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J. Biol. Chem., Vol. 281, Issue 29, 20474-20482, July 21, 2006

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The Adenomatous Polyposis Coli Tumor Suppressor Gene Regulates Expression of Cyclooxygenase-2 by a Mechanism That Involves Retinoic Acid^*

Annie L. Eisinger, Lincoln D. Nadauld, Dawne N. Shelton, Peter W. Peterson, Reid A. Phelps, Stephanie Chidester, Diana M. Stafforini, Stephen M. Prescott, and David A. Jones^¶1

From the Departments of Oncological Sciences and ^¶Medicinal Chemistry and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

Mutations in the adenomatous polyposis coli (APC) gene result in uncontrolled proliferation of intestinal epithelial cells and are associated with the earliest stages of colorectal carcinogenesis. Cyclooxygenase-2 (COX-2) is elevated in human colorectal cancers and plays an important role in colorectal tumorigenesis; however, the mechanisms by which APC mutations result in increased COX-2 expression remain unclear. We utilized APC mutant zebrafish and human cancer cells to investigate how APC modulates COX-2 expression. We report that COX-2 is up-regulated in APC mutant zebrafish because of a deficiency in retinoic acid biosynthesis. Treatment of both APC mutant zebrafish and human carcinoma cell lines with retinoic acid significantly reduces COX-2 expression. Retinoic acid regulates COX-2 levels by a mechanism that involves participation of the transcription factor C/EBP-. APC mutant zebrafish express higher levels of C/EBP- than wild-type animals, and retinoic acid supplementation reduces C/EBP- expression to basal levels. Both morpholino knockdown of C/EBP- in APC mutant zebrafish and silencing of C/EBP- using small interfering RNA in HT29 colon cancer cells robustly decrease COX-2 expression. Our findings support a sequence of events in which mutations in APC result in impaired retinoic acid biosynthesis, elevated levels of C/EBP-, up-regulation of COX-2, increased prostaglandin E₂ accumulation, and activation of Wnt target genes.

Received for publication, March 27, 2006 , and in revised form, May 9, 2006.

^* This work was supported by the American Cancer Society, the NCI, National Institutes of Health, and Huntsman Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112. Tel.: 801-585-6107; E-mail: david.jones{at}hci.utah.edu.

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