D'Auria, Ludovica (2024) Unraveling the role of p73: from healthy skin to Cutaneous Squamous Cell Carcinoma. [Tesi di dottorato]

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Abstract

The skin is a vital protective barrier that undergoes constant renewal orchestrated through intricately regulated processes of keratinocyte proliferation and differentiation. The transcription factor p63 acts as a master regulator of epidermal specific genes. Although p73, a p63 paralog, is also expressed in epidermis and forms functional heterotetramers with p63, much less in known about its function. The aim of our study was to elucidate the roles of p73 in these processes under physiological and cancerous conditions. Four mouse models were employed: control (CTR), epidermal-specific p73 depletion (p73KO), heterozygous p63 expression (p63HET), and simultaneous depletion of p73 with half-dose p63 (p73KO; p63HET). Our data revealed that p73, in collaboration with p63, plays a crucial and previously unsuspected role in supporting keratinocyte proliferation and differentiation, modulating the delicate balance between these processes in the skin. The absence of p73, both in keratinocytes and inflamed skin conditions, led to decreased cell proliferation and increased early and late markers of terminal differentiation, a phenotype distinct from that of p63. Since we have previously found that both p63 and p73 are overexpressed in squamous cell carcinoma (SCC), we tested the possibility that p73 may be relevant for skin carcinogenesis. To this end we applied a skin carcinogenesis on the mouse models described above. Notably, the absence of p73 resulted in a significantly lower tumor incidence compared to control mice, with an even more pronounced reduction in tumor formation in p73KO;p63HET mice, highlighting the crucial involvement of these genes in the complex molecular processes governing skin tumorigenesis. Our investigation identified a temporal window during which p73 and p63 play a key role in tumor initiation, potentially promoting or facilitating tumor initiation. Transcriptomic analysis on keratinocytes and on epidermis under inflammatory conditions confirmed previously identified biological processes, i.e. reduced cell proliferation and increased terminal differentiation in p73KO, and p73KO;p63HET, and revealed significant regulation in the electron transport chain when p73 was absent in keratinocytes. By combining ChIPseq analysis and RNAseq data, we identified several target genes regulated by p63 and p73. Further exploration of the distinct roles of p73 isoforms in cellular metabolism, along with their relevance to cancer biology, is crucial for advancing our understanding and exploring potential applications in cancer research and treatment.

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