Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients.
OBJECTIVE
Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells, and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biologic processes that could be targeted to overcome intrinsic resistance.


METHODS
We analyzed both microRNA and mRNA expression in a large panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of patients with laryngeal cancer.


RESULTS
miRs, mRNAs, and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial-to-mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of patients with laryngeal cancer.


CONCLUSIONS
These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pretreatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors. Clin Cancer Res; 21(24); 5630-8. ©2015 AACR.
Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Monique C
MC
de Jong
Department of Computational Cancer Biology (Department of Molecular Carcinogenesis), The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Jelle J
JJ
Ten Hoeve
Department of Otorhinolaryngology-Head and Neck Surgery and Department of Medical Biochemistry, Turku University Hospital, University of Turku, Turku, Finland.
Reidar
R
Grénman
Department of Computational Cancer Biology (Department of Molecular Carcinogenesis), The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Lodewyk F
LF
Wessels
Central Genomic Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Ron
R
Kerkhoven
Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Hein
H
Te Riele
Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Michiel W M
MW
van den Brekel
Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. m.verheij@nki.nl.
Marcel
M
Verheij
Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Adrian C
AC
Begg
D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics*; D013997:Time Factors; D059467:Transcriptome
D035683:MicroRNAs