Introduction:
At least two subgroups of OPSCC (Oropharyngeal Squamous Cell Carcinoma) can be distinguished
based on high-risk Human Papillomavirus (HPV) infection, namely HPV16. We showed that
upregulation of Aldo-Keto-Reductases (AKR) 1C1 and 1C3 is strongly associated with
poor prognosis irrespective of HPV-status. However, our data suggest that expression
of these proteins might be induced by independent mechanisms in HPV+ and HPV-tumors.
Methods:
We performed a bioinformatic analysis of the AKR1C1-C4 promotor regions located on
Chromosome 10p15 – 14 in a clinical cohort of patients preselected for good clinical
response (n = 26) and appearance of local/distant recurrence (n = 26). AKR1C3 expression
was confirmed by immunohistochemistry of 52 FFPE tumor samples from primary OPSCC
(n = 26 HPV+, n = 26 HPV-) with additional n = 16 samples from corresponding lymph
node metastases. Tumor regions were microdissected for DNA extraction and pyrosequencing
was performed to determine methylation status of CpG islands in the promoter region
of AKR1C3. Results were correlated with clinical and histopathological data.
Results:
The analysis revealed two promising CpG islands upstream of AKR1C3 correlating with
potential C/EBP and SP-1 transcription factor binding sites. Upregulation of AKR1C3
showed poor prognosis for those tumors with unfavorable clinical response (p = 0.0024).
CpG methylation analysis correlated with induction of AKR1C3 expression in HPV- but
not HPV+ tumor samples.
Conclusions:
Our findings show that HPV-tumors presenting AKR1C3 expression correlated with methylation
status of the identified CpG islands, whereas HPV-tumors without AKR1C3 expression
did not. Protein expression in HPV+tumors might be regulated by an independent mechanism
subject of ongoing analysis.
