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.