Dickkopf-3expression is a marker for neuroblastic tumor maturation and is down-regulated by MYCN


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Abstract

Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report thatDickkopf-3(DKK3), a putative extra cellular inhibitor of the Wnt/β-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed thatDKK3is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. LowDKK3expression in neuroblastoma correlated with a poor prognosis. The expression ofDKK3in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of theMYCNoncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed thatDKK3is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. HighDKK3expression in the benign ganglioneuromas and down-regulation ofDKK3by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types.

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