Abstract
Neuroblastoma is the most common extracranial solid tumor in childhood. Gain of chromosome 17q material is found in >60% of neuroblastoma tumors and is associated with poor patient prognosis. The NME1 gene is located in the 17q21.3 region, and high NME1 expression is correlated with poor neuroblastoma patient outcomes. However, the functional roles and signaling activity of NME1 in neuroblastoma cells and tumors are unknown. NME1 and NME2 have been shown to possess histidine (His) kinase activity. Using anti-1- and 3-pHis specific monoclonal antibodies and polyclonal anti-pH118 NME1/2 antibodies, we demonstrated the presence of pH118-NME1/2 and multiple additional pHis-containing proteins in all tested neuroblastoma cell lines and in xenograft neuroblastoma tumors, supporting the presence of histidine kinase activity in neuroblastoma cells and demonstrating the potential significance of histidine kinase signaling in neuroblastoma pathogenesis. We have also demonstrated associations between NME1 expression and neuroblastoma cell migration and differentiation. Our demonstration of NME1 histidine phosphorylation in neuroblastoma and of the potential role of NME1 in neuroblastoma cell migration and differentiation suggest a functional role for NME1 in neuroblastoma pathogenesis and open the possibility of identifying new therapeutic targets and developing novel approaches to neuroblastoma therapy.
Highlights
Neuroblastoma is a pediatric tumor derived from primordial neural crest cells and is the most common extracranial solid tumor in childhood, accounting for 10% of all pediatric malignancies but more than 15% of deaths from cancer in children
The gene for NME1 is located in the chromosome 17q21 region commonly amplified in neuroblastoma tumors [5,6], suggesting a potential oncogenic role in neuroblastoma pathogenesis
In contrast to these adult tumors, elevated NME1 expression correlates with aggressive neuroblastoma tumor features [23,24,25] while increased NME1 expression has been identified as a component of gene expression, signatures most significantly associated with poor neuroblastoma patient outcomes [26]
Summary
Neuroblastoma is a pediatric tumor derived from primordial neural crest cells and is the most common extracranial solid tumor in childhood, accounting for 10% of all pediatric malignancies but more than 15% of deaths from cancer in children. NME1 expression is associated with regulation of genes correlated with adult cancer metastases [20], and NME1 depletion enhances tumor metastases in xenograft models [21,22], suggesting a role for NME1 as a suppressor of metastasis In contrast to these adult tumors, elevated NME1 expression correlates with aggressive neuroblastoma tumor features [23,24,25] while increased NME1 expression has been identified as a component of gene expression, signatures most significantly associated with poor neuroblastoma patient outcomes [26]. The gene for human NME2 is adjacent to the NME1 gene in the amplified chromosome 17q region, and human NME1 and NME2 share 88% sequence homology and, have similar structural and functional attributes Both NME1 and NME2 have been found to have histidine kinase activity, catalyzing transfer of the activated phosphate from the autophosphorylated histidine 118 residue (H118) onto target proteins [27]. This work suggests that histidine kinases and intracellular signaling potentially regulated by histidine phosphorylation represent potential therapeutic targets in neuroblastoma
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