Pathogenesis of Barrett Esophagus

Abstract

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