This Article Full Text Full Text (PDF) Supplementary Figures Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Araki, Y. Articles by Harris, C. C. Search for Related Content PubMed PubMed Citation Articles by Araki, Y. Articles by Harris, C. C.

Regulation of Cyclooxygenase-2 Expression by the Wnt and Ras Pathways¹

Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892

Mutations in the adenomatous polyposis coli (APC) gene and K-ras occur in the majority of human colorectal cancers. Loss of functional APC protein activates the Wnt signal transduction pathway, allowing the nuclear accumulation of ß-catenin, which then binds to T-cell factor-4 (Tcf-4), causing increased transcriptional activation of downstream target genes. We investigated the hypothesis that the activation of the WNT pathway regulates cyclooxygenase-2 (COX-2). COX-2 was down-regulated after the induction of full-length APC in the HT29-APC cell line. We identified a Tcf-4-binding element (TBE) in the COX-2 promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. COX-2 promoter luciferase activity is down-regulated by APC in a promoter reporter construct containing the, TBE but not with mutant TBE. Mutant ß-catenin expression up-regulated the COX-2 promoter activity and the endogenous COX-2 mRNA expression in HuH7, hepatocellular carcinoma cell line, which is partially abrogated by cotransfection with a dominant-negative Tcf-4 expression vector. Although ß-catenin alone did not increase COX-2 protein to detectable levels in HuH7 cells, coexpression of both mutant ß-catenin and mutant K-ras increased COX-2 protein expression, which is consistent with the previous reports that K-ras can stabilize COX-2 mRNA. Taken together, our data support the hypothesis that COX-2 is down-regulated by APC and up-regulated by nuclear ß-catenin accumulation, and additionally implicate the Wnt signal transduction pathway in colon and liver carcinogenesis.

This article has been cited by other articles:

				U. Dougherty, A. Sehdev, S. Cerda, R. Mustafi, N. Little, W. Yuan, S. Jagadeeswaran, A. Chumsangsri, J. Delgado, M. Tretiakova, et al. Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model Clin. Cancer Res., April 15, 2008; 14(8): 2253 - 2262. [Abstract] [Full Text] [PDF]

				Y. H. Lee, Y. J. Suzuki, A. J. Griffin, and R. M. Day Hepatocyte growth factor regulates cyclooxygenase-2 expression via {beta}-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L778 - L786. [Abstract] [Full Text] [PDF]

				H. Wang, S. Wen, N. W. Bunnett, R. Leduc, M. D. Hollenberg, and W. K. MacNaughton Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through -Catenin and Cyclic AMP-response Element-binding Protein J. Biol. Chem., January 11, 2008; 283(2): 809 - 815. [Abstract] [Full Text] [PDF]

				T. Yamashita, A. Budhu, M. Forgues, and X. W. Wang Activation of Hepatic Stem Cell Marker EpCAM by Wnt {beta}-Catenin Signaling in Hepatocellular Carcinoma Cancer Res., November 15, 2007; 67(22): 10831 - 10839. [Abstract] [Full Text] [PDF]

				H. Yoshikawa, K. Matsubara, X. Zhou, S. Okamura, T. Kubo, Y. Murase, Y. Shikauchi, M. Esteller, J. G. Herman, X. Wei Wang, et al. WNT10B Functional Dualism: beta-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer Mol. Biol. Cell, November 1, 2007; 18(11): 4292 - 4303. [Abstract] [Full Text] [PDF]

				S. S. Barbieri and B. B. Weksler Tobacco smoke cooperates with interleukin-1{beta} to alter {beta}-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo FASEB J, June 1, 2007; 21(8): 1831 - 1843. [Abstract] [Full Text] [PDF]

				R. Ren, P. C. Charles, C. Zhang, Y. Wu, H. Wang, and C. Patterson Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses Blood, April 1, 2007; 109(7): 2847 - 2853. [Abstract] [Full Text] [PDF]

				Y. L. Pon and A. S. T. Wong Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the {beta}-Catenin/T-Cell Factor Signaling Pathway Mol. Endocrinol., December 1, 2006; 20(12): 3336 - 3350. [Abstract] [Full Text] [PDF]

				H. K. Lee and S. Jeong {beta}-Catenin stabilizes Cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3'-UTR Nucleic Acids Res., November 14, 2006; 34(19): 5705 - 5714. [Abstract] [Full Text] [PDF]

				A. L. Eisinger, L. D. Nadauld, D. N. Shelton, P. W. Peterson, R. A. Phelps, S. Chidester, D. M. Stafforini, S. M. Prescott, and D. A. Jones The Adenomatous Polyposis Coli Tumor Suppressor Gene Regulates Expression of Cyclooxygenase-2 by a Mechanism That Involves Retinoic Acid J. Biol. Chem., July 21, 2006; 281(29): 20474 - 20482. [Abstract] [Full Text] [PDF]

				Q. Du, K. S. Park, Z. Guo, P. He, M. Nagashima, L. Shao, R. Sahai, D. A. Geller, and S. P. Hussain Regulation of Human Nitric Oxide Synthase 2 Expression by Wnt {beta}-Catenin Signaling. Cancer Res., July 15, 2006; 66(14): 7024 - 7031. [Abstract] [Full Text] [PDF]

				A. Kaidi, D. Qualtrough, A. C. Williams, and C. Paraskeva Direct Transcriptional Up-regulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 Promotes Colorectal Tumor Cell Survival and Enhances HIF-1 Transcriptional Activity during Hypoxia. Cancer Res., July 1, 2006; 66(13): 6683 - 6691. [Abstract] [Full Text] [PDF]

				A. M. Carothers, A. E. Moran, N. L. Cho, M. Redston, and M. M. Bertagnolli Changes in Antitumor Response in C57BL/6J-Min/+ Mice during Long-term Administration of a Selective Cyclooxygenase-2 Inhibitor. Cancer Res., June 15, 2006; 66(12): 6432 - 6438. [Abstract] [Full Text] [PDF]

				C. V. Dang Oncogenic Activation of Reactive Oxygen Species, Genomic Instability, and Tumorigenesis Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 245 - 248. [Full Text] [PDF]

				R. Kaul, S. C. Verma, M. Murakami, K. Lan, T. Choudhuri, and E. S. Robertson Epstein-Barr Virus Protein Can Upregulate Cyclo-Oxygenase-2 Expression through Association with the Suppressor of Metastasis Nm23-H1 J. Virol., February 1, 2006; 80(3): 1321 - 1331. [Abstract] [Full Text] [PDF]

				M. Grade, B. M. Ghadimi, S. Varma, R. Simon, D. Wangsa, L. Barenboim-Stapleton, T. Liersch, H. Becker, T. Ried, and M. J. Difilippantonio Aneuploidy-Dependent Massive Deregulation of the Cellular Transcriptome and Apparent Divergence of the Wnt/{beta}-catenin Signaling Pathway in Human Rectal Carcinomas Cancer Res., January 1, 2006; 66(1): 267 - 282. [Abstract] [Full Text] [PDF]

				J. Ju, J. Hong, J.-n. Zhou, Z. Pan, M. Bose, J. Liao, G.-y. Yang, Y. Y. Liu, Z. Hou, Y. Lin, et al. Inhibition of Intestinal Tumorigenesis in Apcmin/+ Mice by (-)-Epigallocatechin-3-Gallate, the Major Catechin in Green Tea Cancer Res., November 15, 2005; 65(22): 10623 - 10631. [Abstract] [Full Text] [PDF]

				O. A. Mohamed, M. Jonnaert, C. Labelle-Dumais, K. Kuroda, H. J. Clarke, and D. Dufort From The Cover: Uterine Wnt/{beta}-catenin signaling is required for implantation PNAS, June 14, 2005; 102(24): 8579 - 8584. [Abstract] [Full Text] [PDF]

				L. A.A. Brosens, C. A. Iacobuzio-Donahue, J. J. Keller, S. R. Hustinx, R. Carvalho, F. H. Morsink, L. M. Hylind, G. J. Offerhaus, F. M. Giardiello, and M. Goggins Increased Cyclooxygenase-2 Expression in Duodenal Compared with Colonic Tissues in Familial Adenomatous Polyposis and Relationship to the -765G -> C COX-2 Polymorphism Clin. Cancer Res., June 1, 2005; 11(11): 4090 - 4096. [Abstract] [Full Text] [PDF]

				T. Daikoku, D. Wang, S. Tranguch, J. D. Morrow, S. Orsulic, R. N. DuBois, and S. K. Dey Cyclooxygenase-1 Is a Potential Target for Prevention and Treatment of Ovarian Epithelial Cancer Cancer Res., May 1, 2005; 65(9): 3735 - 3744. [Abstract] [Full Text] [PDF]

				K. Nosho, M. Yoshida, H. Yamamoto, H. Taniguchi, Y. Adachi, M. Mikami, Y. Hinoda, and K. Imai Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis Carcinogenesis, May 1, 2005; 26(5): 892 - 899. [Abstract] [Full Text] [PDF]

				J. R. Brown and R. N. DuBois COX-2: A Molecular Target for Colorectal Cancer Prevention J. Clin. Oncol., April 20, 2005; 23(12): 2840 - 2855. [Abstract] [Full Text] [PDF]

				A. Gregorieff and H. Clevers Wnt signaling in the intestinal epithelium: from endoderm to cancer Genes & Dev., April 15, 2005; 19(8): 877 - 890. [Abstract] [Full Text] [PDF]

				A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention J. Clin. Oncol., January 10, 2005; 23(2): 254 - 266. [Abstract] [Full Text] [PDF]

				W. A. Marsman, R. S. Birjmohun, B. P. van Rees, E. Caspers, G. Johan, A. Offerhaus, P. J. Bosma, J. Jan, and B. van Lanschot Loss of Heterozygosity and Immunohistochemistry of Adenocarcinomas of the Esophagus and Gastric Cardia Clin. Cancer Res., December 15, 2004; 10(24): 8479 - 8485. [Abstract] [Full Text] [PDF]

				T. D. WARNER and J. A. MITCHELL Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic FASEB J, May 1, 2004; 18(7): 790 - 804. [Abstract] [Full Text] [PDF]

				Y. Liu, G. L. Borchert, and J. M. Phang Polyoma Enhancer Activator 3, an Ets Transcription Factor, Mediates the Induction of Cyclooxygenase-2 by Nitric Oxide in Colorectal Cancer Cells J. Biol. Chem., April 30, 2004; 279(18): 18694 - 18700. [Abstract] [Full Text] [PDF]

				R. Rao, C.-M. Hao, and M. D. Breyer Hypertonic Stress Activates Glycogen Synthase Kinase 3{beta}-mediated Apoptosis of Renal Medullary Interstitial Cells, Suppressing an NF{kappa}B-driven Cyclooxygenase-2-dependent Survival Pathway J. Biol. Chem., February 6, 2004; 279(6): 3949 - 3955. [Abstract] [Full Text] [PDF]

				L. Mollersen, J. E. Paulsen, H. B. Olstorn, H. K. Knutsen, and J. Alexander Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice Carcinogenesis, January 1, 2004; 25(1): 149 - 153. [Abstract] [Full Text] [PDF]

				J. L. Williams, N. Nath, J. Chen, T. R. Hundley, J. Gao, L. Kopelovich, K. Kashfi, and B. Rigas Growth Inhibition of Human Colon Cancer Cells by Nitric Oxide (NO)-Donating Aspirin Is Associated with Cyclooxygenase-2 Induction and {beta}-Catenin/T-Cell Factor Signaling, Nuclear Factor-{kappa}B, and NO Synthase 2 Inhibition: Implications for Chemoprevention Cancer Res., November 15, 2003; 63(22): 7613 - 7618. [Abstract] [Full Text] [PDF]