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

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 that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/b-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.

GSK3 Inhibitors Regulate MYCN mRNA Levels and Reduce Neuroblastoma Cell Viability through Multiple Mechanisms, Including p53 and Wnt Signaling

“…Wnt Agonist 1 treatment led to altered morphology and neuroblastoma cell fate resulting in apoptosis. Although some studies have shown links between Wnt signaling and neuroblastoma patient outcome (50)(51)(52), relatively few Wnt-neuroblastoma studies appear in the literature when compared with other major signaling pathways. mRNAseq profiling of neuroblastoma cell lines (unpublished) and "gene expression profiling of tumor samples" (personal communication S. Bulashevska, University of Bonn, Bonn, Germany and DKFZ, 11-06-13) is confirming that Wnt signaling components are altered in poor prognosis neuroblastoma.…”

Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma

“…Further studies have revealed that the downregulation of Dkk3 in cancer was a result of epigenetic silencing by DNA methylation (17). It also has been reported that transfection of Dkk3 in certain tumor cells affected their invasive capacity and led to cell apoptosis, indicating that Dkk3 may act as a tumor suppressor (14,32,34,39,40). However, Dkk3 mutant mice showed no enhanced tumorigenesis (41).…”

The NBPF Gene Family

“…Expression profiling of neuroblastic tumours and cell lines for the different Wnt family genes showed that both the canonical Wnt3a and the non-canonical Wnt5 were strongly expressed and that they could activate upstream Wnt signalling in neuroblastoma cells by phosphorylating the dishevelled co-receptor DVL3 (Revet et al, 2010). The importance of DKK3 in neuroblastoma was already shown in previous reports, in which DKK3 was implicated as a marker for neuroblastic tumour maturation and was shown to be down-regulated by MYCN (Bell et al, 2007;Koppen et al, 2008). Additionally, β-catenin has been shown to be strongly expressed and aberrantly localised in the nucleus in high-risk neuroblastoma cells without MYCN amplification (Liu et al, 2008).…”