Journal Article

MicroRNA-218 Is Deleted and Downregulated in Lung Squamous Cell Carcinoma

Bowman, Rayleen V., Clarke, Belinda E., Larsen, Jill E., Duhig, Edwina E., Passmore, Linda H., Davidson, Morgan R., Hayward, Nicholas K., Yang, Ian A., Fong, Kwun M.

2010

Overview

MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non-small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (≥ ± 1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Adult / Aged / Aged, 80 and over / Analysis / Bioinformatics / Cancer / Cancer genetics / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Cell Biology/Gene Expression / Chromosomes / Cigarette smoking / Cohort Studies / Copy number / Datasets / Deoxyribonucleic acid / DNA / DNA probes / Down-Regulation / Drosophila / Epidermal growth factor / Gastric cancer / Gene Deletion / Gene dosage / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Gene mapping / Genes / Genetic aspects / Genetics and Genomics/Cancer Genetics / Genetics and Genomics/Gene Discovery / Genetics and Genomics/Genomics / Genomes / Genomics / Hospitals / Human papillomavirus / Humans / Insects / Kinases / Leukemia / Loci / Lung cancer / Lung carcinoma / Lung diseases / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Medicine / Metastasis / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / Molecular Biology / Non-coding RNA / Non-small cell lung cancer / Non-small cell lung carcinoma / Oncology / Oncology/Lung Cancer / Papillomavirus infections / Prostate cancer / Regulators / Respiratory Medicine/Environmental and Occupational Lung Diseases / Respiratory Medicine/Lung Cancer / Ribonucleic acid / RNA / Small cell lung carcinoma / Smoking / Squamous cell carcinoma / Stomach cancer / Tumor suppressor genes / Tumors / Viruses