Purpose: Head and Neck Squamous Cell Carcinomas (HNSCC) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected microRNAs (miRs) could be used as biomarkers of recurrence in HNSCC. Experimental Design: A Nanostring array was used to identify miRs associated with locoregional recurrence in 44 HNSCC patients. Bioinformatic approaches validated the signature and identified potential miR targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results. Results: Our data identified a four-miR signature that classified HNSCC patients at high- or low-risk of recurrence. These miRs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, while miR-1, miR-133 and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-genes signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. Conclusions: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development.
- Received November 9, 2016.
- Revision received January 23, 2017.
- Accepted January 24, 2017.
- Copyright ©2017, American Association for Cancer Research.