Oral Cancer: from genomic landscape to tumor immunobiology

• Autor(a) principal: Tomás, Inês Martins
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/52846
• topic: Head and neck squamous cell carcinoma (HNSCC); Whole exome sequencing (WES); 4-nitroquinoline-1-oxide (4NQO); Keratin 76 (Krt76); Thymus; Regulatory T cells (Tregs); Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

It is estimated that cancer will cause 9.6 million deaths and 18.1 million new patients diagnosed during 2018. Within this number, over 350 000 have oral tumors with tobacco and alcohol consumption identified as the biggest risk factors. Cancer research is still missing a comprehensive model that mimics human cancer as a whole. Therefore, the aim of this study was to analyse an experimental model that accurately mimics human cancer. To this end we treated mice with the carcinogen 4-nitroquinoline-1-oxide in the drinking water for over 16 weeks. This allowed us to induce differently graded tumors in mice tongue oral cavity. We performed whole-exome sequencing of the tumors and the analysis confirmed similarities with human oral cancer genomic landscape. This study allowed us to gain new insight on the genomic progression of oral cancer and to explore an animal model that mimics not only the histological changes but also the genetic alterations observed in human oral cancer. Previous work has shown that knockout mice for keratin 76 are more susceptible to develop oral cancer due to increased and over-suppressive regulatory T cells in the absence of keratin 76. However, the link between the loss of keratin 76 and these changes in the immune system remains unknown. Keratin 76 is progressively more expressed in mice thymus with aging and there is a parallel with the Hassall’s corpuscles in human thymus. We showed that mice lacking keratin 76 present bigger thymic medullary regions and hypothesise one of the targets in the thymus to be Aire since its expression is reduced in the knockout. This study suggested an important role for keratin 76 in regulating the immune system.