Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV-negative tumors is an indicator of poor prognosis

Christian U. Huebbers*, Femke Verhees, Leonard Poluschkin, Nadine C. Olthof, Jutta Kolligs, Oliver G. Siefer, Mieke Henfling, Frans C. S. Ramaekers, Simon F. Preuss, Dirk Beutner, Julia Seehawer, Uta Drebber, Yueksel Korkmaz, Wan L. Lam, Emily A. Vucic, Bernd Kremer, Jens P. Klussmann, Ernst-Jan M. Speel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

Abstract

Different studies have shown that HPV16-positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). Because we showed that integration neither affects the levels of viral genes, nor those of virally disrupted human genes, a genome-wide screen was performed to identify human genes which expression is influenced by viral integration and have clinical relevance. Thirty-three fresh-frozen HPV-16 positive OPSCC samples with known integration status were analyzed by mRNA expression profiling. Among the genes of interest, Aldo-keto-reductases 1C1 and 1C3 (AKR1C1, AKR1C3) were upregulated in tumors with viral integration. Additionally, 141 OPSCC, including 48 HPV-positive cases, were used to validate protein expression by immunohistochemistry. Results were correlated with clinical and histopathological data. Non-hierarchical clustering resulted in two main groups differing in mRNA expression patterns, which interestingly corresponded with viral integration status. In OPSCC with integrated viral DNA, often metabolic pathways were deregulated with frequent upregulation of AKR1C1 and AKR1C3 transcripts. Survival analysis of 141 additionally immunostained OPSCC showed unfavorable survival rates for tumors with upregulation of AKR1C1 or AKR1C3 (both p

Original languageEnglish
Pages (from-to)2465-2477
Number of pages13
JournalInternational Journal of Cancer
Volume144
Issue number10
DOIs
Publication statusPublished - 15 May 2019

Keywords

  • APOT-PCR
  • DIPS-PCR
  • viral integration
  • immunohistochemistry
  • oxidative stress
  • HUMAN-PAPILLOMAVIRUS
  • OXIDATIVE STRESS
  • OROPHARYNGEAL CARCINOMA
  • HEAD
  • CANCER
  • PATHWAY
  • GENOME
  • SURVIVAL

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