Homeodomain protein CDX2 regulates COX-2 expression in colorectal cancer.
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.
Kim
Sang-Pyo
SP
Institute for Medical Science, Keimyung University School of Medicine, 194 DongSan-Dong Jung-Gu, Daegu 700-712, Republic of Korea.
Park
Jong-Wook
JW
Lee
Sung-Hee
SH
Lim
Jun Hee
JH
Jang
Byeong-Churl
BC
Lee
Sang-Han
SH
Jang
In-Hwan
IH
Freund
Jean-Noel
JN
Suh
Seong-Il
SI
Mun
Kyo Cheol
KC
Song
Dae-Kyu
DK
Ha
Eun-Mi
EM
Lee
Won-Jae
WJ
Kwon
Taeg Kyu
TK
D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015534:Trans-Activators / Q000494:pharmacology; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism
D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D007145:Immunoglobulin kappa-Chains; D007370:Interferon Type I; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D015534:Trans-Activators; C439669:interferon kappa; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019892:eIF-2 Kinase; D013755:Tetradecanoylphorbol Acetate