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

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 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 and , and higher , expression in stage 4 and in -amplified NB. Kaplan-Meier plots showed that high or expression was linked to better survival, while high was linked to worse survival. Gene ontology enrichment and pathway analyses revealed that and co-expressed genes were enriched in those associated with NB differentiation. co-expressed genes were enriched in those associated with cell proliferation. Moreover, the correlation between and was strengthened, while the correlation between and was lost, in -amplified NB. This suggested that differentiation should decrease and increase expression. In agreement, nerve growth factor treatment of cultured sympathetic neurons decreased expression and increased expression. 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 may alter neuritogenesis. The present study shows that expression of distinct BMPRs is associated with different survival outcomes in NB.