Modulation of HPV-dependent phenotype by HAI-1 expression in epithelial stem cells

Author(s)

Bruno Belmonte Martinelli Gomes

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2018-05-03

Examining board members

Katiuchia Uzzun Sales; Aline Corrêa Abrahão; Enilza Maria Espreafico; Ana Paula Lepique

• Advisor: Katiuchia Uzzun Sales

Abstract

Head and neck carcinomas, which are mainly caused by tobacco use and HPV infection are also favoured by the individual genetic predisposition, and are considered the sixth leading cause of cancer worldwide. This type of malignant neoplasm affects about 600,000 new people per year and is also characterised by presenting low survival rates. These low rates are mostly due to (i) the absence of biomarkers; (ii) late diagnosis; and (iii) inespecificity of treatment. High mortality and morbidity rates go along with the disease due to the fact that noble areas of the organism are damaged as a consequence of the aggressive surgical treatment used which, in combination with the radiotherapy, interferes in physiological processes of great importance such as speech and swallowing. Moreover, the more or less aggressive tumour behaviour is a result of the imbalance in the expression of several genes and proteins. In this scenario, many serine proteases, their inhibitors and substrates are altered during the process of carcinogenesis. Matriptase, a transmembrane serine protease that activates pathways related to cell proliferation and survival, has gathered attention for being overexpressed in different cases of cancer. The interaction between this protease and its cognate inhibitor, HAI-1, is of great importance in the prognosis and evolution of different carcinomas. In addition, it is known that HAI-1 overexpression is closely related to a protective effect on lesions caused by increased levels of matriptase. In addition, the same inhibitor is immunohistologically enhanced in cervical carcinomas, a type of cancer caused by HPV infection in more than 90% of cases. In this context and considering the tumorigenic potential of HPV for head and neck carcinomas, transgenic mice that express HAI-1 under the keratin 5 promoter (K5-HAI-1), and mice expressing the E6 oncoproteins and E7 from HPV16 under the keratin 14 promoter (K14-HPV) were used in order to evaluate the possible HAI-1 modulating effect on the phenotype caused by the HPV16 oncogenes. In order to do so, the effects of co-expression of both transgenes on the development of animals were properly observed and the evolution of spontaneous lesions caused by viral oncogenes were quantitatively analysed in the presence or absence of the HAI- 1 transgene. The results indicate that different transgenic animals have a similar development, and finally that HAI-1 expression in epithelial stem cells does not appear to interfere with the appearance and progression of epithelial lesions, which is a characteristic of E6 and E7 expression in the same precursor epithelial cells. (AU)

• FAPESP's process: 16/16715-7 - Regulation of hepatocyte growth factor activator inhibitor-1 (HAI-1) activity by HPV 16 oncogenes E6 and E7
• Grantee: Bruno Belmonte Martinelli Gomes
• Support Opportunities: Scholarships in Brazil - Master