Identification of lethal microRNAs specific for head and neck cancer.
OBJECTIVE
The prognosis of head and neck squamous cell carcinomas (HNSCC) remains disappointing and the development of novel anti-cancer agents is urgently awaited. We identified by a functional genetic screen microRNAs that are selectively lethal for head and neck cancer cells but not for normal cells. We further investigated the genes targeted by these microRNAs.


METHODS
A retroviral expression library of human microRNAs was introduced in HNSCC cell lines and normal oropharyngeal keratinocytes to identify tumor-selective lethal microRNAs. Potential downstream gene targets of these microRNAs were identified by gene expression profiling and validated by functional assays.


RESULTS
We identified six microRNAs that selectively inhibit proliferation of head and neck cancer cells. By gene expression profiling and 3'-untranslated region (UTR) luciferase reporter assays, we showed that the ataxia telangiectasia mutated (ATM) gene is a common target for at least two and likely three of these microRNAs. Specific inhibition of ATM resulted in a similar tumor-specific lethal effect, whereas the phenotype was reverted in rescue experiments.


CONCLUSIONS
These six microRNAs might be developed as novel anti-cancer agents and highlight ATM as an interesting novel therapeutic target for head and neck cancer.
Authors' Affiliations: Departments of Otolaryngology/Head-Neck Surgery, Epidemiology and Biostatistics, and Pathology, VU University Medical Center; Department of Mathematics, VU University; Division of Gene Regulation, The Netherlands Cancer Institute, Amsterdam; and InteRNA Technologies BV, Utrecht, The Netherlands.
Marlon
M
Lindenbergh-van der Plas
Sanne R
SR
Martens-de Kemp
Michiel
M
de Maaker
Wessel N
WN
van Wieringen
Bauke
B
Ylstra
Reuven
R
Agami
Francesco
F
Cerisoli
C René
CR
Leemans
Boudewijn J M
BJ
Braakhuis
Ruud H
RH
Brakenhoff
D020413:3' Untranslated Regions; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020043:Genes, Essential; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010641:Phenotype; D034622:RNA Interference; D000077195:Squamous Cell Carcinoma of Head and Neck
D020413:3' Untranslated Regions; C545322:MIRN326 microRNA, human; C561417:MIRN345 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D064007:Ataxia Telangiectasia Mutated Proteins