AKR1C3 is a biomarker and druggable target for oropharyngeal tumors

Cell Oncol (Dordr). 2021 Apr;44(2):357-372. doi: 10.1007/s13402-020-00571-z. Epub 2020 Nov 19.


Purpose: Oropharynx squamous cell carcinoma (OPSCC) is a subtype of head and neck squamous cell carcinoma (HNSCC) arising from the base of the tongue, lingual tonsils, tonsils, oropharynx or pharynx. The majority of HPV-positive OPSCCs has a good prognosis, but a fraction of them has a poor prognosis, similar to HPV-negative OPSCCs. An in-depth understanding of the molecular mechanisms underlying OPSCC is mandatory for the identification of novel prognostic biomarkers and/or novel therapeutic targets.

Methods: 14 HPV-positive and 15 HPV-negative OPSCCs with 5-year follow-up information were subjected to gene expression profiling and, subsequently, compared to three extensive published OPSCC cohorts to define robust biomarkers for HPV-negative lesions. Validation of Aldo-keto-reductases 1C3 (AKR1C3) by qRT-PCR was carried out on an independent cohort (n = 111) of OPSCC cases. In addition, OPSCC cell lines Fadu and Cal-27 were treated with Cisplatin and/or specific AKR1C3 inhibitors to assess their (combined) therapeutic effects.

Results: Gene set enrichment analysis (GSEA) on the four datasets revealed that the genes down-regulated in HPV-negative samples were mainly involved in immune system, whereas those up-regulated mainly in glutathione derivative biosynthetic and xenobiotic metabolic processes. A panel of 30 robust HPV-associated transcripts was identified, with AKR1C3 as top-overexpressed transcript in HPV-negative samples. AKR1C3 expression in 111 independent OPSCC cases positively correlated with a worse survival, both in the entire cohort and in HPV-positive samples. Pretreatment with a selective AKR1C3 inhibitor potentiated the effect of Cisplatin in OPSCC cells exhibiting higher basal AKR1C3 expression levels.

Conclusions: We identified AKR1C3 as a potential prognostic biomarker in OPSCC and as a potential drug target whose inhibition can potentiate the effect of Cisplatin.

Keywords: AKR1C3; Biomarker; Cisplatin; HPV status; Oropharynx cancer; Prognosis; Target therapy.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aldo-Keto Reductase Family 1 Member C3 / genetics
  • Aldo-Keto Reductase Family 1 Member C3 / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Down-Regulation / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Ontology
  • Gene Regulatory Networks
  • Humans
  • Male
  • Middle Aged
  • Oropharyngeal Neoplasms / genetics
  • Oropharyngeal Neoplasms / metabolism*
  • Oropharyngeal Neoplasms / pathology
  • Oropharyngeal Neoplasms / virology
  • Papillomavirus Infections / complications
  • Prognosis
  • Up-Regulation / genetics


  • Biomarkers, Tumor
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • Cisplatin