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A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma

1
Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
2
Department of Cellular Pathology, Southmead Hospital, Bristol BS10 5NB, UK
3
The Kids Research Institute, The Children’s Hospital at Westmead, Westmead, New South Wales 2145, Australia
*
Authors to whom correspondence should be addressed.
Current Address: Applied Sciences, University of the West of England, Bristol BS16 1QY, UK.
Cells 2020, 9(3), 783; https://doi.org/10.3390/cells9030783
Received: 10 February 2020 / Revised: 18 March 2020 / Accepted: 19 March 2020 / Published: 23 March 2020
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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. View Full-Text
Keywords: neuroblastoma; BMP4; Wnt and Notch signaling; RNA sequencing; growth inhibition neuroblastoma; BMP4; Wnt and Notch signaling; RNA sequencing; growth inhibition
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MDPI and ACS Style

Szemes, M.; Melegh, Z.; Bellamy, J.; Greenhough, A.; Kollareddy, M.; Catchpoole, D.; Malik, K. A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma. Cells 2020, 9, 783.

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