Caterina Peraldo-Neia1, Paola Ostano1, Maurizia Mello-Grand1, Francesca Guana1, Ilaria Gregnanin1, Donatella Boschi2, Simonetta Oliaro-Bosso2, Agnese Chiara Pippione2, Andrea Carenzo3, Loris De Cecco3, Stefano Cavalieri4, Arianna Micali3, Federica Perrone5, Gianluca Averono6, Paolo Bagnasacco6, Riccardo Dosdegani7, Laura Masini8, Marco Krengli8, Paolo Aluffi-Valletti9, Guido Valente8, Giovanna Chiorino10. 1. Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy. 2. Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. 3. Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. 4. Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133, Milan, Italy. 5. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133, Milan, Italy. 6. Otorhinolaryngology Unit, Ospedale degli Infermi, via dei Ponderanesi 1, Ponderano, Biella, Italy. 7. Otorhinolaryngology Unit, Ospedale Sant'Andrea, Vercelli, Italy. 8. Department of Translational Medicine, UPO School of Medicine, Radiotherapy Unit, Novara, Italy. 9. Department of Health Sciences, UPO School of Medicine, Otorhinolaryngology Unit, Novara, Italy. 10. Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy. giovanna.chiorino@fondazionetempia.org.
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.
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.
Authors: Alexander D Rapidis; Patrick Gullane; John D Langdon; Jean Louis Lefebvre; Crispian Scully; Jatin P Shah Journal: Oral Oncol Date: 2009 Apr-May Impact factor: 5.337
Authors: Kevin J Harrington; Robert L Ferris; George Blumenschein; A Dimitrios Colevas; Jérôme Fayette; Lisa Licitra; Stefan Kasper; Caroline Even; Everett E Vokes; Francis Worden; Nabil F Saba; Naomi Kiyota; Robert Haddad; Makoto Tahara; Viktor Grünwald; James W Shaw; Manish Monga; Mark Lynch; Fiona Taylor; Michael DeRosa; Laura Morrissey; Kim Cocks; Maura L Gillison; Joël Guigay Journal: Lancet Oncol Date: 2017-06-23 Impact factor: 41.316
Authors: K Kian Ang; Brian A Berkey; Xiaoyu Tu; Hua-Zhong Zhang; Ruth Katz; Elizabeth H Hammond; Karen K Fu; Luka Milas Journal: Cancer Res Date: 2002-12-15 Impact factor: 12.701
Authors: Robert L Ferris; George Blumenschein; Jerome Fayette; Joel Guigay; A Dimitrios Colevas; Lisa Licitra; Kevin Harrington; Stefan Kasper; Everett E Vokes; Caroline Even; Francis Worden; Nabil F Saba; Lara C Iglesias Docampo; Robert Haddad; Tamara Rordorf; Naomi Kiyota; Makoto Tahara; Manish Monga; Mark Lynch; William J Geese; Justin Kopit; James W Shaw; Maura L Gillison Journal: N Engl J Med Date: 2016-10-08 Impact factor: 91.245