This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-4238v1 69/12/5168    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Brennan, S. E. Articles by Wilson, G. M. PubMed PubMed Citation Articles by Brennan, S. E. Articles by Wilson, G. M.

The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis

¹ Department of Biochemistry and Molecular Biology and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine; ² Laboratory of Cellular and Molecular Biology, National Institute on Aging-NIH; ³ Department of Computer and Information Sciences, Towson University, Baltimore, Maryland and ⁴ Laboratory of Signal Transduction, NIEHS-NIH, Research Triangle Park, North Carolina

Requests for reprints: Gerald Wilson, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201. Phone: 410-706-8904; Fax: 410-706-8297; E-mail: gwils001{at}umaryland.edu.

Key Words: mRNA turnover • RNA-binding protein • prognostic indicator • tumor progression • VEGF

AU-rich element-binding proteins (ARE-BP) regulate the stability and/or translational efficiency of mRNAs containing cognate binding sites. Many targeted transcripts encode factors that control processes such as cell division, apoptosis, and angiogenesis, suggesting that dysregulated ARE-BP expression could dramatically influence oncogenic phenotypes. Using several approaches, we evaluated the expression of four well-characterized ARE-BPs across a variety of human neoplastic syndromes. AUF1, TIA-1, and HuR mRNAs were not systematically dysregulated in cancers; however, tristetraprolin mRNA levels were significantly decreased across many tumor types, including advanced cancers of the breast and prostate. Restoring tristetraprolin expression in an aggressive tumor cell line suppressed three key tumorgenic phenotypes: cell proliferation, resistance to proapoptotic stimuli, and expression of vascular endothelial growth factor mRNA. However, the cellular consequences of tristetraprolin expression varied across different cell models. Analyses of gene array data sets revealed that suppression of tristetraprolin expression is a negative prognostic indicator in breast cancer, because patients with low tumor tristetraprolin mRNA levels were more likely to present increased pathologic tumor grade, vascular endothelial growth factor expression, and mortality from recurrent disease. Collectively, these data establish that tristetraprolin expression is frequently suppressed in human cancers, which in turn can alter tumorigenic phenotypes that influence patient outcomes. [Cancer Res 2009;69(12):5168–76]