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Association of distinct type 1 bone morphogenetic protein receptors with different molecular pathways and survival outcomes in neuroblastoma

O'Keeffe, Gerard W., Sullivan, Aideen M., Hegarty, Shane V., Collins, Louise M., McCarthy, Erin, Wyatt, Sean L. and Alshangiti, Amnah M. 2020. Association of distinct type 1 bone morphogenetic protein receptors with different molecular pathways and survival outcomes in neuroblastoma. Neuronal Signaling 4 (1) , NS20200006. 10.1042/NS20200006

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Abstract

Neuroblastoma (NB) is a paediatric cancer that arises in the sympathetic nervous system. Patients with stage 4 tumours have poor outcomes and 20% of high-risk cases have MYCN amplification. The bone morphogenetic proteins (BMPs) play roles in sympathetic neuritogenesis, by signalling through bone morphogenetic protein receptor (BMPR)2 and either BMPR1A or BMPR1B. Alterations in BMPR2 expression have been reported in NB; it is unknown if the expression of BMPR1A or BMPR1B is altered. We report lower BMPR2 and BMPR1B, and higher BMPR1A, expression in stage 4 and in MYCN-amplified NB. Kaplan–Meier plots showed that high BMPR2 or BMPR1B expression was linked to better survival, while high BMPR1A was linked to worse survival. Gene ontology enrichment and pathway analyses revealed that BMPR2 and BMPR1B co-expressed genes were enriched in those associated with NB differentiation. BMPR1A co-expressed genes were enriched in those associated with cell proliferation. Moreover, the correlation between BMPR2 and BMPR1A was strengthened, while the correlation between BMPR2 and BMPR1B was lost, in MYCN-amplified NB. This suggested that differentiation should decrease BMPR1A and increaseBMPR1Bexpression.Inagreement,nervegrowthfactortreatmentofculturedsympatheticneuronsdecreasedBmpr1aexpressionandincreasedBmpr1bexpression.Overexpression of dominant negative BMPR1B, treatment with a BMPR1B inhibitor and treatment with GDF5, which signals via BMPR1B, showed that BMPR1B signalling is required for optimal neuritogenesis in NB cells, suggesting that loss of BMPR1B may alter neuritogenesis. The present study shows that expression of distinct BMPRs is associated with different survival outcomes in NB.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Additional Information: This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Publisher: Portland Press
ISSN: 2059-6553
Date of First Compliant Deposit: 18 January 2021
Date of Acceptance: 15 April 2020
Last Modified: 18 Jan 2021 09:45
URI: http://orca.cf.ac.uk/id/eprint/137682

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