立的肿瘤球体的生长受到NeuroD1抑制。NeuroD1在细胞运动和肿瘤球体生长中的功能可能提示NeuroD1与神经母细胞瘤的发生有关。事实上，NeuroD1基因敲除显著抑制了肿瘤球源性细胞的肿瘤形成。这些数据与人类神经母细胞瘤的临床特征有关：NeuroD1的高表达与预后不良密切相关。我们的发现确定了神经分化因子NeuroD1在神经母细胞瘤中的关键作用，以及它与神经元排斥因子Slit2的功能关系。癌症资源；71(8)；2938-48。(C)2011年AACR。
The basic helix-loop-helix transcription factor NeuroD1 has been implicated in the neurogenesis and early differentiation of pancreatic endocrine cells. However, its function in relation to cancer has been poorly examined. In this study, we found that NeuroD1 is involved in the tumorigenesis of neuroblastoma. NeuroD1 was strongly expressed in a hyperplastic region comprising neuroblasts in the celiac sympathetic ganglion of 2-week-old MYCN transgenic (Tg) mice and was consistently expressed in the subsequently generated neuroblastoma tissue. NeuroD1 knockdown by short hairpin RNA (shRNA) resulted in motility inhibition of the human neuroblastoma cell lines, and this effect was reversed by shRNA-resistant NeuroD1. The motility inhibition by NeuroD1 knockdown was associated with induction of Slit2 expression, and knockdown of Slit2 could restore cell motility. Consistent with this finding, shRNA-resistant NeuroD1 suppressed Slit2 expression. NeuroD1 directly bound to the first and second E-box of the Slit2 promoter region. Moreover, we found that the growth of tumor spheres, established from neuroblastoma cell lines in MYCN Tg mice, was suppressed by NeuroD1 suppression. The functions identified for NeuroD1 in cell motility and tumor sphere growth may suggest a link between NeuroD1 and the tumorigenesis of neuroblastoma. Indeed, tumor formation of tumor sphere-derived cells was significantly suppressed by NeuroD1 knockdown. These data are relevant to the clinical features of human neuroblastoma: high NeuroD1 expression was closely associated with poor prognosis. Our findings establish the critical role of the neuronal differentiation factor NeuroD1 in neuroblastoma as well as its functional relationship with the neuronal repellent factor Slit2. Cancer Res; 71(8); 2938-48. (C)2011 AACR.