Abstract
Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/β-catenin (CTNNB1) signaling might account for this as MYC is a β-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and β-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant β-catenin–TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical β-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated β-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered β-catenin signaling providing a potential candidate pathway for therapeutic inhibition.
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Acknowledgements
We thank Garrett Brodeur and Mariucz Ratajczak (University of Pennsylvania) for providing cell lines, Kathleen R Cho and Rong Wu (University of Michigan) for assistance with β-cat:TCF reporter assays, Bert Vogelstein (Johns Hopkins University) for β-catenin reporter constructs, the Children's Oncology Group (COG) for primary NB materials, Eric Rappaport (Nucleic Acids/Protein Core at CHOP) for oligonucleotide array assistance, Francis Giardiello (Johns Hopkins Hereditary Colorectal Cancer Registry) for information on neuroblastic tumors in FAP kindreds and Harriet Pais for bioinformatics assistance. This work was supported in part by P01-CA97323, a Career Development Award from the Burroughs Wellcome Fund and the Richard and Sheila Sanford Chair in Pediatric Oncology (MDH).
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Liu, X., Mazanek, P., Dam, V. et al. Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification. Oncogene 27, 1478–1488 (2008). https://doi.org/10.1038/sj.onc.1210769
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DOI: https://doi.org/10.1038/sj.onc.1210769
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