MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling.
MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling.
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DOI：
10.1073/pnas.1710901115
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发表时间：
2018-02-06
影响因子：
11.1
通讯作者：
Arsenian-Henriksson M
中科院分区：
文献类型：
--
作者：
Dzieran J;Rodriguez Garcia A;Westermark UK;Henley AB;Eyre Sánchez E;Träger C;Johansson HJ;Lehtiö J;Arsenian-Henriksson M
高危神经母细胞瘤（NB）是一种交感神经系统癌症，治疗具有挑战性。MYCN在高危NB中经常扩增，并与未分化表型和预后不良有关。雌激素和神经生长因子（NGF）是神经分化的诱导剂，这是一个与有利疾病相关的过程。我们发现MYCN抑制雌激素受体α（ERα），从而抑制NGF信号传导和神经分化。ERα过表达足以干扰不同的肿瘤发生过程和肿瘤生长。在NB患者中，ERα表达与预后良好的几个临床标志物相关。重要的是，不仅ERα，而且大多数其他核激素受体都与有利的NB相关，这表明这些蛋白质具有潜在的预后和治疗价值。神经母细胞瘤（NB）是一种非常异质性的儿童交感神经系统肿瘤，临床表现从自发消退到低分化肿瘤和转移。MYCN在20%的病例中扩增，并与未分化、侵袭性表型和预后不良相关。雌激素受体α（ERα）和神经生长因子（NGF）受体TrkA和p75 NTR参与神经元的分化和存活。我们之前已经证明MYCN通过miR-18 a靶向NB细胞中的ERα。在这里，我们证明了干扰miR-18 a或ERα过表达足以诱导NGF信号传导，并调节MYCN扩增的NB细胞中基础和NGF诱导的神经元分化。蛋白质组学分析证实了神经元特征的增加，并显示与肿瘤发生和进展相关的过程在ERα过表达时受到抑制。事实上，异位ERα表达足以抑制代谢活性和肿瘤发生过程，包括糖酵解、氧化磷酸化、细胞活力、迁移和锚定非依赖性生长。重要的是，ERα过表达降低了NB小鼠模型中的肿瘤负荷，高ERα水平与患者生存率的改善有关。除了ERα，其他几种核激素受体（NHR），包括糖皮质激素和视黄酸受体，与有利的和低阶段NB疾病的临床标志物相关。我们的数据表明MYCN靶向ERα，从而通过NGF信号传导维持未分化和侵袭性表型。值得注意的是，我们确定了雌激素-NGF串扰，以及一组其他NHR，作为潜在的预后标志物和针对NB的治疗策略的目标。
High-risk neuroblastoma (NB), a cancer of the sympathetic nervous system, is challenging to treat. MYCN is frequently amplified in high-risk NB and is linked to an undifferentiated phenotype and poor prognosis. Estrogen and nerve growth factor (NGF) are inducers of neural differentiation, a process associated with a favorable disease. We show that MYCN suppresses estrogen receptor alpha (ERα) and thereby NGF signaling and neural differentiation. ERα overexpression is sufficient to interfere with different tumorigenic processes and tumor growth. In patients with NB, ERα expression correlates with several clinical markers for good prognosis. Importantly, not only ERα but also the majority of other nuclear hormone receptors are linked to favorable NB, suggesting a potential prognostic and therapeutic value for these proteins. Neuroblastoma (NB) is a remarkably heterogenic childhood tumor of the sympathetic nervous system with clinical behavior ranging from spontaneous regression to poorly differentiated tumors and metastasis. MYCN is amplified in 20% of cases and correlates with an undifferentiated, aggressive phenotype and poor prognosis. Estrogen receptor alpha (ERα) and the nerve growth factor (NGF) receptors TrkA and p75NTR are involved in neuronal differentiation and survival. We have previously shown that MYCN, via miR-18a, targets ERα in NB cells. Here, we demonstrate that interference with miR-18a or overexpression of ERα is sufficient to induce NGF signaling and to modulate both basal and NGF-induced neuronal differentiation in MYCN-amplified NB cells. Proteomic analysis confirmed an increase of neuronal features and showed that processes linked to tumor initiation and progression were inhibited upon ERα overexpression. Indeed, ectopic ERα expression was sufficient to inhibit metabolic activity and tumorigenic processes, including glycolysis, oxidative phosphorylation, cell viability, migration, and anchorage independent growth. Importantly, ERα overexpression reduced tumor burden in NB mouse models and high ERα levels were linked to improved survival in patients. In addition to ERα, several other nuclear hormone receptors (NHRs), including the glucocorticoid and the retinoic acid receptors, correlated with clinical markers for favorable and low-stage NB disease. Our data suggest that MYCN targets ERα and thereby NGF signaling to maintain an undifferentiated and aggressive phenotype. Notably, we identified the estrogen–NGF crosstalk, as well as a set of other NHRs, as potential prognostic markers and targets for therapeutic strategies against NB.
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DOI：
10.1158/1078-0432.ccr-08-1815
发表时间：
2009-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
通讯作者：
Evans AE
影响因子：
5.4
作者：
Huang M;Weiss WA
通讯作者：
Weiss WA
影响因子：
5.3
作者：
Gollapudi, L;Oblinger, MM
通讯作者：
Oblinger, MM
影响因子：
--
作者：
Acosta S;Lavarino C;Paris R;Garcia I;de Torres C;Rodríguez E;Beleta H;Mora J
通讯作者：
Mora J
影响因子：
64.8
作者：
Heery, DM;Kalkhoven, E;Parker, MG
通讯作者：
Parker, MG