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

Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.
Molecular Cancer Research (Impact Factor: 4.38). 11/2011; 10(1):167-80. DOI: 10.1158/1541-7786.MCR-11-0337
Source: PubMed


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.

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    • "Micro- RNAs (miRNAs) are dysregulated in numerous diseases including cancer. Validated human miRNAs that target COX-2 for miRNA-mediated repression include miR-146a/b [Sato et al., 2010; Comer et al., 2014], miR-16 [Young et al., 2012], miR-143 [Kim et al., 2011], miR-199a-3p [Akhtar and Haqqi, 2012], miR-26a [Ji et al., 2010], and miR-101a [Tanaka et al., 2009]. Thus, a number of miRNAs have been validated as post-transcriptional regulators of COX-2. "
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    ABSTRACT: Preclinical Research MicroRNA (miR)-155 and cyclooxygenase (COX)-2 are both elevated in numerous cancers including colorectal cancer. MiR-155 enhances COX-2 expression and is an established regulator of epithelial-mesenchymal transition and inflammation. Inhibition of miR-155 or COX-2 exhibit similar negative effects on tumorigenicity. Thus, it is hypothesized that miR-155 may be a promising target for antagonizing COX-2 expression in colorectal and other cancers. © 2015 Wiley Periodicals, Inc.
    Drug Development Research 08/2015; DOI:10.1002/ddr.21276 · 0.77 Impact Factor
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    • "MiR-16 has been shown to play the central role of post-transcriptional regulator of COX-2, and was implicated in the development of colorectal cancer. Inactivation of mismatch repair is induced by miR-155 targeting hMSH2, hMSH6, and hMLH1 52. MiR-34 mediates repression of SIRT1 and leads to apoptosis only in colon cancer cells that express wild-type p53. "
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    ABSTRACT: MicroRNAs (miRNAs) function as regulatory molecules of gene expression with multifaceted activities that exhibit direct or indirect oncogenic properties, which promote cell proliferation, differentiation, and the development of different types of cancers. Because of their extensive functional involvement in many cellular processes, under both normal and pathological conditions such as various cancers, this class of molecules holds particular interest for cancer research. MiRNAs possess the ability to act as tumor suppressors or oncogenes by regulating the expression of different apoptotic proteins, kinases, oncogenes, and other molecular mechanisms that can cause the onset of tumor development. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a large number of oncogenic factors, and therefore are anticipated to be highly efficacious. Given their unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics for a variety of cancers. More than thousand miRNAs have been identified to date, and their molecular mechanisms and functions are well studied. Furthermore, they are established as compelling therapeutic targets in a variety of cellular complications. However, the notion of using them as therapeutic tool was proposed only recently, given that modern imaging methods are just beginning to be deployed for miRNA research. In this review, we present a summary of various molecular imaging methods, which are instrumental in revealing the therapeutic potential of miRNAs, especially in various cancers. Imaging methods have recently been developed for monitoring the expression levels of miRNAs and their target genes by fluorescence-, bioluminescence- and chemiluminescence-based imaging techniques. Mature miRNAs bind to the untranslated regions (UTRs) of the target mRNAs and regulate target genes expressions. This concept has been used for the development of fluorescent reporter-based imaging strategies to monitor the functional status of endogenous miRNAs, or the respective miRNAs transiently co-expressed in cells. Bioluminescence-based imaging strategies have been used to investigate various stages of miRNA processing and its involvement in different cellular processes. Similarly, chemiluminsecence methods were developed for in vitro miRNA imaging such as monitoring their therapeutic roles in various cancer cell lines.
    Theranostics 12/2013; 3(12):964-985. DOI:10.7150/thno.4928 · 8.02 Impact Factor
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    • "In the context of colon cancer cell lines and colon tumors, miR-101 inhibited COX-2 translation [24]. Young et al. [36] demonstrated that miR-16 binds the COX-2 3′UTR and inhibits COX-2 expression by promoting mRNA decay in colon cancer. However, the functional consequences of miR-16 associated with HCC progression have not been established. "
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    ABSTRACT: Cyclooxygenase-2 (COX-2) expression has been detected in human hepatoma cell lines and in human hepatocellular carcinoma (HCC); however, the contribution of COX-2 to the development of HCC remains controversial. COX-2 expression is higher in the non-tumoral tissue and inversely correlates with the differentiation grade of the tumor. COX-2 expression depends on the interplay between different cellular pathways involving both transcriptional and post-transcriptional regulation. The aim of this work was to assess whether COX-2 could be regulated by microRNAs in human hepatoma cell lines and in human HCC specimens since these molecules contribute to the regulation of genes implicated in cell growth and differentiation. Our results show that miR-16 silences COX-2 expression in hepatoma cells by two mechanisms: a) by binding directly to the microRNA response element (MRE) in the COX-2 3'-UTR promoting translational suppression of COX-2 mRNA; b) by decreasing the levels of the RNA-binding protein Human Antigen R (HuR). Furthermore, ectopic expression of miR-16 inhibits cell proliferation, promotes cell apoptosis and suppresses the ability of hepatoma cells to develop tumors in nude mice, partially through targeting COX-2. Moreover a reduced miR-16 expression tends to correlate to high levels of COX-2 protein in liver from patients affected by HCC. Our data show an important role for miR-16 as a post-transcriptional regulator of COX-2 in HCC and suggest the potential therapeutic application of miR-16 in those HCC with a high COX-2 expression.
    PLoS ONE 11/2012; 7(11):e50935. DOI:10.1371/journal.pone.0050935 · 3.23 Impact Factor
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