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

J Clin Invest. 2001 Dec;108(11):1657-65. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions / metabolism
  • Antigens, Surface*
  • Colonic Neoplasms / enzymology*
  • Cyclooxygenase 2
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Endothelial Growth Factors / genetics
  • HT29 Cells
  • Humans
  • 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


  • 3' Untranslated Regions
  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Endothelial Growth Factors
  • Interleukin-8
  • Isoenzymes
  • Lymphokines
  • Membrane Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Mitogen-Activated Protein Kinases