Gastroenterology

Gastroenterology

Volume 136, Issue 5, May 2009, Pages 1669-1679
Gastroenterology

Basic—Alimentary Tract
The mRNA Binding Proteins HuR and Tristetraprolin Regulate Cyclooxygenase 2 Expression During Colon Carcinogenesis

https://doi.org/10.1053/j.gastro.2009.01.010Get rights and content

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.

Section snippets

Colorectal Tissue Specimens

Immunohistochemical analysis was performed on paraffin-embedded human tissue array samples obtained from 2 sources. The colorectal carcinoma progression tissue array (CHTN2003CRCprog) from the Cooperative Human Tissue Network (National Cancer Institute [NCI], Rockville, MD) contained 42 normal colorectal tissue samples derived from 14 cases of nonneoplastic colonic mucosa, 42 adenoma tissue samples derived from 14 cases of adenomatous polyps, and 42 adenocarcinoma tissue samples derived from 14

HuR, TTP, and COX-2 Protein Expression in Human Colorectal Tumorigenesis

We and others have shown increased HuR expression to occur in human colorectal tumors2, 3, 11; however, the state of TTP expression in colon cancer is not known. Based on the opposing effects these RNA-binding proteins elicit on ARE-containing gene expression, we sought to determine whether corresponding changes in HuR and TTP expression exist during colorectal tumorigenesis. HuR and TTP immunoreactivity were evaluated on serial sections of human tissue arrays containing adenocarcinomas,

Discussion

The control of COX-2 expression is a complex regulatory process that requires input from multiple pathways impacting gene expression on both transcriptional and posttranscriptional levels.10 It is generally well accepted that transcriptional activation of the COX-2 gene PTGS2 is an early event in tumorigenesis because evidence demonstrates the presence of COX-2 mRNA in virtually all colorectal adenomas, adenocarcinomas, and colon cancer cells.2, 10, 14, 15 However, the presence of COX-2 mRNA

References (33)

  • D.M. Carrick et al.

    Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines

    Arch Biochem Biophys

    (2007)
  • P.H. King et al.

    Analysis of the 5′ end of the mouse Elavl1 (mHuA) gene reveals a transcriptional regulatory element and evidence for conserved genomic organization

    Gene

    (2000)
  • C.R. Tchen et al.

    The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself

    J Biol Chem

    (2004)
  • N.L. Garneau et al.

    The highways and byways of mRNA decay

    Nat Rev Mol Cell Biol

    (2007)
  • D.A. Dixon et al.

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

    J Clin Invest

    (2001)
  • I. Lopez de Silanes et al.

    Role of the RNA-binding protein HuR in colon carcinogenesis

    Oncogene

    (2003)
  • Cited by (198)

    • Circular RNAs-mediated angiogenesis in human cancers

      2023, Clinical and Translational Oncology
    View all citing articles on Scopus

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by grants P20 RR017698 from the National Institutes of Health, and RSG-06-122-01-CNE from the American Cancer Society (to D.A.D.).

    View full text