Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

Abstract

Cyclooxygenase (COX) catalyzes the first step in prostanoid biosynthesis and exists as two isoforms. COX-1 is a constitutive enzyme involved in physiological processes, whereas COX-2 is induced by a variety of stimuli. MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. Although it is known that COX-2 expression is regulated by miRNAs, there are no data regarding COX-2 involvement in miRNA regulation. Considering our previous results showing that COX-2 expression in hepatocytes protects against insulin resistance, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs implicated in insulin signaling in liver cells. Our results provide evidence of the molecular basis for a novel function of COX-2 in miRNA processing. COX-2 represses miRNA 23b (miR-23b), miR-146b, and miR-183 expression in liver cells by increasing the level of DEAD-box helicase p68 (DDX5) through phosphatidylinositol 3-kinase (PI3K)/p300 signaling and by modulating the enzymatic function of the Drosha (RNase type III) complex through its physical association with DDX5. The decrease of miR-183 expression promotes protection against insulin resistance by increasing insulin receptor substrate 1 (IRS1) levels. These results indicate that the modulation of miRNA processing by COX-2 is a key event in insulin signaling in liver and has potential clinical implications for the management of various hepatic dysfunctions.

ACKNOWLEDGMENTS

This work was supported by the Ministerio de Economía y Competitividad, Spain (SAF2010-16037 and SAF2013-43713-R to P.M.-S., BFU2011-24760 to L.B., and SAF2012-397329 and CIBERehd to M.C.), Comunidad de Madrid, Spain (S2010/BMD-2378 to L.B. and P.M.-S.), and Instituto de Salud Carlos III, Spain (RD12/0042/0019 and CIBERehd to L.B. and P.M.-S. and PI13/01299 to C.G.-M). N.A. is supported by Red de Investigación Cardiovascular (RD12/0042/0019). D.E.F. is supported by Financing Program for short stays abroad CONICET-Argentina. L.C.-S. is supported by a postdoctoral fellowship from CONACYT, Mexico.

We declare no conflict of interest.