Pathogenesis of Barrett's esophagus: bile acids inhibit the Notch signaling pathway with induction of CDX2 gene expression in human esophageal cells.
BACKGROUND
Barrett's esophagus (BE) is the predominant risk factor for the development of esophageal adenocarcinoma. BE is characterized by intestinal metaplasia with goblet cells. Reflux of bile acids is known to induce intestinal metaplasia, but the mechanisms are unclear. Inhibition of Notch signaling accompanied by increased Hath1 and induction of caudal homeobox 2 (CDX2) may be involved in development of intestinal goblet cells.


METHODS
Esophageal adenocarcinoma cell lines OE19 and OE33 were exposed for up to 8 hours to DCA (100-300 microM), and for up to 24 hours with and without the gamma-secretase inhibitor, DAPT (20 microM). Notch signaling components and CDX2 levels were measured by real-time PCR (for mRNA) and by Western blot analysis (for proteins).


RESULTS
DCA induced a time and concentration dependent decrease in Notch pathway components mRNAs in OE33 and in the proteins in both cell lines. CDX2 mRNA and Hath1 protein were increased in OE19 by 3-fold. Inhibition of Notch pathway by DAPT decreased downstream Notch signaling mRNAs and proteins in both cell lines and increased Hath1 and CDX2 proteins only in OE19.


CONCLUSIONS
Bile acid inhibition of Notch signaling in esophageal cells is correlated with an increase in Hath1 and CDX2 and may be one of the key processes contributing to the formation of BE.
Morrow
David J
DJ
Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Avissar
Nelly E
NE
Toia
Liana
L
Redmond
Eileen M
EM
Watson
Thomas J
TJ
Jones
Carolyn
C
Raymond
Dan P
DP
Litle
Virginia
V
Peters
Jeffrey H
JH
D001471:Barrett Esophagus / Q000209:etiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001647:Bile Acids and Salts / Q000633:toxicity*; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D003840:Deoxycholic Acid / Q000633:toxicity; D004151:Dipeptides / Q000494:pharmacology; D004947:Esophagus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; D003840:Deoxycholic Acid; D004151:Dipeptides; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C500942:ATOH1 protein, human; C491270:CDX2 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C078493:HES1 protein, human