Neuroblastoma is a pediatric solid tumor that exhibits striking clinical bipolarity. Despite extensive efforts to treat unfavorable neuroblastoma, survival rate of children with the disease is among the lowest. Previous studies suggest that EPHA2, a member of the EPH family receptor kinases, can either promote or suppress cancer cell growth depending on cellular contexts. In this study, we investigated the biological significance of EPHA2 in neuroblastoma. It was found that tumorigenic N-type

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... uroblastoma cell lines expressed low levels of EPHA2, whereas hypo-tumorigenic S-type neuroblastoma cell lines expressed high levels of EPHA2 (p<0.005). Notably, inhibitors of DNA methylation and histone deacetylase enhanced EPHA2 expression in N-type cells, suggesting that EPHA2 is epigenetically silenced in unfavorable neuroblastoma cells. Furthermore, ectopic high-level expression of EPHA2 in N-type neuroblastoma cell lines resulted in significant growth suppression. However, Kaplan-Meier survival analysis showed that high EPHA2 expression was not associated with a good disease outcome of neuroblastoma, indicating that EPHA2 is not a favorable neuroblastoma gene, but a growth suppressive gene for neuroblastoma. Accordingly, EPHA2 expression was markedly augmented in vitro in neuroblastoma cells treated with doxorubicin, which is commonly used for treating unfavorable neuroblastoma. Taken together, EPHA2 is one of the effectors of chemotherapeutic agents (e.g., gene silencing inhibitors and DNA damaging agents). EPHA2 expression may thus serve as a biomarker of drug responsiveness for neuroblastoma during the course of chemotherapy. In addition, pharmaceutical enhancement of EPHA2 by non-cytotoxic agents may offer an effective therapeutic approach in the treatment of children with unfavorable neuroblastoma.