Epigenetic alterations have emerged as an important mechanism involved in tumorigenesis. The epigenetic impact of DNA methylation in various types of human cancer is not completely understood. Previously, we observed melatonin-induced differential expression of miRNA and miRNA-related genes in human breast cancer cell lines that indicated an anticancer effect of melatonin. In this report, we further characterized epigenetic changes in melatonin-exposed MCF-7 cells through the analysis of DNA methylation profiles in breast cancer cells to provide new insights into the potential mechanisms of the anticancer effect of melatonin. Microarray-based DNA methylation and gene expression profiling were carried out using human breast cancer cell lines. We further identified a number of mRNAs whose expression levels show an inverse correlation with DNA methylation levels. The mRNA expression levels and methylation status of candidate genes in melatonin-exposed cells were confirmed by real-time quantitative PCR and bisulfite PCR. This approach led to the detection of cancer-related genes, which were oncogenic genes, including EGR3 and POU4F2/Brn-3b were down-regulated, while the tumor suppressor gene, GPC3, was up-regulated by 1 nm melatonin-treated MCF-7 cells. Our results provide detailed insights into the DNA methylation patterns induced by melatonin and suggest a potential mechanism of the anticancer effect of aberrant DNA methylation in melatonin-treated breast cancer cells.
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs, producing transcripts of about 22 nucleotides in length. miRNAs usually function as antisense regulators of other RNAs by degrading their targets. Recently, miRNAs have emerged as interesting new drug targets due to their regulatory role in essential biological processes. Salvianolic acid B (SalB) is one of the major pharmacologically active ingredients of Salvia miltiorrhiza, a traditional oriental medicine for treatment of cardiovascular disorders. In this study, we determined whether miRNAs play a role in regulation of various gene expression responses to SalB in human umbilical vein endothelial cells (HUVECs). We used the microarray approach to evaluate levels of both miRNA and mRNA, and found that 171 miRNAs were differentially expressed in SalB-treated HUVECs. We additionally identified 848 messenger RNAs (mRNAs) that are anti-correlated with the miRNAs expression. The Gene Ontology (GO) term enrichment was analyzed for identification of biological processes of target genes affected by differential expression of miRNA. Among 848 genes investigated, cardiovascular diseaserelated genes were selected in SalB-treated HUVECs. These results suggest that SalB may modulate miRNA and their target gene expression in order to exert vascular protective effects in human endothelial cells.
[Show abstract][Hide abstract] ABSTRACT: Methylglyoxal (MG) is a highly toxic compound that contributes to the formation of advanced glycation end products (AGEs). MG is detected at high concentration in plasma of diabetic patients and is involved in the pathogenesis of several diabetic macro- and microvascular complications, such as atherosclerosis, retinopathy, nephropathy and hypertension. MicroRNAs (miRNAs) play a critical role in the negative regulation of genes in many biologic processes. They are also known to post-transcriptionally regulate gene expression involved in cellular responses to toxicants. In this study, we investigated whether miRNAs play a role in the regulation of gene expressions in human umbilical vein endothelial cells (HUVECs) after the treatment with MG. We performed pair-wise correlation analysis, acquired altered expression levels of 274 miRNAs and 686 mRNA, and observed their anti-correlations. Genes associated with diabetic vascular disease were sorted from miRNA-correlated genes, and Gene Ontology (GO) enrichment analysis on the differential expression of selected genes was carried out. Our results revealed the relationship between miRNAs and mRNA in MG-exposed endothelial cells using the expression profiling.
[Show abstract][Hide abstract] ABSTRACT: Acrolein (ACR) is a highly reactive α, β-unsaturated carbonyl compound that is related to several diabetic vascular complications. ACR, a ubiquitous aldehyde pollutant, is a product of incomplete combustion reactions and a major component of cigarette smoke. ACR is also endogenously generated during lipid peroxidation. Glycosylphosphatidylinositol (GPI)-anchored proteins is a membrane bound protein, which have a variety of cellular functions. It is reported that some of them showed the reduced level under diabetic conditions. In this study, we explored whether ACR may affect GPI anchor related gene expression in human umbilical vein endothelial cells (HUVECs) by modulation of miRNA expression that play a significant role in the post-transcriptional regulation of genes. We performed global gene expression analysis, acquired altered expression levels of 27 miRNAs and 21 mRNAs that are relevant to GPI anchored proteins, and observed their anti-correlations. Gene Ontology (GO) terms that are closely associated with GPI anchor biosynthesis were highest when analysis was based on biological processes characterized by enriched GO categories. Our results revealed that ACR may control miRNAs to regulate genes involving in GPI anchor biosynthesis in human endothelial cells.
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