| Autor: |
Peraldo-Neia, Caterina, Ostano, Paola, Mello-Grand, Maurizia, Guana, Francesca, Gregnanin, Ilaria, Boschi, Donatella, Oliaro-Bosso, Simonetta, Pippione, Agnese Chiara, Carenzo, Andrea, De Cecco, Loris, Cavalieri, Stefano, Micali, Arianna, Perrone, Federica, Averono, Gianluca, Bagnasacco, Paolo, Dosdegani, Riccardo, Masini, Laura, Krengli, Marco, Aluffi-Valletti, Paolo, Valente, Guido |
| Předmět: |
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| Zdroj: |
Cellular Oncology (2211-3428); Apr2021, Vol. 44 Issue 2, p357-372, 16p |
| 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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