NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK.
NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK.
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DOI：
10.1111/cas.12628
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发表时间：
2015-04
期刊：
影响因子：
5.7
通讯作者：
Kadomatsu K
中科院分区：
文献类型：
--
作者：
Lu F;Kishida S;Mu P;Huang P;Cao D;Tsubota S;Kadomatsu K
神经母细胞瘤起源于神经脊细胞的交感神经元谱系，是儿童颅外实体瘤中最常见的一种。神经分化因子NeuroD1通过抑制Slit2的表达来促进神经母细胞瘤的细胞运动。在此，我们报道了NeuroD1还参与了神经母细胞瘤细胞的增殖，包括人类细胞系和从模型小鼠肿瘤组织培养的原代肿瘤球体。有趣的是，NeuroD1基因敲除诱导的神经母细胞瘤细胞生长抑制伴随着ALK表达的降低。ALK被认为是神经母细胞瘤的重要易感基因之一。NeuroD1基因敲除所产生的表型被ALK强制表达抑制，因此，NeuroD1主要通过ALK促进神经母细胞瘤细胞的增殖。此外，我们还发现NeuroD1直接结合到ALK基因的启动子区域。此外，启动子中特定的E-box负责NeuroD1介导的ALK的表达。这些结果表明，alk基因可能是NeuroD1的直接靶基因。最后，NeuroD1和ALK在神经母细胞瘤模型小鼠早期肿瘤病变中的表达在体内是一致的。我们的结论是，新的机制将调节神经母细胞瘤中ALK的表达，并且NeuroD1应该显著参与神经母细胞瘤的发生。
Neuroblastoma is derived from the sympathetic neuronal lineage of neural crest cells, and is the most frequently observed of the extracranial pediatric solid tumors. The neuronal differentiation factor, NeuroD1, has previously been shown to promote cell motility in neuroblastoma by suppressing the expression of Slit2. Here we report that NeuroD1 is also involved in the proliferation of neuroblastoma cells, including human cell lines and primary tumorspheres cultured from the tumor tissues of model mice. Interestingly, the growth inhibition of neuroblastoma cells induced by knockdown of NeuroD1 was accompanied by a reduction of ALK expression. ALK is known to be one of the important predisposition genes for neuroblastoma. The phenotype resulting from knockdown of NeuroD1 was suppressed by forced expression of ALK and, therefore, NeuroD1 appears to act mainly through ALK to promote the proliferation of neuroblastoma cells. Furthermore, we showed that NeuroD1 directly bound to the promoter region of ALK gene. In addition, the particular E-box in the promoter was responsible for NeuroD1-mediated ALK expression. These results indicate that ALK should be a direct target gene of NeuroD1. Finally, the expressions of NeuroD1 and ALK in the early tumor lesions of neuroblastoma model mice coincided in vivo. We conclude that the novel mechanism would regulate the expression of ALK in neuroblastoma and that NeuroD1 should be significantly involved in neuroblastoma tumorigenesis.
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影响因子：
9.7
作者：
Nakagawara, A;Ohira, M
通讯作者：
Ohira, M
影响因子：
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Nakagawara, Akira
影响因子：
64.8
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通讯作者：
Maris, John M.
影响因子：
3.7
作者：
Cao D;Kishida S;Huang P;Mu P;Tsubota S;Mizuno M;Kadomatsu K
通讯作者：
Kadomatsu K