Oncogenic functions of beta-human papillomavirus genomes and risk factors for cutaneous squamous cell carcinomas in human keratinocytes

• Applicant: Professor Dr. Frank Stubenrauch
• Subject Area: Virology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504072750

Beta-human papillomaviruses (HPV) have been suspected to contribute to cutaneous squamous cell cancer (cSCC) in epidermodysplasia verruciformis (EV) patients and organ transplant recipients. Currently, physiologically relevant tissue culture systems that support beta-HPV genome replication allowing the analysis of oncogenic properties of viral genomes and the influence of risk factors for cSCC development such as EV-susceptibility genes and UV irradiation on the viral replication cycle have not been reported. Our preliminary work indicates that beta-HPV8, 38 and 49 replicate in normal human keratinocytes (NHK), the in vivo target cell. Our analyses also surprisingly reveal, that the HPV49 genome only immortalizes NHK, when the viral E8^E2 repressor is inactivated (E8-), indicating that immortalization is restricted at the level of gene expression. Immortalization of HPV49 E8-genomes is dependent on the viral E6 and E7 oncoproteins. Aim of the project is to determine the contributions of cellular E6 and E7 interaction partners, such as p53, MAML1 (Mastermind-like protein 1), pRB, and PTPN14 (Tyrosine-protein phosphatase non-receptor type 14), to keratinocyte immortalization and beta-HPV replication. Furthermore, it will be tested, if the EV-susceptibility genes TMC6 (Transmembrane channel-like protein 6), TMC8 (Transmembrane channel-like protein 8), and CIB1 (Calcium and integrin-binding protein 1) act as restriction factors for beta-HPV in keratinocytes.

• DFG Programme: Research Grants