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Carcinogenesis Advance Access originally published online on September 4, 2008
Carcinogenesis 2008 29(12):2385-2393; 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 Park, Kook Hwan Kim, Hye Young Kim, KyeongJin Kim and JaeHun Cheong*

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

* To whom correspondence should be addressed. Tel: +82 51 510 2277; Fax: +82 51 513 9258; Email: 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 (IM) of the stomach in gastric cancer. Gastric IM 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, small heterodimer partner (SHP). Finally, it was verified that the expression of COX-2, CDX1, SHP and CCAAT element-binding protein beta messenger RNA in human IM 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.

Abbreviations: COX-2, cyclooxygenase-2; CDCA, chenodeoxycholic acid; C/EBPβ, CCAAT element-binding protein beta; DCA, deoxycholic acid; EDTA, ethylenediaminetetraacetic acid; IM, intestinal metaplasia; mRNA, messenger RNA; NF-{kappa}B, nuclear factor-kappa B; NR, nuclear receptor; PCR, polymerase chain reaction; RT, reverse transcription; SDS, sodium dodecyl sulfate; SHP, small heterodimer partner; siRNA, small-interference RNA

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


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