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Cyclooxygenase-2 regulates mirna expression in liver cells through dead box helicase P68 (ddx5). Role in Insulin signaling

AuthorsMotiño, Omar ; Francés, Daniel E.; Mayoral, Rafael ; Castro-Sánchez, Luis; Fernández-Velasco, María ; Boscá, Lisardo ; García-Monzón, Carmelo; Casado, Marta ; Agra, Noelia ; Martín-Sanz, Paloma
Issue Date2015
Citation50th International Liver Congress (2015)
Abstract[Background and Aims]: Our previous results revealed that Cyclooxygenase 2 (COX-2) expression is regulated by miRNAs. However, the role of COX-2 in miRNA regulation remains unknown. In the present work, we have studied whether COX-2 regulates the expression profile of miRNAs in liver, and examined the targets of these miRNAs together with their physiopathological properties. [Methods]: An RT2miRNA PCR array was performed with microRNA isolated from liver extracts of Wt and transgenic mice overexpressed human COX-2 in hepatocytes. We attempted to confirm the array data in different cell models: in isolated hepatocytes from mice models and in human liver cells stably transfected with a COX-2 expression vector. Western blot analyses were carried out to analyze proteins involved in the biosynthesis of miRNAs with or without treatment with pharmacological inhibitors of different signaling pathways. To evaluate the role of COX-2 in insulin signaling, cells were treated with palmitate to induce insulin resistance. To confirm the results the cells were transfected with DDX5 or COX-2 siRNAs or vector expressing specific miRNAs. Finally, the relationship between COX-2 and miRNA regulation was also studied in human biopsy samples of non-alcoholic steatosis (NAS). [Results]: COX-2 represses the expression of miR-23b, miR-146b and miR-183 in liver cells by upregulating the DEAD-box helicase p68 (DDX5) expression through phosphatidylinositol (PI) 3-kinase (PI3K) signaling pathway. Furthermore, COX-2 was shown to inhibit miRNA maturation by associating with the Drosha complex through DDX5 and preventing the conversion of primiRNAs into premiRNAs. Analysis of pathways and networks for these miRNAs using the DAVID platform identified the insulin signaling pathway as target. Our results showed that the down-regulation of miRNAs by COX-2 enhances insulin signaling. Finally, the relationship between COX-2 and the miRNAs was confirmed in NAS. [Conclusions]: COX-2 represses the expression of miRNAs implicated in the insulin signaling pathway via a PI3K/p300-dependent upregulation of DDX5, and by modulating the activity of the Drosha complex. Our study proposes a novel miRNA-dependent mechanism through which COX-2 promotes insulin signaling in liver cells.
DescriptionResumen del póster presentado al 50th Annual Meeting of the European Association for the Study of the Liver, celebrado en Viena (Austria) del 22 al 26 de abril de 2015.
Appears in Collections:(IIBM) Comunicaciones congresos
(IBV) Comunicaciones congresos
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