The pathogenesis of Barrett's esophagus: secondary bile acids upregulate intestinal differentiation factor CDX2 expression in esophageal cells.
BACKGROUND
Clinical evidence strongly suggests that bile acids are important in the development of Barrett's esophagus, although the mechanism remains unknown. Caudal-related homeobox 2 (CDX2) is a transcription factor recently implicated in early differentiation and maintenance of normal intestinal epithelium and is suggested to play a key role in the pathogenesis of intestinal metaplasia in Barrett's esophagus.


OBJECTIVE
The aim of this study was to investigate the effect of primary and secondary bile acids on CDX2 mRNA expression in human esophageal cells.


METHODS
Human esophageal cells: (1) squamous, immortalized by SV40 (Het-1A); (2) adenocarcinoma (SEG-1); and (3) squamous cell carcinoma (HKESC-1 & HKESC-2), were exposed in cell culture for 1-24 h to 100-1,000 microM deoxycholic, chenodeoxycholic, and glycocholic acids. Total RNA was extracted before and after bile acid treatment and reverse transcribed to cDNA. CDX2 mRNA expression was determined by both quantitative real-time and reverse transcription PCR (RT-PCR).


RESULTS
CDX2 mRNA expression was absent before bile acid exposure in all cell lines. CDX2 expression increased in a dose- and time-dependent fashion with deoxycholic and chenodeoxycholic, but not glycocholic, acid in all four cell lines. The maximal induction of CDX2 expression was seen in SEG-1 adenocarcinoma cells. Expression in Het-1A cells also increased significantly as did expression in HKESC-1,2 cells, although to a lesser extent than in adenocarcinoma.


CONCLUSIONS
These findings show that secondary bile acid stimulation upregulates CDX2 gene expression in both normal and cancer cell lines. They further support the role of bile acids in the pathogenesis of Barrett's esophagus and link the clinical evidence of a high prevalence of luminal bile acids in Barrett's to expression of the gene thought to be responsible for the phenotypic expression of intestinal metaplasia.
Hu
Yingchuan
Y
Department of Surgery, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Rochester, New York 14642, USA.
Williams
Valerie A
VA
Gellersen
Oliver
O
Jones
Carolyn
C
Watson
Thomas J
TJ
Peters
Jeffrey H
JH
D001471:Barrett Esophagus / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D001647:Bile Acids and Salts / Q000502:physiology*; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D002460:Cell Line; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D055262:Mucin-2; D009077:Mucins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C524625:MUC2 protein, human; D055262:Mucin-2; D009077:Mucins; D012333:RNA, Messenger