Pathogenesis of Barrett esophagus: deoxycholic acid up-regulates goblet-specific gene MUC2 in concert with CDX2 in human esophageal cells.
OBJECTIVE
Bile acid exposure can induce caudal-related homeobox 2 (CDX2) messenger RNA (mRNA) expression, a transcription factor that plays a crucial role in the development of Barrett esophagus. We investigated mucin 2 (MUC2) and CDX2 mRNA expression before and after treatment with deoxycholic acid in 4 human esophageal cell lines.


METHODS
Four human esophageal cell lines-(1) normal squamous cells immortalized by SV40 (Het-1A), (2) adenocarcinoma (SEG-1), and (3 and 4) squamous cell carcinoma (HKESC-1 and HKESC-2)-were exposed in culture for 1 to 24 hours to 100 microM to 1000 microM deoxycholic acid. Total RNA was extracted before and after bile acid treatment and reverse transcribed to complementary DNA.


METHODS
MUC2 and CDX2 mRNA expression as determined by semiquantitative reverse transcription-polymerase chain reaction.


RESULTS
MUC2 mRNA expression was absent before deoxycholic acid exposure in all 4 cell lines. MUC2 expression increased in a dose- and time-dependent manner with deoxycholic acid in all cell lines. Deoxycholic acid activated MUC2 up-regulation, which correlated directly with CDX2 up-regulation in all 4 cell lines.


CONCLUSIONS
Bile acids up-regulate both intestinal differentiation factor CDX2 and goblet cell-specific gene MUC2 in normal esophageal and cancer cell lines. Further, bile acid-stimulated MUC2 up-regulation correlates directly with CDX2 up-regulation. The simultaneous up-regulation of both CDX2 and MUC2 after bile acid exposure provides molecular evidence of the role of bile acid in the pathogenesis of Barrett esophagus.
Hu
Yingchuan
Y
Department of Surgery, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Jones
Carolyn
C
Gellersen
Oliver
O
Williams
Valerie A
VA
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 / Q000473:pathology*; 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