Target genes of the WNT/beta-catenin pathway in Wilms tumors.
The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Physiological Chemistry I, Biozentrum, University of Wuerzburg, Germany.
Birgit
B
Zirn
Birgit
B
Samans
Stefanie
S
Wittmann
Thorsten
T
Pietsch
Ivo
I
Leuschner
Norbert
N
Graf
Manfred
M
Gessler
D018076:DNA, Complementary / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008954:Models, Biological; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
D018076:DNA, Complementary; D051153:Wnt Proteins; D051176:beta Catenin