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Impact of of E6/E7 genetic variability upon the oncogenic potential of HPV-18

Grant number: 15/26345-0
Support type:Regular Research Grants
Duration: March 01, 2016 - June 30, 2018
Field of knowledge:Biological Sciences - Biochemistry - Biochemistry of Microorganisms
Principal Investigator:Laura Cristina Sichero Vettorazzo
Grantee:Laura Cristina Sichero Vettorazzo
Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Luisa Lina Villa

Abstract

HPV-16 and HPV-18 are strongly associated with risk of developing cervical cancer. Worldwide, HPV-16 type is the most prevalent type in invasive squamous cell carcinomas of the cervix, followed by HPV-18, whereas HPV-18 is the most prevalent type in adenocarcinoma specimens. HPV-18 intratypic nucleotide variability has been studied resulting in important findings concerning the evolution and phylogeny of the virus and the natural history of infections. In an epidemiological study of the natural history of HPV infection in women conducted in our country, we found that HPV-18 variants and are more associated with persistence of viral infection. Although the studies about the clinical relevance of HPV-18 genetic variability are very limited, overall it is suggested that As+AI and E variants represent variants with a higher oncogenic potential compared to Af variants. Furthermore, it was observed that Af HPV-18 variants are exclusively detected in samples of invasive squamous cell carcinoma of the cervix, whereas variants As+AI and E variants are more prevalent in adenocarcinoma and adenosquamous cell carcinoma. With regard to biological differences between HPV-18 variants, it is crucial to emphasize that the few studies conducted so far explored only the variability of the viral E6 oncoprotein, and most importantly, none of the studies was performed in HPV-18 natural host cell models, which are primary human keratinocytes. For these reasons, this project aims to comprehensively characterize the differential activity of E6/E7 of As+AI, E and Af HPV-18 variants in primary human keratinocytes transduced with these proteins. More specifically, the objective is to examine these cells infected by the different variants concerning the ability to (1) induce degradation of P53; (2) inhibit serum and calcium induced cell differentiation; (3) immortalize human keratinocytes by colony formation assays after low density plating and analysis of telomerase activity; (4) induce EMT phenotype (epithelial-mesenchymal transition); (5) inhibit cell cycle following DNA damage; (6) grow independently of adhesion to the substrate; (7) migrate; (8) invade through collagen matrix; (9) activate cell signaling pathways induced by AKT and MAPK; and (10) form stratified epithelia in raft cultures. (AU)