An Integrated Approach Identifies Mediators of Local Recurrence in Head and Neck Squamous Carcinoma.
Purpose:Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC.Experimental Design:A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines.In vivoexperiments validated thein vitroresults.Results:Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process.In silicoand wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-gene 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.Clin Cancer Res; 23(14); 3769-80. ©2017 AACR.
Division of Molecular Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Francesca
F
Citron
Division of Molecular Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Joshua
J
Armenia
Oncologic Radiotherapy, CRO Aviano, National Cancer Institute, Aviano, Italy.
Giovanni
G
Franchin
Cancer Epidemiology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Jerry
J
Polesel
Cancer Epidemiology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Renato
R
Talamini
Division of Molecular Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Sara
S
D'Andrea
Division of Pathology, Azienda Ospedaliera Santa Maria degli Angeli, Pordenone, Italy.
Sandro
S
Sulfaro
Department of Cancer Biology and Genetics/CCC, The Ohio State University, Columbus, Ohio.
Carlo M
CM
Croce
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
William
W
Klement
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
David
D
Otasek
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Chiara
C
Pastrello
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Tomas
T
Tokar
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Canada.|Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
Igor
I
Jurisica
Faculty of Medicine and Psicology, Department of Clinical and molecular Medicine, University of Rome "La Sapienza," Santo Andrea Hospital, Rome, Italy.
Deborah
D
French
Clinical and Experimental Onco-Hematology Unit, CRO Aviano, National Cancer Institute, Aviano, Italy.
Riccardo
R
Bomben
Medical Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Emanuela
E
Vaccher
Cancer Epidemiology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Diego
D
Serraino
Division of Molecular Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy.
Barbara
B
Belletti
Department of Cancer Biology and Genetics/CCC, The Ohio State University, Columbus, Ohio. gbaldassarre@cro.it andrea.vecchione@uniroma1.it luigibarzan@libero.it.|Faculty of Medicine and Psicology, Department of Clinical and molecular Medicine, University of Rome "La Sapienza," Santo Andrea Hospital, Rome, Italy.
Andrea
A
Vecchione
Department of Surgery, CRO Aviano, National Cancer Institute, Aviano, Italy. gbaldassarre@cro.it andrea.vecchione@uniroma1.it luigibarzan@libero.it.
Luigi
L
Barzan
Division of Molecular Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy. gbaldassarre@cro.it andrea.vecchione@uniroma1.it luigibarzan@libero.it.
Gustavo
G
Baldassarre
D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053535:Keratin-13 / Q000235:genetics; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D016212:Transforming Growth Factor beta / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D053535:Keratin-13; D035683:MicroRNAs; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C507426:KRT13 protein, human; C544547:MIRN1 microRNA, human; C548234:MIRN133 microRNA, human; C533097:MIR150, human; C541874:MIRN92 microRNA, human; C474743:SASH1 protein, human; C108209:SP1 protein, human