1. AKR1C3 is a biomarker and druggable target for oropharyngeal tumors.
- Author
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Peraldo-Neia C, Ostano P, Mello-Grand M, Guana F, Gregnanin I, Boschi D, Oliaro-Bosso S, Pippione AC, Carenzo A, De Cecco L, Cavalieri S, Micali A, Perrone F, Averono G, Bagnasacco P, Dosdegani R, Masini L, Krengli M, Aluffi-Valletti P, Valente G, and Chiorino G
- Subjects
- Aged, Aged, 80 and over, Aldo-Keto Reductase Family 1 Member C3 genetics, Biomarkers, Tumor genetics, 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 pathology, Oropharyngeal Neoplasms virology, Papillomavirus Infections complications, Prognosis, Up-Regulation genetics, Aldo-Keto Reductase Family 1 Member C3 metabolism, Biomarkers, Tumor metabolism, Oropharyngeal Neoplasms metabolism
- Abstract
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.
- Published
- 2021
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