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Cancer Genes and Genomics

Oncogenic Ras and Transforming Growth Factor-β Synergistically Regulate AU-Rich Element–Containing mRNAs during Epithelial to Mesenchymal Transition

Departments of ¹ Cancer Biology, ² Surgery, ³ Cell and Developmental Biology, ⁴ Biomedical Informatics, ⁵ Pharmacology, and ⁶ Radiology and ⁷ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; ⁸ Program in BioMolecular Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and ⁹ Department of Biological Sciences and South Carolina Cancer Center, University of South Carolina, Columbia, South Carolina

Requests for reprints: R. Daniel Beauchamp, Department of Surgery, Vanderbilt University Medical Center, D-4316 Medical Center North, Nashville, TN 37232-2730. Phone: 615-322-2363; Fax: 615-343-5365. E-mail: daniel.beauchamp{at}vanderbilt.edu

Colon cancer progression is characterized by activating mutations in Ras and by the emergence of the tumor-promoting effects of transforming growth factor-β (TGF-β) signaling. Ras-inducible rat intestinal epithelial cells (RIE:iRas) undergo a well-described epithelial to mesenchymal transition and invasive phenotype in response to H-RasV12 expression and TGF-β treatment, modeling tumor progression. We characterized global gene expression profiles accompanying Ras-induced and TGF-β–induced epithelial to mesenchymal transition in RIE:iRas cells by microarray analysis and found that the regulation of gene expression by the combined activation of Ras and TGF-β signaling was associated with enrichment of a class of mRNAs containing 3' AU-rich element (ARE) motifs known to regulate mRNA stability. Regulation of ARE-containing mRNA transcripts was validated at the mRNA level, including genes important for tumor progression. Ras and TGF-β synergistically increased the expression and mRNA stability of vascular endothelial growth factor (VEGF), a key regulator of tumor angiogenesis, in both RIE:iRas cells and an independent cell culture model (young adult mouse colonocyte). Expression profiling of human colorectal cancers (CRC) further revealed that many of these genes, including VEGF and PAI-1, were differentially expressed in stage IV human colon adenocarcinomas compared with adenomas. Furthermore, genes differentially expressed in CRC are also significantly enriched with ARE-containing transcripts. These studies show that oncogenic Ras and TGF-β synergistically regulate genes containing AREs in cultured rodent intestinal epithelial cells and suggest that posttranscriptional regulation of gene expression is an important mechanism involved in cellular transformation and CRC tumor progression. (Mol Cancer Res 2008;6(7):1124–36)