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Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN
Author(s) -
Koppen Arjen,
AitAissa Rachida,
Koster Jan,
Øra Ingrid,
Bras Johannes,
van Sluis Peter G.,
Caron Huib,
Versteeg Rogier,
Valentijn Linda J.
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23180
Subject(s) - neuroblastoma , ganglioneuroma , oncogene , ganglioneuroblastoma , cancer research , wnt signaling pathway , biology , pathology , medicine , cell , cell culture , gene , cell cycle , genetics
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 that Dickkopf‐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 that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down‐regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down‐regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types. © 2007 Wiley‐Liss, Inc.