Feo, Federica (2020) Identification of FOXE1 biological functions in Non-Melanoma Skin Cancers (NMSC). [Tesi di dottorato]

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FOXE1 is a thyroid–specific transcription factor belonging to the family of the Forkhead box (FOX) proteins, an evolutionarily conserved group of transcriptional regulators with a central role in a variety of developmental and physiological processes. Alterations in the FOX genes function is often associated to cancer. FOXE1 mutations are causative of the Bamforth-Lazarus syndrome, characterized by congenital hypothyroidism, cleft palate and spiky hair. Our findings have shown that in Basal Cell Carcinoma (BCC), the most common type of human cancer, the constitutive induction of the Sonic Hedgehog pathway leads to a strong upregulation of Foxe1 expression. In contrast, FOXE1 is absent in the more aggressive Squamous Cell Carcinoma (SCC), which is associated with a substantial risk of metastasis. Here we show that FOXE1 acts as a selective regulator of BCC formation, resulting in inhibition of cell proliferation and migration. We identified its putative targets genes in skin, revealing a positive correlation between Foxe1 expression and genes modulating the extracellular matrix structure and the cell-matrix interactions, actin cytoskeleton organization and regulation of cell adhesion. Accordingly, functional assays revealed that its expression negatively affects cell migration and increases cell adhesion. Moreover, we found that its expression is negatively correlated with cell cycle progression, resulting in an increased self-renewal capacity when depleted in BCC cells. Importantly, these in vitro findings correlate with studies in vivo. Using two distinct BCC mouse models, K5-Gli2 and K14-CreER; SmoM2, we demonstrate that Foxe1 is an important determinant of BCC architecture in vivo and that is likely to have a significant impact on BCC formation and maintenance by conferring at least in part the well-organized poorly invasive structure of this tumor. We propose a novel intriguing role for this transcription factor, which seems to play a negative contribution in skin tumorigenesis. These observations apparently odd for a gene overexpressed in cancer, may explain at least in part the relative slow proliferation rate and aggressiveness of BCC as compared to more invasive SCC.

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