AKR1C3 is a biomarker and druggable target for oropharyngeal tumors
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ORIGINAL ARTICLE
AKR1C3 is a biomarker and druggable target for oropharyngeal tumors Caterina Peraldo-Neia 1 & Paola Ostano 1 & Maurizia Mello-Grand 1 & Francesca Guana 1 & Ilaria Gregnanin 1 & Donatella Boschi 2 & Simonetta Oliaro-Bosso 2 & Agnese Chiara Pippione 2 & Andrea Carenzo 3 & Loris De Cecco 3 & Stefano Cavalieri 4 & Arianna Micali 3 & Federica Perrone 5 & Gianluca Averono 6 & Paolo Bagnasacco 6 & Riccardo Dosdegani 7 & Laura Masini 8 & Marco Krengli 8 & Paolo Aluffi-Valletti 9 & Guido Valente 8 & Giovanna Chiorino 1 Accepted: 21 October 2020 # International Society for Cellular Oncology 2020
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 HPVnegative 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 topoverexpressed 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 Oropharynx cancer . HPV status . Prognosis . AKR1C3 . Biomarker . Target therapy . Cisplatin Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s13402-02000571-z. * Giovanna Chiorino [email protected] 1
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Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900 Biella, Italy Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125 Turin, Italy Integrated Biology Platform, Dep
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