Upregulation of Aldo-Keto-Reductase 1C1 and 1C3 is associated with poor prognosis in OPSCC independent of HPV status

Introduction:

Studies have shown that HPV16-positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). We showed integration did neither affect the levels of viral genes, nor those of virally disrupted human genes.

Methods:

RNA from 33 HPV-16 positive OPSCC samples (9 integrated, 4 mixed, 20 episomal) was analyzed by mRNA expression profiling using Microarrays. Non-hierarchical clustering and pathway analysis identifyed genes of interest. Aldo-keto-reductases 1C1 and 1C3 (AKR1C1, AKR1C3) expression was confirmed by RT-qPCR and Immunohistochemistry. 141 OPSCC, including 48 HPV-positive cases, were used to validate gene expression by immunohistochemistry. Results were correlated clinically and histopathologically.

Results:

Non-hierarchical clustering resulted in two groups of mRNA expression patterns corresponding to either integrated or episomal viral DNA. Deregulated pathways were identified, in which AKR1C1 and AKR1C3 were predominantly involved. Viral DNA integration corresponded with oxidative stress pathways. Survival analysis of 141 OPSCC showed unfavorable survival rates for those patients with tumors exhibiting upregulation of AKR1C1 or AKR1C3 both in HPV-positive (p ≤0.001) and -negative (p ≤0.017) tumors (together p < 0.0001).

Conclusions:

OPSCCs with integrated HPV16 have upregulated expression of AKR1C1, AKR1C3 and oxidative stress pathway signatures. Upregulation of AKR1Cs very strongly correlates with worse survival rates. Also in HPV-negative tumors, upregulation of these proteins correlates with poor outcome. This agrees with data from other tumors, making these genes promising candidates as indicators of prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.

Publication History

Publication Date:
23 April 2019 (online)