Nappi, Annarita (2021) Thyroid hormone orchestrates the epithelial carcinogenesis through the NANOG-D2-T3-ZEB1 axis. [Tesi di dottorato]

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Keratinocyte carcinomas (KCs), also known as non-melanocytic skin cancers (NMSCs), are the most common cutaneous malignancies diagnosed in fair-skinned populations. Molecular, epidemiologic, and clinical studies have led to understanding of the cellular events that occur during skin tumorigenesis and have provided new strategies for treatment and prevention of KCs. Genomic analyses have uncovered high-risk susceptibility genes, and somatic events that underlie common pathways important in KC tumorigenesis. Moreover, an emerging role for the endocrine therapy in the treatment of skin cancer has also been recognized in recent years. In this context, thyroid hormones (THs) are key endocrine regulators, whose action is critical both in physiological and pathological conditions, as in the case of the two most common subtypes of NMSC, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). In the target tissues THs availability is regulated by the concerted actions of the TH-activating and inactivating enzymes, namely type 2 and type 3 deiodinases (D2 and D3), which act as a cell-specific pre-receptor mechanisms to control TH signaling independently of circulating levels of THs. In the last decade, our group provided the evidence of a functional link between TH, its activating/inactivating enzymes, D2 and D3, and cancer formation. In particular, we demonstrated that: i) type 3 deiodinase (D3) enhances the proliferation of normal and malignant keratinocytes (1); ii) in the basal cell carcinoma (BCC) D3 is under the control of sonic hedgehog and is highly expressed in the early phases of tumorigenesis (2); iii) the microRNA-21 up-regulates D3 thereby reducing the TH level in BCC (3); iv) the concerted action of type 2 and type 3 deiodinases regulates the cell cycle and survival of basal cell carcinoma cells (4). While the role of D3 has been investigated in the growth and differentiation of keratinocytes, both in pathological and in cancerous skin contexts, the effective role of TH D2-produced in the cancer progression was never been clarified. In this PhD program, we investigated the functional implication of D2 in KCs, identifying a comprehensive mechanistic insights into the regulation of D2 in cutaneous tumors (4). Elucidating the functional role of THs and tissue-specific modulation of deiodinases in tumorigenesis is crucial for the use of hormonal regulation as a new tool in a therapeutic context.

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