Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification.
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/beta-catenin (CTNNB1) signaling might account for this as MYC is a beta-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 beta-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant beta-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 beta-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated beta-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 beta-catenin signaling providing a potential candidate pathway for therapeutic inhibition.
Liu
X
X
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
Mazanek
P
P
Dam
V
V
Wang
Q
Q
Zhao
H
H
Guo
R
R
Jagannathan
J
J
Cnaan
A
A
Maris
J M
JM
Hogarty
M D
MD
D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000502:physiology*
C495270:CTNNB1 protein, human; C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin