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MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF.

ABSTRACT: Atherosclerosis progress is regulated by a variety of factors. Here, we show that miR-320a, an intergenic miRNA, is markedly elevated in the peripheral blood of coronary heart disease patients and high-risk patients. Microarray analysis and qRT-PCR assays showed that circulating miRNA-320a was highly expressed in coronary artery disease patients. In vivo study showed that overexpression of miR-320a resulted in significant increase in levels of plasma lipid (total cholesterol, Triglyceride and low-density lipoprotein) and serum inflammatory cytokines (IL-6, MCP-1, sICAM, pSelectin, TNF-? and fibrinogen). In ApoE(-/-) mice, miR-320a expression attenuates endothelium cell function and promotes atherogenesis. Bioinformatics analysis identified serum response factor as a potential target for miR-320a, which was validated by luciferase reporter activity assay and western-blot in vitro and in vivo. Moreover, miR-320a expression inhibits human-derived endothelium cell proliferation and induces apoptosis. We also found that SP1 transcriptionally up-regulates hsa-miR-320a expression. Our observations indicate that miR-320a is a key regulator contributing to multiple aspects of atherogenesis.

SUBMITTER: Chen C

PROVIDER: S-EPMC4420600 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF.

Chen Chen C Wang Yan Y Yang Shenglan S Li Huaping H Zhao Gang G Wang Feng F Yang Lei L Wang Dao Wen DW

Journal of cellular and molecular medicine 20150227 5

Atherosclerosis progress is regulated by a variety of factors. Here, we show that miR-320a, an intergenic miRNA, is markedly elevated in the peripheral blood of coronary heart disease patients and high-risk patients. Microarray analysis and qRT-PCR assays showed that circulating miRNA-320a was highly expressed in coronary artery disease patients. In vivo study showed that overexpression of miR-320a resulted in significant increase in levels of plasma lipid (total cholesterol, Triglyceride and lo ...[more]

PMID: 25728840

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Project description:BACKGROUND:Development of resistance to inhibitors of BRAF (BRAFi) and MEK (MEKi) remains a great challenge for targeted therapy in patients with BRAF-mutant melanoma. Here, we explored the role of miRNAs in melanoma acquired resistance to BRAFi. METHODS:miRNA expression in two BRAF-mutant melanoma cell lines and their dabrafenib-resistant sublines was determined using Affymetrix GeneChip® miRNA 3.1 microarrays and/or qRT-PCR. The effects of miR-126-3p re-expression on proliferation, apoptosis, cell cycle, ERK1/2 and AKT phosphorylation, dabrafenib sensitivity, invasiveness and VEGF-A secretion were evaluated in the dabrafenib-resistant sublines using MTT assays, flow cytometry, immunoblotting, invasion assays in Boyden chambers and ELISA. ADAM9, PIK3R2, MMP7 and CXCR4 expression in the sensitive and dabrafenib-resistant cells was determined by immunoblotting. Small RNA interference was performed to investigate the consequence of VEGFA or ADAM9 silencing on proliferation, invasiveness or dabrafenib sensitivity of the resistant sublines. Long-term proliferation assays were carried out in dabrafenib-sensitive cells to assess the effects of enforced miR-126-3p expression or ADAM9 silencing on resistance development. VEGF-A serum levels in melanoma patients treated with BRAFi or BRAFi+MEKi were evaluated at baseline (T0), after two months of treatment (T2) and at progression (TP) by ELISA. RESULTS:miR-126-3p was significantly down-regulated in the dabrafenib-resistant sublines as compared with their parental counterparts. miR-126-3p replacement in the drug-resistant cells inhibited proliferation, cell cycle progression, phosphorylation of ERK1/2 and/or AKT, invasiveness, VEGF-A and ADAM9 expression, and increased dabrafenib sensitivity. VEGFA or ADAM9 silencing impaired proliferation and invasiveness of the drug-resistant sublines. ADAM9 knock-down in the resistant cells increased dabrafenib sensitivity, whereas miR-126-3p enforced expression or ADAM9 silencing in the drug-sensitive cells delayed the development of resistance. At T0 and T2, statistically significant differences were observed in VEGF-A serum levels between patients who responded to therapy and patients who did not. In responder patients, a significant increase of VEGF-A levels was observed at TP versus T2. CONCLUSIONS:Strategies restoring miR-126-3p expression or targeting VEGF-A or ADAM9 could restrain growth and metastasis of dabrafenib-resistant melanomas and increase their drug sensitivity. Circulating VEGF-A is a promising biomarker for predicting patients' response to BRAFi or BRAFi+MEKi and for monitoring the onset of resistance.

Dataset Information

MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF.

Publications

MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF.

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