Upregulation of Aldo-Keto-Reductase 1C2 is associated with unfavourable prognosis in subgroups of OPSCC

Introduction:

Previous studies of our group showed that increased expression of the oxidative stress response genes AKR1C1 and C3 correlate with unfavorable prognosis both in subgroups of HPV-positive and -negative OPSCC. Here, we analyzed expression of the close homolog AKR1C2, which is involved in the metabolism of steroid hormones, prostaglandins and turnover of tobacco smoke components with distinct substrate specificities differing from AKR1C1 and AKR1C3.

Materials and Methods:

To analyze the AKR1C2 protein expression, immunohistochemistry was performed in a series of OPSCC preselected for good clinical performance (n = 26) or treatment failure (n = 26). Both groups included equal amounts of HPV-positive and -negative tumors. Results were correlated with clinical and histopathological data.

Results:

Overexpression of AKR1C2 in tumor tissue compared to adjacent normal epithelium correlated with unfavorable 5-year survival rates in subgroups with good and worse clinical performance (p = 0.0007) and interestingly in female patients (p = 0.0122).

No correlation was observed in respect to HPV positivity, T- and N-stage or risk factors like nicotine or alcohol consumption.

Conclusion:

Whereas the AKR1C2 gene is located in close proximity to the AKR1C3 promoter region, both enzymes showed different expression profiles indicating independent regulation. In contrast to AKR1C3, no correlation with HPV-positivity could be observed. However, overexpression correlated with unfavorable prognosis in female patients. Recently it was shown that female steroid hormones significantly inhibit the capability of AKR1C2 to detoxify nicotine-derived nitrosamine ketones (NKK). The availability selective drugs targeting AKR1C gene products may be utilized for individualized treatment in future.

Publication History

Publication Date:
23 April 2019 (online)