Gene Expression in Wilms Tumor: Disturbance of the Wnt Signaling Pathway and MicroRNA Biogenesis

ABSTRACT

Wilms tumor (WT) originates from the metanephric blastemal cells that are unable to complete the mesenchymal–epithelial transition, resulting in a tumor with triphasic histology, including blastemal, epithelial, and stromal components. WT shows morphological and molecular characteristics that resemble the fetal kidney. Thus, the study of molecular pathways relevant to normal kidney differentiation provides insight into the events that drive Wilms tumorigenesis. The Wnt signaling pathway has been shown to be crucial for correct kidney differentiation. This pathway is activated by WNT proteins and consists of two highly connected main branches: the canonical (or β-catenin dependent) and the noncanonical (or β-catenin independent). Both branches are essential for controlling embryonic development and adult cell homeostasis. The activation of the canonical Wnt pathway leads to the nuclear accumulation of β-catenin, which acts as a coactivator for transcription factors. In the absence of WNT ligands, this pathway is inactivated by a destruction complex that phosphorylates β-catenin, leading to ubiquitination, proteasomal degradation, and the prevention of β-catenin accumulation in the nucleus. In this context, the expression and mutation analyses of genes involved in Wnt signaling pathways constitute an important approach for understanding WT etiology. Although the activation of the Wnt pathway is well understood in WT samples relative to normal kidney tissue or differentiated kidney cells, there is a remarkable variation among subgroups of WTs. Recently, five WT subgroups were identified, mainly through the use of gene expression data, and only two of them showed clear evidence of Wnt pathway activation, as measured by the presence of β-catenin in the nucleus. Interestingly, some of these subgroups exhibited recurrent germline or somatic mutations in genes involved in microRNA biogenesis, such as DROSHA and DICER. Here, we will review relevant findings regarding Wilms tumorigenesis as revealed by gene expression and mutation analyses, mainly in genes belonging to the Wnt signaling and microRNA biogenesis pathways.