Bile acid alone, or in combination with acid, induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR).
OBJECTIVE
Bile acids and acid are implicated in the development of Barrett's esophagus. Evidence suggests that Barrett's esophagus intestinal metaplasia may occur via induction of caudal homeobox gene 2 (CDX2). We hypothesized that induction of CDX2 by bile acids may be due to ligand-dependent transactivation of epidermal growth factor receptor (EGFR).


METHODS
Human mucosal epithelial cells (SEG-1) were treated for 0 to 24 h with up to 300 microM deoxycholic acid (DCA) at pH 7 or 5 with or without (w/wo) antibodies against EGFR ligand-binding site (Mab528, 3-5 mug/ml). Treatment with 100 ng/ml EGF served as control. CDX2 mRNA expression was determined by real-time polymerase chain reaction. EGFR activation was analyzed by Westerns of phosphorylated EGFR tyrosines.


RESULTS
Acid (pH 5) increased the induction of CDX2 mRNA expression caused by DCA. CDX2 mRNA induction was markedly reduced by EGFR blockade with Mab528. Each treatment (pH 5, DCA or pH 5 plus DCA) activated the EGFR on all tyrosines tested but in different time courses. Phosphorylation by DCA was inhibited by Mab528. Activation of EGFR by DCA at pH 5 resulted in EGFR degradation, while that by DCA alone did not.


CONCLUSIONS
Thus, CDX2 induction by DCA w/wo acid occurs through ligand-dependent transactivation of the EGFR. The variations in EGFR degradation pattern with DCA or DCA at pH 5 indicate differential transactivation pathways. The molecular pathogenesis of Barrett's esophagus may occur via bile-stimulated cell signaling through the EGFR.
Department of Surgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. nelly_avissar@urmc.rochester.edu
Nelly E
NE
Avissar
Liana
L
Toia
Yingchuan
Y
Hu
Thomas J
TJ
Watson
Carolyn
C
Jones
Daniel P
DP
Raymond
Alexi
A
Matousek
Jeffrey H
JH
Peters
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000071616:CDX2 Transcription Factor; D018929:Cell Culture Techniques; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects* / Q000502:physiology; D004938:Esophageal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D008024:Ligands; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D066246:ErbB Receptors