Universität zu Köln

Ziogas, Maria ORCID: 0000-0002-7130-4015 (2026). Analysis of Expression and Regulation of AKR1C2 in HPV-Positive and -Negative Oropharyngeal Squamous Cell Carcinoma. PhD thesis, Universität zu Köln.

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Abstract

Oropharyngeal squamous cell carcinoma (OPSCC) is a significant subtype of head and neck squamous cell carcinoma (HNSCC) with increasing global incidence, largely due to human papillomavirus (HPV) infection. HPV-positive OPSCC differs epidemiologically and clinically from its HPV-negative counterpart, exhibiting better prognosis and treatment response. Notwithstanding the advances that have been made in the fields of diagnosis and treatment, OPSCC continues to be associated with a high mortality rate. A subset of HPV-positive tumors, despite generally having a more favorable outlook, can exhibit poor prognosis similar to their HPV-negative counterparts. However, this subgroup is still not adequately characterized by diagnostic markers. Oxidative stress has emerged as a crucial factor in OPSCC pathogenesis, influencing tumor progression, therapy resistance, and prognosis. Reactive oxygen species (ROS) contribute to genomic instability, promoting malignant transformation. Aldo-keto reductases (AKRs), particularly AKR1C2, play a pivotal role in oxidative stress response and steroid metabolism in OPSCC. The objective of this research is to examine potential differences in AKR1C2 expression between HPV-positive and HPV-negative OPSCC, as well as within clinically significant subgroups of each. Furthermore, the study seeks to determine how these expression variations relate to patient outcomes in a series of 51 OPSCC tumor samples with known HPV status. In addition, in vitro experiments were conducted using HEK293 cell line models overexpressing the HPV16 E6*I splice variant to investigate its impact on AKR1C transcription and the activation of oxidative stress pathways. Upregulated AKR1C2 expression is associated with a poor prognosis both in HPV-positive and HPV-negative OPSCC. Notably, AKR1C2 expression exhibits sex-specific effects, correlating with improved survival in female patients but poorer outcomes in males when increased. However, the expression of AKR1C2 showed no correlation with Nrf2 expression or with the expression of its family members, AKR1C1 and AKR1C3. Unlike the established regulation of AKR1C1 and AKR1C3, in vitro studies show that increased E6*I expression does not lead to a corresponding increase in AKR1C2 levels. These findings underscore the complex interplay among AKR1C2, HPV, and patient sex, highlighting the need for personalized treatment strategies for OPSCC. Targeted inhibition of AKR1C2, considering sex-specific differences, may enhance therapeutic outcomes. Future research should investigate these mechanisms to enhance treatment efficacy.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Ziogas, Maria mziogas@smail.uni-koeln.de https://orcid.org/0000-0002-7130-4015 UNSPECIFIED
Corporate Creators:	Medizinische Fakultät:Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde der Universität zu Köln, Molecular Head and Neck Oncology, Translational Research in Infectious Diseases and Oncology (TRIO) Research Building, University Hospital of Cologne, 50937 Cologne, Germany
URN:	urn:nbn:de:hbz:38-795972
Date:	2026
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Hals-Nasen-Ohrenheilkunde > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language human papillomavirus; oropharyngeal squamous cell carcinoma; aldo-keto-reductase 1 C2; oxidative stress English
Date of oral exam:	18 September 2025
Referee:	Name Academic Title Klußmann, Jens Peter Universitätsprofessor Dr. med. George, Julie Universitätsprofessorin Dr. rer. nat.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79597