The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2.
The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2.
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DOI：
10.1158/1541-7786.mcr-11-0337
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Dixon DA
中科院分区：
文献类型：
--
作者：
Young LE;Moore AE;Sokol L;Meisner-Kober N;Dixon DA
Commonly observed in colorectal cancer (CRC) is elevated expression of the prostaglandin synthase cyclooxygenase-2 (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 demonstrate that the COX-2 ARE can mediate degradation through microRNA-mediated regulation. We identified miR-16 to bind the COX-2 3′UTR and inhibit COX-2 expression by promoting rapid mRNA decay. In CRC cells and tumors, miR-16 levels were decreased ~2-fold and miR-16 expression in cancer cells attenuated COX-2 expression and prostaglandin synthesis. The COX-2 ARE is also bound by the RNA-binding protein HuR. In CRC 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 demonstrated 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 down regulation of miR-16. These new results identify miR-16 as a central post-transcriptional regulator of COX-2 and demonstrate the ability of elevated levels of HuR to antagonize miR-16 function. Along with insight into altered ARE-mediated mRNA decay observed in CRC, these findings provide a new explanation for tumor-derived loss of miR-16.
