Genome-Wide miRNA Expression Profiling Identifies miR-9-3 and miR-193a as Targets for DNA Methylation in Non–Small Cell Lung Cancers
| Autor: | Gerwin Heller, Marlene Weinzierl, Walter Klepetko, Sabine Zöchbauer-Müller, Barbara Ziegler, György Lang, Christoph C. Zielinski, Britt Madeleine Arns, Yuliya Grin, Valerie N. Babinsky, Balazs Dome, Christian Noll, Corinna Altenberger, Christoph Minichsdorfer, Adelheid End-Pfützenreuter |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Lung Neoplasms medicine.drug_class DNA Methyltransferase Inhibitor Antineoplastic Agents Biology Decitabine Hydroxamic Acids Carcinoma Non-Small-Cell Lung Cell Line Tumor microRNA medicine Humans Gene silencing Gene Silencing Molecular Targeted Therapy Lung Oligonucleotide Array Sequence Analysis Microarray analysis techniques Gene Expression Profiling Histone deacetylase inhibitor Methylation DNA Methylation Middle Aged Molecular biology respiratory tract diseases MicroRNAs Oncology CpG site DNA methylation Azacitidine Cancer research Female |
| Zdroj: | Clinical Cancer Research. 18:1619-1629 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non–small cell lung cancers (NSCLC). Experimental Design: We conducted microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I–III NSCLC. Results: By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis [HR = 3.8; 95% confidence interval (CI), 1.3–11.2, P = 0.017] and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013). Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC. Clin Cancer Res; 18(6); 1619–29. ©2012 AACR. |
| Databáze: | OpenAIRE |
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