Implications ofEPHB6,EFNB2, andEFNB3expressions in human neuroblastoma

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Abstract
Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2,EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and highTrkAexpression. In this study, we showed thatEFNB2andTrkAexpressions were associated with both tumor stage and age, whereasEPHB6andEFNB3expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression ofEPHB6,EFNB2, andEFNB3predicted favorable NB outcome (P< 0.005), and their expression combined withTrkAexpression predicted the disease outcome more accurately than each variable alone (P< 0.00005). Interestingly, if any one of the four genes (EPHB6,EFNB2,EFNB3, orTrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a “favorable NB gene,” we examined the effect ofEPHB6on NB cell lines. Transfection ofEPHB6cDNA into IMR5 and SY5Y expressing little endogenousEPHB6resulted in inhibition of their clonogenicity in culture. Furthermore, transfection ofEPHB6suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such asEPHB6, can in fact suppress malignant phenotype of unfavorable NB.