The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis

Gastroenterology. 2009 May;136(5):1669-79. doi: 10.1053/j.gastro.2009.01.010. Epub 2009 Jan 15.


Background & aims: During tumorigenesis, loss of rapid messenger RNA (mRNA) decay allows for overexpression of cancer-associated genes. The RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) bind AU-rich elements in the 3' untranslated region of many cancer-associated mRNAs and target them for stabilization or rapid decay, respectively. We examined the functions of HuR and TTP during colon tumorigenesis and their ability to regulate cyclooxygenase (COX-2), a mediator of prostaglandin synthesis that increases in the colon tumor microenvironment.

Methods: We evaluated expression of HuR and TTP during colorectal tumorigenesis and in colon cancer cells and associated them with COX-2 expression. HuR and TTP-inducible cells were created to investigate HuR- and TTP-mediated regulation of COX-2.

Results: In normal colon tissues, low levels of nuclear HuR and higher levels of TTP were observed. By contrast, increased HuR expression and cytoplasmic localization were observed in 76% of adenomas and 94% of adenocarcinomas, and TTP expression was lost in >75% of adenomas and adenocarcinomas. Similar results were obtained for HuR and TTP mRNA levels in normal and staged tumor samples. In both adenomas and adenocarcinomas, COX-2 overexpression was associated with increased HuR and decreased TTP (P < .0001); similar associations were observed in colon cancer cells. HuR overexpression in cells up-regulated COX-2 expression, whereas overexpression of TTP inhibited it; limited TTP expression antagonized HuR-mediated COX-2 overexpression.

Conclusions: Increased expression of the mRNA stability factor HuR and loss of the decay factor TTP occurs during early stages of colorectal tumorigenesis. These changes promote COX-2 overexpression and could contribute to colon tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenoma / genetics
  • Adenoma / metabolism
  • Antigens, Surface / metabolism
  • Antigens, Surface / physiology*
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • Cytoplasm / metabolism
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • RNA, Messenger / analysis
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Transfection
  • Tristetraprolin / metabolism
  • Tristetraprolin / physiology*


  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tristetraprolin
  • Cyclooxygenase 2