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 Wn… Show more
“…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 mRNAseq profiling of neuroblastoma cell lines (unpublished) and "gene expression profiling of tumor samples" (personal communication S. Bulashevska, University of Bonn, Bonn, Germany and DKFZ, 11-06-13) is confirming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.…”
Neuroblastoma is an embryonal tumor accounting for approximately 15% of childhood cancer deaths. There exists a clinical need to identify novel therapeutic targets, particularly for treatment-resistant forms of neuroblastoma. Therefore, we investigated the role of the neuronal master regulator GSK3 in controlling neuroblastoma cell fate. We identified novel GSK3-mediated regulation of MYC (c-MYC and MYCN) mRNA levels, which may have implications for numerous MYC-driven cancers. In addition, we showed that certain GSK3 inhibitors induced large-scale cell death in neuroblastoma cells, primarily through activating apoptosis. mRNA-seq of GSK3 inhibitor-treated cells was performed and subsequent pathway analysis revealed that multiple signaling pathways contributed to the loss of neuroblastoma cell viability. The contribution of two of the signaling pathways highlighted by the mRNA-seq analysis was functionally validated. Inhibition of the p53 tumor suppressor partly rescued the cell death phenotype, whereas activation of canonical Wnt signaling contributed to the loss of viability, in a p53-independent manner. Two GSK3 inhibitors (BIO-acetoxime and LiCl) and one small-molecule Wnt agonist (Wnt Agonist 1) demonstrated therapeutic potential for neuroblastoma treatment. These inhibitors reduced the viability of numerous neuroblastoma cell lines, even those derived from high-risk MYCN-amplified metastatic tumors, for which effective therapeutics are currently lacking. Furthermore, although LiCl was lethal to neuroblastoma cells, it did not reduce the viability of differentiated neurons. Taken together our data suggest that these small molecules may hold potential as effective therapeutic agents for the treatment of neuroblastoma and other MYC-driven cancers. Mol Cancer Ther; 13(2); 454-67. Ó2013 AACR.
“…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.…”
Neuroblastoma is an embryonal tumor accounting for approximately 15% of childhood cancer deaths. There exists a clinical need to identify novel therapeutic targets, particularly for treatment-resistant forms of neuroblastoma. Therefore, we investigated the role of the neuronal master regulator GSK3 in controlling neuroblastoma cell fate. We identified novel GSK3-mediated regulation of MYC (c-MYC and MYCN) mRNA levels, which may have implications for numerous MYC-driven cancers. In addition, we showed that certain GSK3 inhibitors induced large-scale cell death in neuroblastoma cells, primarily through activating apoptosis. mRNA-seq of GSK3 inhibitor-treated cells was performed and subsequent pathway analysis revealed that multiple signaling pathways contributed to the loss of neuroblastoma cell viability. The contribution of two of the signaling pathways highlighted by the mRNA-seq analysis was functionally validated. Inhibition of the p53 tumor suppressor partly rescued the cell death phenotype, whereas activation of canonical Wnt signaling contributed to the loss of viability, in a p53-independent manner. Two GSK3 inhibitors (BIO-acetoxime and LiCl) and one small-molecule Wnt agonist (Wnt Agonist 1) demonstrated therapeutic potential for neuroblastoma treatment. These inhibitors reduced the viability of numerous neuroblastoma cell lines, even those derived from high-risk MYCN-amplified metastatic tumors, for which effective therapeutics are currently lacking. Furthermore, although LiCl was lethal to neuroblastoma cells, it did not reduce the viability of differentiated neurons. Taken together our data suggest that these small molecules may hold potential as effective therapeutic agents for the treatment of neuroblastoma and other MYC-driven cancers. Mol Cancer Ther; 13(2); 454-67. Ó2013 AACR.
“…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).…”
Abstract. The expression patterns of the Dickkopf (Dkk) family of proteins varies in different cancers. In the present study, the expression levels of Dkk1 and Dkk3 were investigated in clear cell renal cell carcinoma (ccRCC) tissues. Dkk1 and Dkk3 serum levels were also examined in patients with ccRCC, and the association between clinicopathological features and Dkk levels was investigated. Serum Dkk1 and Dkk3 were quantified using ELISA in 64 patients with ccRCC and in 30 healthy individuals (controls). The expression levels of Dkk1 and Dkk3 were analyzed in tumor and adjacent normal tissues obtained from patients with ccRCC (n=20) using quantitative polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry. The mean serum levels of Dkk1 and Dkk3 in the patients with ccRCC were significantly lower than those in the healthy controls. Furthermore, the serum Dkk1 levels were significantly lower at higher tumor-node-metastasis stages and tumor grades. qPCR, western blot analysis and immunohistochemistry revealed a significant decrease in the Dkk1 and Dkk3 mRNA and protein levels in the tumor tissues compared with the adjacent normal tissues. Consequently, Dkk1 and Dkk3 may present a novel molecular target for the diagnosis and therapeutic treatment of ccRCC.
“…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).…”
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