AKR1C3 is a biomarker and druggable target for oropharyngeal tumors.

Autor: Peraldo-Neia C; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Ostano P; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Mello-Grand M; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Guana F; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Gregnanin I; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Boschi D; Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Oliaro-Bosso S; Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Pippione AC; Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Carenzo A; Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., De Cecco L; Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Cavalieri S; Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133, Milan, Italy., Micali A; Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Perrone F; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133, Milan, Italy., Averono G; Otorhinolaryngology Unit, Ospedale degli Infermi, via dei Ponderanesi 1, Ponderano, Biella, Italy., Bagnasacco P; Otorhinolaryngology Unit, Ospedale degli Infermi, via dei Ponderanesi 1, Ponderano, Biella, Italy., Dosdegani R; Otorhinolaryngology Unit, Ospedale Sant'Andrea, Vercelli, Italy., Masini L; Department of Translational Medicine, UPO School of Medicine, Radiotherapy Unit, Novara, Italy., Krengli M; Department of Translational Medicine, UPO School of Medicine, Radiotherapy Unit, Novara, Italy., Aluffi-Valletti P; Department of Health Sciences, UPO School of Medicine, Otorhinolaryngology Unit, Novara, Italy., Valente G; Department of Translational Medicine, UPO School of Medicine, Radiotherapy Unit, Novara, Italy., Chiorino G; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy. giovanna.chiorino@fondazionetempia.org.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2021 Apr; Vol. 44 (2), pp. 357-372. Date of Electronic Publication: 2020 Nov 19.
DOI: 10.1007/s13402-020-00571-z
Abstrakt: 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.
Databáze: MEDLINE
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