Universität zu Köln

Huebbers, Christian U., Verhees, Femke, Poluschkin, Leonard ORCID: 0000-0002-2727-2765, Olthof, Nadine C., Kolligs, Jutta, Siefer, Oliver G., Henfling, Mieke, Ramaekers, Frans C. S., Preuss, Simon F., Beutner, Dirk, Seehawer, Julia, Drebber, Uta, Korkmaz, Yueksel, Lam, Wan L., Vucic, Emily A., Kremer, Bernd, Klussmann, Jens P. and Speel, Ernst-Jan M. (2019). Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV-negative tumors is an indicator of poor prognosis. Int. J. Cancer, 144 (10). S. 2465 - 2478. HOBOKEN: WILEY. ISSN 1097-0215

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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 <0.0001), both in HPV-positive (p <= 0.001) and -negative (p <= 0.017) tumors. OPSCC with integrated HPV16 show upregulation of AKR1C1 and AKR1C3 expression, which strongly correlates with poor survival rates. Also in HPV-negative tumors, upregulation of these proteins correlates with unfavorable outcome. Deregulated AKR1C expression has also been observed in other tumors, making these genes promising candidates to indicate prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Huebbers, Christian U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verhees, Femke UNSPECIFIED UNSPECIFIED UNSPECIFIED Poluschkin, Leonard UNSPECIFIED orcid.org/0000-0002-2727-2765 UNSPECIFIED Olthof, Nadine C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolligs, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Siefer, Oliver G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Henfling, Mieke UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramaekers, Frans C. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Preuss, Simon F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Beutner, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Seehawer, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Drebber, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Korkmaz, Yueksel UNSPECIFIED UNSPECIFIED UNSPECIFIED Lam, Wan L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vucic, Emily A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremer, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Klussmann, Jens P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Speel, Ernst-Jan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-148194
DOI:	10.1002/ijc.31954
Journal or Publication Title:	Int. J. Cancer
Volume:	144
Number:	10
Page Range:	S. 2465 - 2478
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN-PAPILLOMAVIRUS; OXIDATIVE STRESS; OROPHARYNGEAL CARCINOMA; HEAD; CANCER; PATHWAY; GENOME; SURVIVAL Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14819