Characterization of microRNA regulation and function in developmental and tumorigenic processes

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MicroRNAs are short, non-coding RNAs identified in a broad range of eukaryotes. They regulate gene expression by targeting coding mRNAs for cleavage or translational blockage. In a variety of species, microRNAs have been linked to developmental processes and have recently been implicated in tumorigenesis. The proposed project will focus on the role of microRNAs in epithelial plasticity and thus contribute to our understanding of microRNA function in development, tumorigenesis and tumor progression. First, microRNAs will be characterized at the transition from epithelial to mesenchymal cells (EMT), which is important in development and metastasis. Expression differences during EMT have already been determined. Target genes, function and effects on EMT signaling pathways of the regulated microRNAs will be characterized. Since EMT is an essential process in metastasis, microRNA expression will be analyzed in metastasis samples and their effect on migration and invasion will be studied. During kidney development, the process of EMT is reversed and cells undergo mesenchymal to epithelial transition (MET). Therefore, microRNA function will be characterized in kidney development and Wilms tumorigenesis in the second part of the project. Expression of microRNAs has already been profiled in Wilms tumors, fetal and adult kidney. For microRNAs at least tenfold regulated, target genes, function and signaling pathways will be identified. Particularly, two microRNAs overexpressed in Wilms tumors will be of special interest since they are processed from an intron of IGF2 - a gene that is intimately linked to Wilms tumorigenesis. In summary, these studies shall make a valuable contribution to elucidate the role of microRNAs in development, tumorigenesis and metastasis.