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Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV‐negative tumors is an indicator of poor prognosis
Author(s) -
Huebbers Christian U.,
Verhees Femke,
Poluschkin Leonard,
Olthof Nadine C.,
Kolligs Jutta,
Siefer Oliver G.,
Henfling Mieke,
Ramaekers Frans C.S.,
Preuss Simon F.,
Beutner Dirk,
Seehawer Julia,
Drebber Uta,
Korkmaz Yüksel,
Lam Wan L.,
Vucic Emily A.,
Kremer Bernd,
Klussmann Jens P.,
Speel ErnstJan M.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31954
Subject(s) - downregulation and upregulation , cancer research , expression (computer science) , medicine , oncology , biology , computer science , genetics , gene , programming language
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.