title: The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2.
abstract: Commonly observed in colorectal cancer is the elevated expression of the prostaglandin (PG) synthase COX-2. In normal intestinal epithelium, the COX-2 mRNA is targeted for rapid decay through the 3'-untranslated region (3'-UTR) adenylate- and uridylate (AU)-rich element (ARE), whereas in tumors ARE-mediated decay is compromised. Here we show that the COX-2 ARE can mediate degradation through microRNA (miRNA)-mediated regulation. We identified miR-16 to bind the COX-2 3'-UTR and inhibit COX-2 expression by promoting rapid mRNA decay. In colorectal cancer cells and tumors, miR-16 levels were decreased approximately twofold and miR-16 expression in cancer cells attenuated COX-2 expression and PG synthesis. The COX-2 ARE is also bound by the RNA-binding protein HuR. In colorectal cancer tumors, HuR is overexpressed and localized within the cytoplasm, where it promotes ARE-mRNA stabilization. Under conditions of HuR overexpression, miR-16 was unable to promote rapid mRNA decay through the COX-2 ARE. Ribonucleoprotein immunoprecipitation of HuR showed direct association with miR-16 that was reversed when cytoplasmic trafficking of HuR was inhibited. Furthermore, this interaction between HuR and miR-16 promoted the downregulation of miR-16. These new results identify miR-16 as a central posttranscriptional regulator of COX-2 and show the ability of elevated levels of HuR to antagonize miR-16 function. Along with insight into altered ARE-mediated mRNA decay observed in colorectal cancer, these findings provide a new explanation for tumor-derived loss of miR-16.
authors: Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.
authors: Lisa E
authors: LE
authors: Young
authors: Ashleigh E
authors: AE
authors: Moore
authors: Lena
authors: L
authors: Sokol
authors: Nicole
authors: N
authors: Meisner-Kober
authors: Dan A
authors: DA
authors: Dixon
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D051959:ELAV Proteins; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D038621:Regulatory Sequences, Ribonucleic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human