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Genome-wide microRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA methylation in non-small cell lung cancers

ABSTRACT: Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on microRNA (miRNA) silencing in non-small cell lung cancers (NSCLC). Experimental Design: We performed 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 non-malignant lung tissue samples of 101 stage I-III NSCLC patients. 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 analysed. Moreover, miR-9-3 and miR-193a were found to be tumor-specifically methylated in NSCLC patients. We observed a shorter disease-free survival of miR-9-3 methylated lung squamous cell carcinoma (LSCC) patients compared to miR-9-3 unmethylated LSCC patients by multivariate analysis (HR = 3.8, 95% CI = 1.3 to 11.2, p = 0.017) and a shorter overall survival of miR-9-3 methylated LSCC patients compared to miR-9-3 unmethylated LSCC patients 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 LSCC patients. MiRNA expression (LC Sciences, mirBASE12) was analyzed before and after treatment of A549 cells with 5-aza-2´-deoxycytidine (Aza-dC) and a combination of Aza-dC and trichostatin A (TSA). Experiments were performed in duplicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Heller G

PROVIDER: S-ECPF-GEOD-31579 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Project description:BackgroundGingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis.ResultsThere is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls.ConclusionsOur findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC.

Project description:BackgroundMeasuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM.MethodsHistopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR.ResultsThe detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ2 test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue.ConclusionsOur results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.

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Genome-wide microRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA methylation in non-small cell lung cancers

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