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

• Published in: The Journal of clinical investigation Vol. 108; no. 11; pp. 1657 - 1665
• Main Authors: Dixon, D A, Tolley, N D, King, P H, Nabors, L B, McIntyre, T M, Zimmerman, G A, Prescott, S M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-12-2001
• Subjects: 3' Untranslated Regions - metabolism; Antigens, Surface; Colonic Neoplasms - enzymology; Cyclooxygenase 2; ELAV Proteins; ELAV-Like Protein 1; Endothelial Growth Factors - genetics; HT29 Cells; Humans; HuR protein; Interleukin-8 - genetics; Isoenzymes - genetics; Lymphokines - genetics; Membrane Proteins; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Prostaglandin-Endoperoxide Synthases - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - physiology; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0021-9738
• DOI: 10.1172/jci12973

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.