Role of the transcription factor TEAD4 as a prognostic biomarker in cervical cancer.

• Grant number: 25/04602-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2025
• End date: May 31, 2027
• Field of knowledge: Health Sciences - Collective Health - Epidemiology
• Principal Investigator: Laura Cristina Sichero Vettorazzo
• Grantee: Beatriz Gonzalez Bueno
• Host 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
• 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 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 carcinoma, 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).In the context of HPV infections, it is reasonable to suppose that many of the TFs (transcription factors) that regulate the expression and, consequently, the levels of viral oncoproteins can 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.TEAD4 is a TF that plays a relevant role in cell proliferation and survival, tissue regeneration, and stem cell maintenance. Functionally, TEAD4 is involved in different cancer hallmarks including metastasis, EMT, and chemoresistance. High levels of TEAD4 are detected in several tumor tissues, suggesting that this protein may play an important role as a prognostic biomarker in gastric tumors, melanoma, and head and neck cancer (HNSCC). Regarding HNSCC, it was observed that TEAD4 mRNA and protein levels were significantly increased compared to adjacent tumor tissue and were also significantly associated with lymph node metastasis, advanced clinical stage, and shorter overall and disease-free survival. However, the role and mechanism of the YAP/TAZ-TEAD4 pathway in cervical cancer remain to be clarified. In our laboratory, it was observed that TEAD4 potentially induces the transcriptional activity of HPV-16. Furthermore, in silico analysis indicated putative binding sites to the HPV-16 LCR, indicating that this TF may play an important role in HPV-induced tumorigenesis by increasing the levels of viral oncoproteins.This project aims to investigate the role of TEAD4 as a prognostic biomarker in HPV-induced cervical carcinogenesis. Our hypothesis is that high TEAD4 expression contributes to HPV-associated carcinogenesis by activating viral transcription and thus impacting high levels of the viral oncoproteins E6 and E7. In this case, high TEAD4 expression could be used as a biomarker of tumor progression, in addition to constituting an important therapeutic target in HPV-induced tumors. (AU)