MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3.
Neuroblastoma is the most common extra-cranial solid childhood cancer; it arises from neural crest-derived cells of the sympathetic nervous system. The anomalous regulation of embryonic developmental pathways like Delta-Notch and Wnt has been implicated in aberrant cell growth and differentiation in many (childhood) tumours. We have previously found regulation of Delta-Notch pathway genes by the MSX1 neural crest development gene in a neuroblastoma cell line, and significant correlations between these genes in neuroblastic tumours. However, a clear role for the Wnt pathway in neuroblastic tumours has not yet been determined. We now analyze the complete spectrum of genes regulated by inducible expression of MSX1 in the SJNB8 neuroblastoma cell line using Affymetrix expression profiling. We show that MSX1 induces the expression of four different Wnt pathway inhibitor genes: Dickkopf 1-3 (DKK1-3) and secreted frizzled-related protein 1 (SFRP1), and provide evidence that high expression of two of these genes correlates with good prognosis. We were able to demonstrate that both the canonical Wnt3 and the alternative Wnt5A ligands are highly expressed in neuroblastic tumours and cell lines, and specifically activate the DVL3 Wnt co-receptor protein in SJNB8 neuroblastoma cells. These results suggest involvement of MSX1 in Wnt signalling and demonstrate activity of the more upstream Wnt pathway in neuroblastic cells.
Revet
Ingrid
I
Department of Human Genetics, Academic Medical Center, University of Amsterdam, AZ Amsterdam, The Netherlands.
Huizenga
Gerda
G
Koster
Jan
J
Volckmann
Richard
R
van Sluis
Peter
P
Versteeg
Rogier
R
Geerts
Dirk
D
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015152:Blotting, Northern; D015153:Blotting, Western; D018925:Chemokines; D000072261:Dishevelled Proteins; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics*; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D000072261:Dishevelled Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases; D051957:MSX1 Transcription Factor; D008565:Membrane Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D051176:beta Catenin; C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; C498622:DKK2 protein, human; C498624:DKK3 protein, human; C000606584:DVL3 protein, human; C484083:MSX1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C555507:WNT3 protein, human; C085389:WNT5A protein, human