AimsAccumulating evidence suggest that numerous microRNAs (miRNAs) play important roles in cell proliferation, apoptosis, and differentiation, as well as various diseases that accompany inflammatory responses. Inflammation is known to be a major contributor to atherogenesis. Previous studies provide promising evidence in support of the role of miRNAs in cardiovascular disease. However, mechanistic data on these small molecules in atherosclerosis (AS) are still missing. The present study aims to investigate the potential role of miRNAs in AS.Methods and ResultsThe miRNA transcriptase was verified by TaqMan real-time polymerase chain reaction assay. Thoracic aorta samples were obtained from Apolipoprotein E knockout mice, and plasma samples were from coronary artery disease (CAD) patients. The results showed that the miR-155 level was the most significantly elevated both in AS mice and CAD patients relative to the normal control. The functional role of miR-155 in the atherosclerotic path physiological process was also observed in vivo and in vitro. The observations suggested that miR-155 is a part of a negative feedback loop, which down-modulates inflammatory cytokine production and decreases AS progression. miR-155 was also found to mediate the inflammatory response and mitogen-activated protein kinase (MAPK) pathway by targeting mitogen-activated protein kinase kinase kinase 10.ConclusionsmiR-155 contributes to the prevention of AS development and progression. It may also be involved in the posttranscriptional regulation of the inflammatory response and MAPK pathway by targeting mitogen-activated protein kinase kinase kinase 10.

Many studies have indicated that the aberrant expression of long noncoding RNAs (lncRNAs) is responsible for drug resistance, which represents a substantial obstacle for cancer therapy. In the present study, we aimed to investigate the role of the lncRNA HOXA-AS3 in drug resistance and elucidate its underlying mechanisms in non-small-cell lung carcinoma (NSCLC) cells. The role of HOXA-AS3 in drug resistance was demonstrated by the cell counting kit-8 assay (CCK-8), ethynyldeoxyuridine (EDU) assay, and flow cytometry analysis. Tumor xenografts in nude mice were established to evaluate the antitumor effects of HOXA-AS3 knockdown in vivo. Western blotting and quantitative real-time PCR were used to evaluate protein and RNA expression. RNA pull-down assays, mass spectrometry, and RNA immunoprecipitation were performed to confirm the molecular mechanism of HOXA-AS3 in the cisplatin resistance of NSCLC cells. We found that HOXA-AS3 levels increased with cisplatin treatment and knockdown of HOXA-AS3 enhance the efficacy of cisplatin in vitro and in vivo. Mechanistic investigations showed that HOXA-AS3 conferred cisplatin resistance by down-regulating homeobox A3 (HOXA3) expression. Moreover, HOXA-AS3 was demonstrated to interact with both the mRNA and protein forms of HOXA3. In addition, HOXA3 knockdown increased cisplatin resistance and induced epithelial-mesenchymal transition (EMT). Taken together, our findings suggested that additional research into HOXA-AS3 might provide a better understanding of the mechanisms of drug resistance and promote the development of a novel and efficient strategy to treat NSCLC.

Edited by Tamas Dalmay Keywords:MicroRNA-29a Oxidized low density lipoprotein Dendritic cell Lipoprotein lipase Immuno-inflammation a b s t r a c t There is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with DC immuno-inflammatory responses with oxidized low density lipoprotein (oxLDL) stimulation is not yet known. Our study aims to explore the link of miRNAs with lipidoverload and immuno-inflammatory mechanism for atherosclerosis. In DCs transfected with microRNA-29a mimics or inhibitors, we showed that microRNA-29a plays an important role in proinflammatory cytokine secretion and scavenger receptor expression upon oxLDL-treatment. Furthermore, we suggest an additional explanation for the mechanism of microRNA-29a regulation of its functional target, lipoprotein lipase. We conclude that microRNA-29a could regulate proinflammatory cytokine secretion and scavenger receptor expression by targeting lipoprotein lipase in oxLDL-stimulated dendritic cells.

a b s t r a c tThere is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether miRNAs are associated with dendritic cell (DC) immuno-inflammatory responses to oxidized low density lipoprotein (oxLDL) stimulation is yet unknown. Our study aims to explore the link of miRNA to lipid-overload and the immuno-inflammatory mechanism for atherosclerosis. Human primary monocyte-derived DCs were transfected with miR-146a mimics and inhibitor, and then stimulated by oxLDL. For the flow cytometric analysis of the DC immunophenotype, supernatants were collected to determine inflammatory chemokine markers. Our study clearly revealed that miRNA146a regulates the maturation process and pro-inflammatory cytokine secretion in DCs by targeting CD40L in ox-LDL-stimulated DCs.

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MicroRNA-214(miR-214) has been recently reported to regulate angiogenesis and embryonic stem cells (ESCs) differentiation. However, very little is known about its functional role in vascular smooth muscle cells (VSMCs) differentiation from ESCs. In the present study, we assessed the hypothesis that miR-214 and its target genes play an important role in VSMCs differentiation. Murine ESCs were seeded on collagen-coated flasks and cultured in differentiation medium for 2 to 8 days to allow VSMCs differentiation. miR-214 was significantly upregulated during VSMCs differentiation. miR-214 overexpression and knockdown in differentiating ESCs significantly promoted and inhibited VSMCs -specific genes expression, respectively. Importantly, miR-214 overexpression in ESCs promoted VSMCs differentiation in vivo. Quaking (QKI) was predicted as one of the major targets of miR-214, which was negatively regulated by miR-214. Luciferase assay showed miR-214 substantially inhibited wild type, but not the mutant version of QKI-3-UTR-luciferase activity in differentiating ESCs, further confirming a negative regulation role of miR-214 in QKI gene expression. Mechanistically, our data showed that miR-214 regulated VSMCs gene expression during VSMCs differentiation from ESCs through suppression of QKI. We further demonstrated that QKI down-regulated the expression of SRF, MEF2C and Myocd through transcriptional repression and direct binding to promoters of the SRF, MEF2c and Myocd genes. Taken together, we have uncovered a central role of miR-214 in ESC-VSMC differentiation, and successfully identified QKI as a functional modulating target in miR-214 mediated VSMCs differentiation.

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The ability to reprogram induced pluripotent stem (iPS) cells from somatic cells may facilitate significant advances in regenerative medicine. MicroRNAs (miRNAs) are involved in a number of core biological processes, including cardiogenesis, hematopoietic lineage differentiation and oncogenesis. An improved understanding of the complex molecular signals that are required for the differentiation of iPS cells into endothelial cells (ECs) may allow specific targeting of their activity in order to enhance cell differentiation and promote tissue regeneration. The present study reports that miR‑199a is involved in EC differentiation from iPS cells. Augmented expression of miR‑199a was detected during EC differentiation, and reached higher levels during the later stages of this process. Furthermore, miR‑199a inhibited the differentiation of iPS cells into smooth muscle cells. Notably, sirtuin 1 was identified as a target of miR‑199a . Finally, the ability of miR‑199a to induce angiogenesis was evaluated in vitro, using Matrigel plugs assays. This may indicate a novel function for miR‑199a as a regulator of the phenotypic switch during vascular cell differentiation. The present study provides support to the notion that with an understanding of the molecular mechanisms underlying vascular cell differentiation, stem cell regenerative therapy may ultimately be developed as an effective treatment for cardiovascular disease.