Midkine Promotes Neuroblastoma through Notch2 Signaling
Midkine Promotes Neuroblastoma through Notch2 Signaling
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DOI：
10.1158/0008-5472.can-12-3070
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发表时间：
2013-02-15
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：
Kishida, Satoshi;Mu, Ping;Kadomatsu, Kenji
中期因子是一种肝素结合生长因子，在各种癌症中高度表达，包括神经母细胞瘤，最常见的颅外儿科实体瘤。MYCN扩增的神经母细胞瘤患者的预后仍然特别差。在这项研究中，我们使用MYCN转基因模型的神经母细胞瘤，中期因子是高度表达的癌前病变的交感神经节。在该模型中，中期因子的基因消除延迟了肿瘤形成并降低了肿瘤发生率。此外，特异性结合中期因子的RNA适体在体外和体内肿瘤异种移植物中抑制神经母细胞瘤细胞的生长。在癌前病变中，中期因子缺陷的MYCN转基因小鼠表现出Notch 2（一种候选中期因子受体）活化和Notch靶基因HES 1表达的缺陷。同样，RNA适体处理的肿瘤异种移植物也显示Notch 2-HES 1信号传导减弱。我们的研究结果确立了中期因子-Notch 2信号传导轴在神经母细胞瘤肿瘤发生中的关键作用，这暗示了治疗神经母细胞瘤的新策略。Cancer Res; 73（4）; 1318-27.（C）2012年AACR。
Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma. Cancer Res; 73(4); 1318-27. (C)2012 AACR.