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首页> 外文期刊>Oncogene >Deregulated Wnt|[sol]||[beta]|-catenin program in high-risk neuroblastomas without MYCN amplification
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Deregulated Wnt|[sol]||[beta]|-catenin program in high-risk neuroblastomas without MYCN amplification

机译：没有MYCN扩增的高风险神经母细胞瘤中Wnt | [sol] ||β| -catenin程序失控

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Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/β-catenin (CTNNB1) signaling might account for this as MYC is a β-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and β-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant β-catenin–TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical β-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated β-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered β-catenin signaling providing a potential candidate pathway for therapeutic inhibition.
机译：神经母细胞瘤（NB）是儿童期常见的致死性肿瘤。 MYCN扩增解释了亚型中的侵袭性表型，而大多数没有一致鉴定出的分子像差，但经常以高水平表达MYC。我们假设激活的Wnt /β-catenin（CTNNB1）信号可能是造成这种情况的原因，因为MYC是β-catenin的转录靶标，并且多个胚胎和神经rest恶性肿瘤在该途径中具有致癌性改变。没有MYCN扩增的NB细胞系比MYCN扩增的细胞系表达更高水平的MYC和β-catenin（核定位异常）。使用来自73个原发性NB的表达谱证明了β-catenin–TCF异常转录活性的证据。研究结果包括增加的WNT配体（WNT1，WNT6，WNT7A，WNT10B），DVL1和TCF7在没有MYCN扩增的高风险NB中的表达，与典型的β-catenin信号传导一致。更直接地，基因表达和基因集富集分析的模式表明与高风险MYCN相比，β-catenin靶基因（例如MYC，PPARD，NRCAM，CD44，TCF7）在没有MYCN扩增的高风险NB中协同上调。 -放大或中等风险的NB，支持此子集中的途径激活。因此，没有MYCN扩增的高危NB可能通过改变的β-catenin信号传导而解除MYC和其他致癌基因的调控，从而为治疗抑制提供了潜在的候选途径。

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