Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma.
Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma.
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DOI：
10.1016/j.neo.2018.01.009
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Malik K
中科院分区：
文献类型：
--
作者：
Szemes M;Greenhough A;Melegh Z;Malik S;Yuksel A;Catchpoole D;Gallacher K;Kollareddy M;Park JH;Malik K
神经母细胞瘤是儿童期最常见和最致命的实体瘤之一，被认为是由于神经嵴的交感肾上腺素能谱系的发育分化中断所致。神经母细胞瘤表现出肿瘤内和肿瘤间的异质性，高风险肿瘤的特点是分化差，这可能是由于MYCN介导的抑制基因参与神经元分化。已知MYCN与致癌信号传导途径如Alk、Akt和MEK/ERK信号传导合作，并且已经显示与c-MYC一起在各种组织中被Wnt信号传导激活。然而，我们以前的工作表明，Wnt 3a/Rspo 2治疗一些神经母细胞瘤细胞系，矛盾的是，减少c-MYC和MYCN蛋白。这促使我们使用RNA测序来定义神经母细胞瘤特异性Wnt 3a/Rspo 2驱动的转录组，并研究伴随的细胞生物学变化。在这里，我们报告了90个Wnt靶基因的鉴定，并表明Wnt信号是神经母细胞瘤中众多转录因子和信号通路的上游。使用活细胞成像，我们表明Wnt信号传导可以驱动SK-N-BE（2）-C和SH-SY 5 Y细胞系的分化，但相反，SK-N-AS细胞的增殖。我们表明，分化的细胞系显示诱导促分化BMP 4和EPAS 1蛋白，这在SK-N-AS细胞中不明显。相比之下，SK-N-AS细胞显示响应于Wnt 3a/Rspo 2的CCND 1、磷酸化RB和E2 F1增加，与它们的增殖反应一致，并且这些蛋白质在分化系中不增加。通过对我们的90个基因在原发性肿瘤基因表达数据库中的表达进行荟萃分析，我们证明了我们的Wnt基因在具有不同预后的患者队列中的离散表达模式。此外，我们的分析揭示了我们的Wnt基因的子集内的互连性，其中一个子集由MYCN抑制的神经元分化的新推定驱动因素组成。β-连环蛋白免疫组织化学评估显示，在分化较好的肿瘤中β-连环蛋白水平较高，进一步支持了经典Wnt信号传导在神经母细胞瘤分化中的作用。
Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation.
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影响因子：
--
作者：
Duffy DJ;Krstic A;Schwarzl T;Halasz M;Iljin K;Fey D;Haley B;Whilde J;Haapa-Paananen S;Fey V;Fischer M;Westermann F;Henrich KO;Bannert S;Higgins DG;Kolch W
通讯作者：
Kolch W
复发的神经母细胞瘤显示出频繁的RAS-MAPK途径突变。
影响因子：
30.8
作者：
Eleveld TF;Oldridge DA;Bernard V;Koster J;Colmet Daage L;Diskin SJ;Schild L;Bentahar NB;Bellini A;Chicard M;Lapouble E;Combaret V;Legoix-Né P;Michon J;Pugh TJ;Hart LS;Rader J;Attiyeh EF;Wei JS;Zhang S;Naranjo A;Gastier-Foster JM;Hogarty MD;Asgharzadeh S;Smith MA;Guidry Auvil JM;Watkins TB;Zwijnenburg DA;Ebus ME;van Sluis P;Hakkert A;van Wezel E;van der Schoot CE;Westerhout EM;Schulte JH;Tytgat GA;Dolman ME;Janoueix-Lerosey I;Gerhard DS;Caron HN;Delattre O;Khan J;Versteeg R;Schleiermacher G;Molenaar JJ;Maris JM
通讯作者：
Maris JM
影响因子：
4.6
作者：
Ferlemann FC;Menon V;Condurat AL;Rößler J;Pruszak J
通讯作者：
Pruszak J
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng