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Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3

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Abstract

Previously we found decreased expression of SOCS3 in neointimal hyperplastic region following balloon angioplasty in atherosclerotic micro swine. In our recent in vitro studies using human coronary artery smooth muscle cells (HCASMC), we observed the inhibition of SOCS3 expression in the presence of both TNF-α and IGF-1, correlating with the in vivo findings in microswine. We also reported that two independent mechanisms, JAK/STAT3/NFκB and promoter methylation of SOCS3 were responsible for TNF-α and IGF-1 induced SOCS3 inhibition. In this study, using miRNA array and gene expression approaches, we explored the molecular mechanisms involved in the above SOCS3 repression and identified several miRNAs that are associated with the regulation of SOCS3 expression. Our miRNA expression profiling revealed profound down-regulation of two specific miRNAs, hsa-miR-758 and hsa-miR-1264, whose expression levels were decreased by 8–10 folds in HCASMCs that were treated with both TNF-α and IGF-1. This was accompanied with a significant up-regulation of three specific miRNAs, hsa-miR-155, hsa-miR-146b-5p and hsa-miR-146a, which showed about 3–7 fold increases in their expression levels. Importantly, we also found that the miRNA hsa-miR-1264 targets DNA methyltransferase-1 (DNMT1) transcripts by binding to its 3′UTR region to affect its expression. Expression of hsa-miR-1264 in HCASMCs not only resulted in decreased DNMT1 mRNA transcripts but it also increased SOCS3 expression. The treatment with TNF-α and IGF-1 resulted in drastic decrease in hsa-miR-1264 levels with no change in the expression of DNMT1. Consequently, the DNMT1 activity caused hypermethylation in the CpG island of the SOCS3 promoter region and inhibited its expression. This could be a causative epigenetic mechanism associated with TNF-α and IGF-1 induced smooth muscle cell proliferation involved in the pathogenesis of coronary artery hyperplasia and restenosis.

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Abbreviations

SOCS3:

Suppressor of cytokine signaling-3

HCASMC:

Human coronary artery smooth muscle cell

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

DNMT1:

DNA methyl transferase-1

IGF-1:

Insulin like growth factor-1

TNF-α:

Tumor necrotic factor-α

miR:

microRNA

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Acknowledgments

The research awards R01HL104516, R01HL112597, and R01HL120659 from the Office of the Director, and National Heart Lung and Blood Institute, National Institutes of Health, USA to DKA supported this work. The content of this research article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Biomedical Sciences, School of Medicine Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA

    Chandra S. Boosani, Kajari Dhar & Devendra K. Agrawal

  2. Center for Clinical & Translational Science, School of Medicine Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

  3. The Peekie Nash Carpenter Endowed Chair in Medicine, School of Medicine Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

  4. Department of Biomedical Sciences, Internal Medicine, and Medical Microbiology & Immunology, School of Medicine Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

  5. Clinical and Translational Research, School of Medicine Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

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  1. Chandra S. Boosani
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  2. Kajari Dhar
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Correspondence to Devendra K. Agrawal.

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Kajari Dhar—Former postdoctoral fellow.

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Boosani, C.S., Dhar, K. & Agrawal, D.K. Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3. Mol Biol Rep 42, 1365–1376 (2015). https://doi.org/10.1007/s11033-015-3882-x

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