Studying the role of survivin in basal cell carcinoma initiation

• Autor(a) principal: Cardoso, Erik Caeiro
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/127586
• topic: Carcinoma Basocelular; Basal Cell Carcinoma; Ciências Médicas

Abstract Basal cell carcinoma (BCC) is the most common human cancer, with more than 5 million new cases diagnosed each year. BCC arises from the constitutive activation of the Hedgehog signalling pathway in epidermal basal cells. Loss-of-functions mutations of the patched 1 (PTCH1) gene and gain-of-function mutations of the smoothened (SMO) gene are among the most common genetic alterations leading to BCC formation in patients. Recent studies have demonstrated that only stem cells (SCs) residing at the interfollicular epidermis, and not committed cell progenitors (CPs), are competent to originate a BCC upon the expression of an oncogenic form of the smoothened gene (SmoM2). However, the mechanisms that mediate the competence of SCs and the resistance of CPs to initiate tumour formation are still poorly understood. Data from the host lab reported that survivin, an anti-apoptotic protein involved in the control of cell proliferation is upregulated in SCs when compared to CPs, upon SmoM2 expression. Here, we studied the potential role of survivin in conferring competence to BCC initiation. To this end, we combined genetic mouse models of BCC, immunofluorescence in skin whole-mounts, and imaging, to assess: (1) whether the deletion of survivin in epidermal SCs prevents BCC formation and (2) whether survivin overexpression in epidermal CPs leads to tumour initiation. Our analysis revealed that survivin deletion in SmoM2-expressing SCs hampers tumour formation. Upon oncogenic SmoM2 activation and survivin deletion, SCs originated preneoplastic lesions that did not evolve into BCC formation. Our results also indicated that survivin overexpression in SmoM2-expressing CPs increases clone size, which allowed for some clones to develop into a BCC. Together, these results suggest that survivin expression promotes clonal expansion upon oncogenic Hedgehog signalling, conferring the ability for BCC formation. However, further studies are necessary to understand whether the competence to tumour formation mediated by survivin is dependent on the inhibition of apoptosis, on the increase of cell proliferation, or both. This study provides evidence which indicate that in the future, therapies targeting survivin could present promising strategies to prevent tumour progression.