Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Identification of miR-181a target genes in Epithelial Ovarian Cancer

ABSTRACT: We have identified a single miRNA, miR-181a, that can modulate TGF-Î² signaling to induce and maintain EMT, and effect further downstream events of tumour cell survival, altered response to chemotherapy, migration, invasion and dissemination in vivo. Our present study provides an understanding of how enhanced expression of miR-181a can confer malignant and invasive traits through the modulation of a canonical signaling pathway and a consequent maintenance of a mesenchymal state. Furthermore, inhibition of miR-181a led to a reversion of EMT and subsequent events through decreased TGF-Î² signaling. Our data confirmed Smad7 as a functional target through which TGF-Î²-mediated EMT occurs; re-expression of Smad7 lacking its 3'UTR was able to rescue miR-181a-mediated phenotypes, deeming Smad7 as a critical mediator of miR-181a-induced EMT. Other recent studies support the crucial role(s) that miRNAs play in mediating EMT and consequent aggressive disease traits. For example, the miR-106b-25 cluster has also been shown to target Smad7 and mediate TGF-Î²-induced EMT downstream to Six1 in breast cancer34. miR-9 directly targets E-cadherin and inhibition of miR-9 had led to an inhibition of metastasis35. Conversely, the miR-200 and -205 family was shown to target transcriptional repressors of E-cadherin, ZEB1 and SIP1, and re-expression of these miRNAs led to a mesenchymal-to-epithelial transition and prevented TGF-Î² -induced EMT36. A2780 ovarian cancer cell lines stably expressing either pBABE (control vector), p181a#1( clone 1 expressing miR-181a) or p181a#2( clone 2 expressing miR-181a)

ORGANISM(S): Homo sapiens

SUBMITTER: Analisa DiFeo

PROVIDER: E-GEOD-52077 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA) -related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) in NSCLC. MiRNA expression profiles were examined before and after transforming growth factor-beta1 (TGF-M-NM-21) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. MiRNA array and quantitative RT-PCR revealed that TGF-M-NM-21 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN (phosphatase and tensin homolog), was diminished in A549 cells with EMT after the TGF-M-NM-21 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-M-NM-21-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-M-NM-21-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, whose suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be new therapeutic targets in advanced lung adenocarcinoma patients, depending on the EMT phenomenon. miRNA expression profiles before and after TGF-M-NM-21 exposure were assessed in the four lung adenocarcinoma cell lines, A549, LC2/ad, PC3, and, PC9 by TaqMan miRNA arrays. Relative ratios of miRNAs in cells after TGF-M-NM-21 exposure were calculated when compared with the cells before TGF-M-NM-21 exposure.

Project description:Induction of the inhibitory Smad, Smad7 serves as a negative feedback mechanism that restrains TGF-b-mediated actions in injured tissues. In inflammatory cells, Smad7 has been suggested to exert both pro-inflammatory actions attributed to inhibition of TGF-b-induced suppression of inflammation, and anti-inflammatory effects due to disruption of the TAK-1/NF-kB system. Myocardial infarction triggers a macrophage-driven inflammatory response that plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that Smad7 upregulation in infarct macrophages may play a modulatory role in cardiac repair, by restraining effects of TGF-b. To test the hypothesis, we investigated the response of Myeloid cell-specific Smad7 knockout mice (MyS7KO) following myocardial infarction protocols, and we examined the in vitro effects of Smad7 in isolated macrophages. Smad7 was upregulated in a subset of infarct macrophages, peaking 7 days after infarction. Myeloid cell-specific Smad7 loss did not affect baseline macrophage gene expression and had no significant effects on homeostatic functions. Although RNA-seq analysis predicted that, in the absence of Smad7, infarct macrophages may have attenuated activation of inflammatory pathways and suppressed TREM1 signaling, myeloid cell-specific Smad7 loss had no significant effects on ventricular dysfunction, adverse remodeling, scar remodeling and collagen deposition after myocardial infarction. In isolated macrophages, TGF-b attenuated pro-inflammatory cytokine and chemokine expression, modulated synthesis of matrix remodeling genes, and had profound effects on macrophage profile, inducing genes associated with activation of sphingosine-1 phosphate and integrin signaling pathways, and inhibiting cholesterol biosynthesis genes. However, RNA-seq and PCR array experiments showed that Smad7 loss has minimal effects on TGF-b-mediated macrophage responses, restraining synthesis of only a small fraction of TGF-b-induced genes, such as Itga5, Olfml3 and Fabp7. Smad7 absence did not affect the anti-inflammatory actions of TGF-b in TNF-stimulated cells. In conclusion, our findings suggest a limited role for macrophage Smad7 in regulation of post-infarction inflammation and repair, and demonstrate that the anti-inflammatory effects of TGF-b in macrophages are not restrained by endogenous Smad7 induction.

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Identification of miR-181a target genes in Epithelial Ovarian Cancer

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