Homeodomain protein CDX2 regulates COX-2 expression in colorectal cancer.

Abstract

CDX2 is an intestine-specific tumor suppressor gene encoding homeodomain-containing transcription factor, which is involved in a variety of developmental, proliferating, and differentiating processes. Moreover, the expression of CDX2 is reduced in a subset of primary colorectal cancers. In contrast, cyclooxygenase-2 (COX-2) is often up-regulated in human colorectal cancers. However, the molecular relationship between CDX2 down-regulation and COX-2 up-regulation is unknown. Here we show that CDX2 down-regulates COX-2 promoter activity by interacting with NF-kappaB. The ectopic expression of CDX2 was found to suppress PMA-induced COX-2 promoter activity in a dose-dependent manner. In addition, the treatment of colorectal cancer cells with PMA resulted in significant reduction in the level of endogenous CDX2 and a significant increase in the level of endogenous COX-2, in a dose-dependent manner. Furthermore, CDX2 was found to co-immunoprecipitate with the p65 subunit of NF-kappaB and to inhibit p65-induced NF-kappaB minimal promoter activity in colon cancer cells. These results suggest that reduced CDX2 expression may be involved in colorectal carcinogenesis by enhancing NF-kappaB-mediated inflammatory genes such as COX-2.

• Authors: Sang-Pyo Kim, Jong-Wook Park, Sung-Hee Lee, Jun Hee Lim, Byeong-Churl Jang, Sang-Han Lee, In-Hwan Jang, Jean-Noel Freund, Seong-Il Suh, Kyo Cheol Mun, Dae-Kyu Song, Eun-Mi Ha, Won-Jae Lee, Taeg Kyu Kwon
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 315 Issue 1 Pg. 93-9 (Feb 27 2004) ISSN: 0006-291X [Print] United States
• PMID: 15013430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDX2 Transcription Factor
• Homeodomain Proteins
• Immunoglobulin kappa-Chains
• Interferon Type I
• Isoenzymes
• Membrane Proteins
• NF-kappa B
• Trans-Activators
• interferon kappa
• Luciferases
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• eIF-2 Kinase
• Tetradecanoylphorbol Acetate

Topics

• CDX2 Transcription Factor
• Caco-2 Cells
• Cell Line
• Colorectal Neoplasms (enzymology, genetics, metabolism)
• Cyclooxygenase 2
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects, genetics)
• Genes, Reporter (genetics)
• Homeodomain Proteins (biosynthesis, genetics)
• Humans
• Immunoglobulin kappa-Chains (metabolism)
• Interferon Type I (metabolism)
• Isoenzymes (biosynthesis, genetics)
• Luciferases (metabolism)
• Membrane Proteins
• NF-kappa B (metabolism)
• Plasmids (genetics)
• Promoter Regions, Genetic
• Prostaglandin-Endoperoxide Synthases (biosynthesis, genetics)
• Tetradecanoylphorbol Acetate (antagonists & inhibitors, pharmacology)
• Trans-Activators (pharmacology)
• Transfection
• eIF-2 Kinase (metabolism)