Role of the transcription factor PPAR¿ in human papillomavirus (HPV)-induced carcinogenesis: an epidemiological and functional approach.

• Grant number: 25/12132-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: June 30, 2026
• Field of knowledge: Health Sciences - Collective Health - Epidemiology
• Principal Investigator: Laura Cristina Sichero Vettorazzo
• Grantee: Cristiana de Jesus Costa Cavalieri
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). São Paulo , SP, Brazil
• Associated research grant: 24/13024-0 - Cellular transcription factors as prognostic biomarker and therapeutic target in tumors induced by human papillomavirus 16 (HPV-16)., AP.R

Abstract

Persistent infections by high-risk HPVs (human papillomavirus) are associated with thedevelopment of cervical, vaginal and vulvar cancer in women, penile cancer in men, in addition toanal canal and oropharyngeal tumors in both genders. Among this group, HPV-16 is worldwide themost prevalent type in cervical carcinomas, followed by HPV-18. In neoplasia of other anogenitalsites 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 ofassociated diseases using prophylactic HPV vaccines, and the screening of cervical cancer precursorlesions by cytology and HPV testing, these measures require greater adherence of populationsmainly in underdeveloped and developing countries where 80% of HPV-induced tumors occur. Ingeneral, 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). Despiteimportant 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 anddevelopment of new therapies becomes relevant. Furthermore, it is plausible that target-specifictherapies 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 keratinocyteswas mapped to the LCR-E6-E7 viral region. HPV transcription and replication are regulated by thebinding 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 regulatecritical cellular functions such as survival, proliferation and self-renewal often encode transcriptswith short half-lives, so the initiation of transcription is an important control point for theexpression of these genes. Thus, the activity of transcription factors (TFs), which coordinate geneexpression, are highly regulated. In the context of HPV, it is reasonable to assume that many of theTFs that regulate the expression and consequently the levels of viral oncoproteins may affect theclinical outcome of infections. Several of these so-called oncogenic TFs have been described andhave 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 thebiology and pathogenesis of HPVs in studies based on the analysis of the regulation of viraltranscription, with important contributions. In this innovative project, we aim to carry out anintegrated epidemiological and therapeutic assessment of the role of selected TFs as prognosticbiomarkers, as therapeutic targets for tumors induced by HPV-16, or as factors that increase theresponse to QT and/or RT. This project aims to evaluate PARP¿ in this scenario. The results of thisstudy can lead to a better understanding of the molecular mechanisms relevant to HPV-associatedtumorigenesis, in addition to generating knowledge that could impact the clinical management ofthese diseases and/or the development/repurposing of cheaper and more effective drugs for theirtreatment.