Human Molecular Genetics Advance Access originally published online on September 23, 2009
Human Molecular Genetics 2009 18(24):4818-4829; doi:10.1093/hmg/ddp446
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Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma
1 Division of Applied Molecular Oncology, 2 Department of Biostatistics, 3 Department of Computer Science, 4 Department of Signaling Biology and 5 Department of Pathology, Toronto General Hospital, Ontario Cancer Institute, The University Health Network, Toronto, ON M5G 2C4, Canada, 6 Department of Genetics, Bioscience Institute, Sao Paulo State University, Botucatu, SP, Brazil, 7 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L5, Canada, 8 Department of Pediatric Laboratory Medicine, and the Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada, 9 Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada, 10 Department of Otolaryngology, Hospital Calderon Guardia, San Jose, Costa Rica, 11 Dalla Lana School of Public Health Sciences, University of Toronto, Toronto, ON M5T 3M7, Canada and 12 Department of Otolaryngology/Surgical Oncology, Princess Margaret Hospital, The University of Toronto and The University Health Network, Toronto, ON M5G 2M9, Canada
* To whom correspondence should be addressed at: Princess Margaret Hospital, Ontario Cancer Institute and University Health Network, 610 University Avenue, Room 9-622, Toronto, ON M5G 2M9, Canada. Tel: +1 4163404800 ext. 5739; Fax: +1 4163403596; Email: suzanne.kamel-reid{at}uhn.on.ca
Received June 30, 2009; Revised August 25, 2009; Accepted September 21, 2009
MicroRNAs (miRs) are non-coding RNA molecules involved in cancer initiation and progression. Deregulated miR expression has been implicated in cancer; however, there are no studies implicating an miR signature associated with progression in oral squamous cell carcinoma (OSCC). Although OSCC may develop from oral leukoplakia, clinical and histological assessments have limited prognostic value in predicting which leukoplakic lesions will progress. Our aim was to quantify miR expression changes in leukoplakia and same-site OSCC and to identify an miR signature associated with progression. We examined miR expression changes in 43 sequential progressive samples from 12 patients and four non-progressive leukoplakias from four different patients, using TaqMan Low Density Arrays. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and OSCCs, and five non-progressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from non-progressive leukoplakias/normal tissues. One hundred and nine miRs were highly expressed exclusively in progressive leukoplakia and invasive OSCC. miR-21, miR-181b and miR-345 expressions were consistently increased and associated with increases in lesion severity during progression. Over-expression of miR-21, miR-181b and miR-345 may play an important role in malignant transformation. Our study provides the first evidence of an miR signature potentially useful for identifying leukoplakias at risk of malignant transformation.