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DNA methylation of microRNA-coding genes in non-small cell lung cancer patients
AuthorZöchbauer-Müller, Sabine ; Heller, Gerwin ; Altenberger, Corinna ; Steiner, Irene ; Topakian, Thais ; Ziegler, Barbara ; Tomasich, Erwin ; Lang, György ; End-Pfützenreuter, Adelheid ; Döme, Balazs ; Arns, Britt-Madeleine ; Klepetko, Walter ; Zielinski, Christoph C. ; Zehetmayer, Sonja
Published in
The Journal of Pathology, 2018, Vol. 245, Issue 4, page 387-398
PublishedWiley-Blackwell, 2018
Document typeJournal Article
Keywords (EN)CpG island methylation / miRNA / MeDIPchip / MSHRM analysis / nonsmallcell lung cancer
URNurn:nbn:at:at-ubmuw:3-524 Persistent Identifier (URN)
 The work is publicly available
DNA methylation of microRNA-coding genes in non-small cell lung cancer patients [1.49 mb]
Abstract (English)

Deregulated DNA methylation leading to transcriptional inactivation of certain genes occurs frequently in nonsmallcell lung cancers (NSCLCs). As well as proteincoding genes, microRNA (miRNA)coding genes may be targets for methylation in NSCLCs; however, the number of known methylated miRNA genes is still small. Thus, we investigated methylation of miRNA genes in primary tumour (TU) samples and corresponding nonmalignant lung tissue (NL) samples of 50 NSCLC patients by using methylated DNA immunoprecipitation followed by customdesigned tiling microarray analyses (MeDIPchip), and 252 differentially methylated probes between TU samples and NL samples were identified. These probes were annotated, which resulted in the identification of 34 miRNA genes with increased methylation in TU samples. Some of these miRNA genes were already known to be methylated in NSCLCs (e.g. those encoding miR93 and miR124), but methylation of the vast majority of them was previously unknown. We selected six miRNA genes (those encoding miR10b, miR1179, miR137, miR572, miR3150b, and miR1292) for genespecific methylation analyses in TU samples and corresponding NL samples of 104 NSCLC patients, and observed a statistically significant increase in methylation of these genes in TU samples (p < 0.0001). In silico target prediction of the six miRNAs identified several oncogenic/cell proliferationpromoting factors (e.g. CCNE1 as an miR1179 target). To investigate whether miR1179 indeed targets CCNE1, we transfected miR1179 gene mimics into CCNE1expressing NSCLC cells, and observed downregulated CCNE1 mRNA expression in these cells as compared with control cells. Similar effects on cyclin E1 expression were seen in western blot analyses. In addition, we found a statistically significant reduction in the growth of NSCLC cells transfected with miR1179 mimics as compared with control cells. In conclusion, we identified many methylated miRNA genes in NSCLC patients, and found that the miR1179 gene is a potential tumour cell growth suppressor in NSCLCs. Overall, our findings emphasize the impact of miRNA gene methylation on the pathogenesis of NSCLCs. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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