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Carcinogenesis Advance Access published online on September 4, 2008
Carcinogenesis, doi:10.1093/carcin/bgn207
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells

Min Jung Park1, Kook Hwan Kim1, Hye Young Kim1, KyeongJin Kim1 and JaeHun Cheong1,*

1 Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Korea

* corresponding author: JaeHun Cheong, Ph.D., Department of Molecular Biology, Pusan National University, Busan, 609-735, Korea, Tel: 82-51-510-2277, Fax: 82-51-513-9258, E-mail: molecule85{at}pusan.ac.kr.

The Caudal-related homeobox gene, CDX1, encodes for an intestinal-specific transcription factor, and is involved in the induction of intestinal metaplasia of the stomach in gastric cancer. Gastric intestinal metaplasia induced by bile reflux is a precancerous gastric adenocarcinomal lesion, and has been associated with the induction of cyclooxygenase-2 (COX-2). In this study, we demonstrate the molecular mechanisms underlying the transcriptional regulation of COX-2 by bile acid in gastric cells. We noted that the ectopic expression of CDX1 enhanced COX-2 gene expression and that bile acid was associated with the induction of CDX1 expression. Furthermore, the induction of CDX1 by bile acid was mediated by the orphan nuclear receptor, SHP. Finally, it was verified that the expression of COX-2, CDX1, SHP, and C/EBPβ mRNA in human intestinal metaplasial lesions were significantly higher than in lesions associated with gastritis. Collectively, these results reveal that bile acid induces an increase in the gene expression of COX-2 via the sequential transcriptional induction of SHP and CDX1 in precancerous lesions of human gastric cancer.

Key Words: Intestinal metaplasia • gastric cancer • SHP • DCA • CDX1 • COX-2 • C/EBPβ

Received January 25, 2008; revised August 25, 2008; accepted August 25, 2008.


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