The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2

• Published in: Molecular cancer research Vol. 10; no. 1; pp. 167 - 180
• Main Authors: Young, Lisa E, Moore, Ashleigh E, Sokol, Lena, Meisner-Kober, Nicole, Dixon, Dan A
• Format: Journal Article
• Language: English
• Published: United States 01-01-2012
• Subjects: Animals; Caco-2 Cells; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Cells, Cultured; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Down-Regulation - genetics; ELAV Proteins - genetics; ELAV Proteins - metabolism; ELAV Proteins - physiology; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HeLa Cells; HT29 Cells; Humans; Mice; Mice, Transgenic; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Protein Binding; Protein Transport - genetics; Regulatory Sequences, Ribonucleic Acid - genetics; Regulatory Sequences, Ribonucleic Acid - physiology; RNA Stability - genetics; Tumor Cells, Cultured
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-11-0337

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.