Skin cancers are the most common types of cancer in the caucasian population, and their incidence has reached epidemic proportions. In addition to skin cancer, inflammatory skin diseases are also extremely common. For the development of novel therapies for skin diseases it is essential to unravel the mechanisms that regulate skin homeostasis and pathological alterations. Recently, the host laboratory made the surprising observation that fibroblast growth factor receptor (FGFR) signalling has a tumor-suppressive function in the epidermis, since loss of FGFR1 and FGFR2 in mouse keratinocytes resulted in the development of skin inflammation, followed by spontaneous formation of carcinomas. The goal of the proposed project is to unravel the mechanisms underlying the functions of FGFRs in the epidermis with a particular focus on micro-RNAs (miRNAs). These small RNAs are emerging as new key players in the regulation of cancer-associated pathways in various tissues. However, FGF-regulated miRNAs in the skin remain to be characterized. FGF-regulated miRNAs and their targets will be identified starting from a combination of miRNA and mRNA profiling of RNA samples from epidermis of control and FGFR mutant mice at different stages of postnatal development and of tumors. Preliminary bioinformatic analysis already identified 5 miRNAs that show significant differences in expression between mutant and control mice. Accordingly, the expression level of more than 300 mRNAs was altered. Based on these data, we will identify those miRNAs that are expressed in keratinocytes in an FGF-dependent manner and we will characterize their functions and the relevant targets in cultured keratinocytes and in normal, inflamed and tumorigenic skin in vivo. Since miRNAs have already been proven to be valuable targets for the treatment of many human diseases, the proposed project has the potential to identify new possible targets for the therapy of major human skin diseases.
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