Canonical WNT signalling determines lineage specificity in Wilms tumour

被引:50
作者
Fukuzawa, R. [1 ]
Anaka, M. R. [1 ]
Weeks, R. J. [1 ]
Morison, I. M. [1 ]
Reeve, A. E. [1 ]
机构
[1] Univ Otago, Dept Biochem, Canc Genet Lab, Dunedin, New Zealand
关键词
WTX; cancer stem cell; nephrogenic rest; mesenchymal stem cell; multiplex ligation-dependent probe amplification; GROWTH-FACTOR-II; BETA-CATENIN; STEM-CELLS; NEPHROGENIC RESTS; CTNNB1; MUTATIONS; TARGET GENES; WT1; CANCER; OVEREXPRESSION; PATHOGENESIS;
D O I
10.1038/onc.2008.455
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of beta-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of beta-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of beta-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.
引用
收藏
页码:1063 / 1075
页数:13
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