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| Author(s): |
Valéria Talpe Nunes
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2024-12-13 |
| Examining board members: |
Laura Cristina Sichero Vettorazzo;
Roger Chammas;
Claudimara Ferini Pacicco Lotfi;
Giovana Tardin Torrezan
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| Advisor: | Laura Cristina Sichero Vettorazzo |
| Abstract | |
The persistent infection by high-risk oncogenic human papillomaviruses (HPV) is associated with the development of cervical cancer, and tumors in anogenital regions as the vulva, vagina, penis, anal canal, in addition to the oropharynx. Several cellular transcription factors (TF) bind to the viral LCR and can regulate HPV transcriptional activity, modulating the expression of the E6 and E7 open reading frames (ORF), which comprises the main oncoproteins that interact with cellular pathways to maintain a favorable cellular ambient to the virus, and possible lead to a tumorigenic process. Given the importance of the binding sites of cellular TFs in the LCR, the nucleotide variability in this region could be an important factor contributing to the differential oncogenic potential between different HPV types and sublineages. Thus, we evaluated the impact of over 500 human TFs upon the transcriptional activity of the early promoter of HPV-16 (P97) and HPV-18 (P105) with a double luciferase expression assay. We transfected C33A cells with cDNA expression plasmids of each TFs and plasmids containing the complete region of the LCR and early promoter of the different HPV types and sublineages controlling the firefly luciferase gene. The renilla luciferase was used as the assay normalizer. In total, we identified 130 TFs with a differential impact upon the transcriptional activity of HPV-16 and -18, and among those, 70 TFs had an impact over or bellow two times the basal early promoter activity. Putative binding site in silico analysis shown that 27 of these TFs could directly bind to the viral LCR. We selected six TFs among these possible interactors for further validation: HOXB13, NR2E1, c-MYB, GATA3, FOXO1 and TBX21, confirming or not the impact of these TFs over the transcriptional activity of HPV-16 and -18. Thus, the TFs identified in our study could lead to new therapeutic targets to treat tumors associated with high-risk HPV infection, and further elucidate the molecular mechanisms of viral transcriptional regulation (AU) | |
| FAPESP's process: | 19/05141-8 - Identification of transcription factors with potential therapeutic effect in cells infected by different variants of HPVs 18 and 16 |
| Grantee: | Valéria Talpe Nunes |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |