Cellular transcription factors as prognostic biomarker and therapeutic target in tumors induced by human papillomavirus 16 (HPV-16).

• Grant number: 24/13024-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: April 30, 2026
• Field of knowledge: Health Sciences - Collective Health - Epidemiology
• Principal Investigator: Laura Cristina Sichero Vettorazzo
• Grantee: Laura Cristina Sichero Vettorazzo
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Aline Lopes Ribeiro ; Luisa Lina Villa
• Associated scholarship(s): 25/12575-5 - The role of the transcription factor STAT1 in radio and chemoresistance in tumors of the oral cavity and oropharynx: epidemiological and functional approach., BP.DR; 25/19159-7 - Evaluation of MYB transcription factor expression in head and neck squamous cell carcinoma (HNSCC), and its correlation with HPV status and clinicopathological parameters, BP.IC; 25/12531-8 - Impact of the transcription factor TEAD4 on the proliferation and migration of HPV-positive and HPV-negative human keratinocytes., BP.IC; + associated scholarships 25/04602-2 - Role of the transcription factor TEAD4 as a prognostic biomarker in cervical cancer., BP.MS; 25/12132-6 - Role of the transcription factor PPAR¿ in human papillomavirus (HPV)-induced carcinogenesis: an epidemiological and functional approach., BP.DR; 25/06774-5 - Impact of TEAD4 on the transcriptional activity of HPV-16, BP.IC - associated scholarships

Abstract

Persistent infections by high-risk HPVs (human papillomavirus) are associated with the development of cervical, vaginal and vulvar cancer in women, penile cancer in men, in addition to anal canal and oropharyngeal tumors in both genders. Among this group, HPV-16 is worldwide the most prevalent type in cervical carcinomas, followed by HPV-18. In neoplasia of other anogenital sites and the oropharynx, HPV-16 is detected in almost all the tumors attributable to HPV. Although it is possible primary prevention of HPV infection and, consequently, the development of associated diseases using prophylactic HPV vaccines, and the screening of cervical cancer precursor lesions by cytology and HPV testing, these measures require greater adherence of populations mainly in underdeveloped and developing countries where 80% of HPV-induced tumors occur. In general, the stage and extent of cervical and head and neck tumors determine treatment strategy, and may include one or a combination of surgery, radiation (RT) and chemotherapy (CT). Despite important advances in RT and QT, and although a complete response is observed in most patients, resistance is commonly observed throughout treatment. In this context, the discovery and development of new therapies becomes relevant. Furthermore, it is plausible that target-specific therapies have a relevant role in increasing the response to RT and/or QT.The region of the HPV genome required for the immortalization of primary human keratinocytes was mapped to the LCR-E6-E7 viral region. HPV transcription and replication are regulated by the binding of cellular and viral proteins to cis-elements within the LCR (long control region).Cellular phenotype is ultimately determined by gene expression patterns. Genes that regulate critical cellular functions such as survival, proliferation and self-renewal often encode transcripts with short half-lives, so the initiation of transcription is an important control point for the expression of these genes. Thus, the activity of transcription factors (TFs), which coordinate gene expression, are highly regulated. In the context of HPV, it is reasonable to assume that many of the TFs that regulate the expression and consequently the levels of viral oncoproteins may affect the clinical outcome of infections. Several of these so-called oncogenic TFs have been described and have been the focus of epidemiological, basic science, translational, and therapeutic studies.In the last two decades, our laboratory has been interested in evaluating different aspects of the biology and pathogenesis of HPVs in studies based on the analysis of the regulation of viral transcription, with important contributions. In this innovative project, we aim to carry out an integrated epidemiological and therapeutic assessment of the role of selected TFs as prognostic biomarkers, as therapeutic targets for tumors induced by HPV-16, or as factors that increase the response to QT and/or RT. This project is divided into 5 subprojects that will be conducted in parallel and aim to evaluate the FOXA1, STAT1, TEAD4, PARPg and MYB in this scenario. We believe that the results of this study can lead to a better understanding of the molecular mechanisms relevant to HPV-associated tumorigenesis, in addition to generating knowledge that could impact the clinical management of these diseases and/or the development/repurposing of cheaper and more effective drugs for their treatment. (AU)