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AKR1C3 is a biomarker and druggable target for oropharyngeal tumors
- Publication Year :
- 2021
-
Abstract
- 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. 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. 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. We identified AKR1C3 as a potential prognostic biomarker in OPSCC and as a potential drug target whose inhibition can potentiate the effect of Cisplatin.
- Subjects :
- Male
0301 basic medicine
Cancer Research
AKR1C3
Biomarker
Cisplatin
HPV status
Oropharynx cancer
Prognosis
Target therapy
Basal (phylogenetics)
0302 clinical medicine
Gene Regulatory Networks
Aged, 80 and over
General Medicine
Middle Aged
Up-Regulation
Gene Expression Regulation, Neoplastic
Lingual tonsils
Oropharyngeal Neoplasms
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Carcinoma, Squamous Cell
Molecular Medicine
Biomarker (medicine)
Female
medicine.drug
Cell Survival
Down-Regulation
03 medical and health sciences
Immune system
Cell Line, Tumor
Biomarkers, Tumor
medicine
Humans
Aged
Cell Proliferation
business.industry
Gene Expression Profiling
Papillomavirus Infections
Therapeutic effect
Aldo-Keto Reductase Family 1 Member C3
medicine.disease
Head and neck squamous-cell carcinoma
Gene expression profiling
Gene Ontology
030104 developmental biology
Cancer research
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f35439cbe319cb6a7e97ff88f667333a