MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma
MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma
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DOI：
10.1073/pnas.0913517107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Henriksson, Marie
中科院分区：
文献类型：
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作者：
Loven, Jakob;Zinin, Nikolay;Henriksson, Marie
MYCN是一种原癌基因，通常在迁移的神经嵴中表达，其扩增状态是人类神经母细胞瘤（NB）发生的关键因素。然而，MYCN介导的NB进展的机制知之甚少。在这里，我们提出了一个MYCN诱导的miRNA签名在人类NB涉及激活和transrepression的几个miRNA基因的旁系同源集群。来自miR-17类似于92簇的几个家族成员，包括miR-18 a和miR-19 a，在上调的miRNA中。这些miRNA在NB肿瘤中的表达分析证实了MYCN扩增样品中的水平增加。具体来说，我们表明miR-18 a和miR-19 a靶向并抑制雌激素受体-α（ESR 1）的表达，雌激素受体-α是一种与神经元分化有关的配体诱导型转录因子。免疫组化染色显示ESR 1在人胎儿交感神经节中表达，提示ESR 1在交感神经系统发育过程中的作用。一致地，慢病毒恢复NB细胞中的ESR 1导致生长停滞和神经元分化。此外，慢病毒介导的抑制NB细胞中的miR-18 a导致严重的生长迟缓、含有静脉曲张的神经突的生长以及神经元交感神经分化标记物的诱导。NB肿瘤微阵列数据的生物信息学分析显示，高ESR 1表达与NB患者无事件生存率增加和良好的疾病结局相关。因此，MYCN扩增可能通过ESR 1的失调破坏原始交感神经细胞中的雌激素信号敏感性，从而阻止成神经细胞分化的正常诱导。总的来说，我们的研究结果证明了MYCN驱动的肿瘤中异常miRNA转录的分子后果，并为MYCN扩增的NB的病理学提供了独特的见解。
MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 similar to 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.