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MiRNA expression in moncytes in response to estradiol

ABSTRACT: This profiling experiment evaluates the global changes in miRNA expression in monocytic cells in response to 10 nM Estradiol treatment. Levels of circulating 17β-estradiol (E2) may influence the progression of many human diseases. We hypothesize that E2 modulates the inflammatory response of circulating innate immune cells through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), a multifunctional antiprotease with immunomodulatory functions. Monocytes were treated with E2 or control, and differentially expressed miRNAs in monocytes were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and SLPI mRNA and protein levels were quantified by qPCR and ELISA, respectively. Luciferase activity assay was performed using SLPI-3’UTR reporter constructs. ChIP was carried out on monocytes treated with E2. SLPI expression is downregulated, and miR-19 is upregulated in response to E2 in monocytes, via increased MIR17HG promoter activity mediated by c-MYC. Transfection of monocytic cells with premiR-19b reduced SLPI expression. This was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3’UTR as determined by luciferase activity assay. The data show that E2 decreases expression of SLPI in human monocytic cells, via changes in miRNA expression and further highlights the potential for E2 to modulate key components of innate immunity. Modulation of these miRNAs may offer a new therapeutic approach in the treatment of chronic inflammatory diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84254 | GEO | 2016/07/12

SECONDARY ACCESSION(S): PRJNA328478

REPOSITORIES: GEO

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Project description:Altered expression of microRNAs (miRNAs), an abundant class of small non-protein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real time RTPCR experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy thereby showing an estrogen-dependent in vivo regulation of miRNA expression. Overall, our data indicates that the extensive alterations in miRNA regulation upon estrogen signalling pathway plays a key role in estrogen-dependent functions and highlights the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. 9 samples analyzed. Triplicates were done. MCF-7+miR26a+E2 (n=1 to 3) ; MCF7+miRctrl+E2 (n=1 to 3) ; MCF7+miRctrl+vehicle (n=1 to 3). We generated pairwise comparisons using EASANA from GenoSplice technology: MCF-7+miR26a+E2 versus MCF7+miRctrl+E2 and MCF-7+miRctrl+E2 versus MCF7+miRctrl+vehicle. Fold change ≥1.5 were selected.

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MiRNA expression in moncytes in response to estradiol

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