A Wnt-BMP4 signalling axis induces MSX and NOTCH proteins and promotes growth suppression and differentiation in neuroblastoma
A Wnt-BMP4 signalling axis induces MSX and NOTCH proteins and promotes growth suppression and differentiation in neuroblastoma
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Wnt-BMP4 信号轴诱导 MSX 和 NOTCH 蛋白并促进神经母细胞瘤的生长抑制和分化
DOI：
10.1101/2020.02.07.938654
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Szemes M
中科院分区：
文献类型：
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作者：
Szemes M
Wnt和骨形态发生蛋白(BMP)信号通路在包括交感神经系统在内的神经脊谱系的发育中起着至关重要的作用。令人惊讶的是，它们在儿童神经母细胞瘤中的作用仍然相对缺乏特征性，儿童神经母细胞瘤是由该家族产生的典型肿瘤。我们先前已经证明，Wnt/β-catenin信号对神经母细胞瘤的表型有细胞特异性的影响，包括生长抑制和分化，并且BMP4mRNA和蛋白是由Wnt3a/Rsp2诱导的。在这项研究中，我们描述了BMP4对神经母细胞瘤细胞的表型效应，展示了Wnt和BMP4信号对MSX同源框转录因子的趋同诱导以及BMP4诱导的生长抑制和分化。BMP4在原发神经母细胞瘤中表达的免疫组织化学分析证实，BMP4在低分化肿瘤中明显缺乏，而在神经节细胞中高表达。这些结果与BMP4在神经母细胞瘤中的肿瘤抑制作用一致。BMP4处理后的RNA测序显示Notch信号的诱导，Notch3和Hes1蛋白的增加证实了这一点。总之，我们的数据首次证明了Wnt-BMP-Notch信号串扰与神经母细胞瘤的生长抑制有关。
The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.