380 Alcohol Induces ALDH2 As a Novel Cytoprotective Mechanism to Suppress Acetaldehyde-Derived DNA Adduct Formation in Esophageal Epithelial Cells

Abstract

no statistically significant difference among different cell lines. We also treat CP-A Barrett's cell line with acid (pH 6.5) for 24 hours and measured NOTCH signaling molecules by PCR array. We found that acid treatment significantly decreased NOTCH1 (2 fold decrease) and JAG1 (1.6 fold decrease), and increased NOTCH3 (1.7 fold increase) and NOTCH4 (3.9 fold increase) in CP-A Barrett's cells. Acid treatment did not cause significant changes of DLL1, DLL2, DLL4, JAG2, NOTCH2 and NUMB. In addition, Western blot analysis showed that acid upregulated NOTCH3 and NOTCH4 protein expression. Acid-induced increase in cell proliferation in CP-A Barrett's cells was significantly decreased by knockdown of NOTCH3 (from 285% control to 162% control, p<0.001) and NOTCH4 (from 236% control to 192% control, P<0.001) with their small interfering RNAs. We conclude that downregulation of NOTCH1 and overexpression of NOTCH3 may play an important role in the development of Barrett's associated adenocarcinoma. It is possible that acid reflux present in BE patients may downregulate NOTCH1 and upregulate NOTCH3, increasing cell proliferation and thereby contributing to the progression from Barrett's esophagus to esophageal adenocarcinoma. Supported by NIH NIDDK R01 DK080703.