A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature).
A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature).
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DOI：
10.1038/s41598-017-00122-x
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发表时间：
2017-03-03
影响因子：
4.6
通讯作者：
Cunningham JM
中科院分区：
文献类型：
--
作者：
Yang XH;Tang F;Shin J;Cunningham JM
假设c-Myc失调是胚胎干细胞（ESC）和成人侵袭性肿瘤之间共享的“干细胞性”-自我更新和多能性-的原因。高危神经母细胞瘤（HR-NB）是儿童期最常见的侵袭性颅外实体瘤。使用HR-NB作为平台，我们对转录组数据进行了网络分析，并提出了一个c-Myc子网络，该网络富集了先前报道为ESC样癌症特征的基因。随后的药物-基因相互作用分析鉴定了优先与该HR-NB特异性ESC样特征相互作用的药物基因组学试剂。该药物Roniciclib（BAY 1000394）在体外抑制神经母细胞瘤细胞生长并诱导细胞凋亡。它还在体外抑制癌基因c-Myc和神经ESC标记物CDK 2的表达，这伴随着以时间依赖性方式改变c-Myc靶向的细胞周期调节因子CCND 1、CDKN 1A和CDKN 2D的表达。在295和243名独立患者中对这种HR-NB特异性ESC样特征的进一步研究揭示并验证了CDK 2和CDKN 3与CDKN 2D和CDKN 1B相比的一般预后指数。这些发现强调了Roniciclib通过靶向c-Myc调节的ESC样肿瘤发生在HR-NB中的非常有效的治疗益处。这项工作提供了一个假设驱动的系统计算模型，有助于将基因组和转录组特征转化为高危肿瘤的分子机制。
c-Myc dysregulation is hypothesized to account for the ‘stemness’ – self-renewal and pluripotency – shared between embryonic stem cells (ESCs) and adult aggressive tumours. High-risk neuroblastoma (HR-NB) is the most frequent, aggressive, extracranial solid tumour in childhood. Using HR-NB as a platform, we performed a network analysis of transcriptome data and presented a c-Myc subnetwork enriched for genes previously reported as ESC-like cancer signatures. A subsequent drug-gene interaction analysis identified a pharmacogenomic agent that preferentially interacted with this HR-NB-specific, ESC-like signature. This agent, Roniciclib (BAY 1000394), inhibited neuroblastoma cell growth and induced apoptosis in vitro. It also repressed the expression of the oncogene c-Myc and the neural ESC marker CDK2 in vitro, which was accompanied by altered expression of the c-Myc-targeted cell cycle regulators CCND1, CDKN1A and CDKN2D in a time-dependent manner. Further investigation into this HR-NB-specific ESC-like signature in 295 and 243 independent patients revealed and validated the general prognostic index of CDK2 and CDKN3 compared with CDKN2D and CDKN1B. These findings highlight the very potent therapeutic benefits of Roniciclib in HR-NB through the targeting of c-Myc-regulated, ESC-like tumorigenesis. This work provides a hypothesis-driven systems computational model that facilitates the translation of genomic and transcriptomic signatures to molecular mechanisms underlying high-risk tumours.