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Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells
Dan A. Dixon, … , Guy A. Zimmerman, Stephen M. Prescott
Dan A. Dixon, … , Guy A. Zimmerman, Stephen M. Prescott
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1657-1665. https://doi.org/10.1172/JCI12973.
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Article

Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells

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Abstract

Cyclooxygenase-2 (COX-2) expression is normally tightly regulated. However, constitutive overexpression plays a key role in colon carcinogenesis. To understand the molecular nature of enhanced COX-2 expression detected in colon cancer, we examined the ability of the AU-rich element–containing (ARE-containing) 3′ untranslated region (3′UTR) of COX-2 mRNA to regulate rapid mRNA decay in human colon cancer cells. In tumor cells displaying enhanced growth and tumorigenicity that is correlated with elevated COX-2, vascular endothelial growth factor (VEGF), and IL-8 protein levels, the corresponding mRNAs were transcribed constitutively and turned over slowly. The observed mRNA stabilization is owing to defective recognition of class II-type AREs present within the COX-2, VEGF, and IL-8 3′UTRs; c-myc mRNA, containing a class I ARE decayed rapidly in the same cells. Correlating with cellular defects in mRNA stability, the RNA-binding of trans-acting cellular factors was altered. In particular, we found that the RNA-stability factor HuR binds to the COX-2 ARE, and overexpression of HuR, as detected in tumors, results in elevated expression of COX-2, VEGF, and IL-8. These findings demonstrate the functional significance rapid mRNA decay plays in controlling gene expression and show that dysregulation of these trans-acting factors can lead to overexpression of COX-2 and other angiogenic proteins, as detected in neoplasia.

Authors

Dan A. Dixon, Neal D. Tolley, Peter H. King, L. Burt Nabors, Thomas M. McIntyre, Guy A. Zimmerman, Stephen M. Prescott

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Figure 1

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Enhanced growth and tumorigenicity correlates with COX-2 protein express...
Enhanced growth and tumorigenicity correlates with COX-2 protein expression. (a) Tumor growth from HT29 and LoVo cell implants in nude mice was measured biweekly, and data shown are the mean tumor volume obtained from four xenografts each of HT29 cells (circles) and LoVo cells (triangles). (b) Growth curves of HT29 (circles) and LoVo (triangles) cells in culture under identical conditions. Growth in the presence of NS-398 is indicated with a dotted line. Each point represents the mean of four replicates. (c) Immunoblot of COX-2 protein in 50 μg of HT29 and LoVo cell lysates. β-actin was detected on the same blot as a control for protein loading. Molecular-weight standards (kilodaltons) are listed on the left. The data shown represent three experiments. (d) COX activity in HT29 and LoVo cells treated with NS-398 (filled bars) or carrier (open bars). PGE2 levels were measured by ELISA in the media containing arachidonic acid and are the average of three experiments.

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