Omeprazole prevents CDX2 and SOX9 expression by inhibiting hedgehog signaling in Barrett's esophagus cells.

Abstract

Activation of hedgehog (Hh) signaling contributes to the progression of Barrett's esophagus (BE), which increases the risk of esophageal adenocarcinoma. Recent clinical studies revealed that proton-pump inhibitors (PPIs) but not H2 receptor antagonists (H2RAs) were associated with a decreased risk of esophageal adenocarcinoma. We would like to know whether PPIs interfere with BE progression during BE treatment. Here, we explored the role of omeprazole on Hh signaling and expression of two crucial biomarkers of BE, SOX9 and CDX2. We demonstrated that bile acids elevated expression of Hh pathway target genes, such as GLI1 and PTCH1, and induced SOX9 and CDX2 up-regulation in both CP-A and CP-B cells. Omeprazole, but not famotidine, down-regulated these genes induced by bile acids. In addition, omeprazole-induced down-regulation of SOX9 and CDX2 was mediated by Hh signaling. To explore the mechanisms by which omeprazole inhibits Hh signaling, we performed luciferase assay but did not find any effects of omeprazole on the activity of GLI1 promoter, the critical transcription factor of Hh signaling. Therefore, we used miRNA sequencing and a bioinformatics tool in our study to identify the differently expressed miRNAs in BE organoids treated with or without omeprazole, and we identified miR-2116-3p was involved in omeprazole-mediated inhibition of Hh signaling and subsequent down-regulation of SOX9 and CDX2. Collectively, our data indicate omeprazole inhibits Hh signaling and subsequent SOX9 and CDX2 expression via up-regulating miR-2116-3p. We have demonstrated a novel acid-independent mechanism of omeprazole that might yield valuable insight into clinical management of BE progression, irrespective of acid reflux symptoms.

• Authors: Jiao Huang, Hua Liu, Tiantian Sun, Jing-Yuan Fang, Jilin Wang, Hua Xiong
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 133 Issue 3 Pg. 483-495 (02 14 2019) ISSN: 1470-8736 [Electronic] England
• PMID: 30705106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Antineoplastic Agents
• CDX2 Transcription Factor
• CDX2 protein, human
• Hedgehog Proteins
• SOX9 Transcription Factor
• SOX9 protein, human
• Omeprazole

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Barrett Esophagus (drug therapy, genetics, metabolism)
• CDX2 Transcription Factor (genetics, metabolism)
• Cell Line, Tumor
• Esophageal Neoplasms (drug therapy, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hedgehog Proteins (genetics, metabolism)
• Humans
• Omeprazole (pharmacology)
• SOX9 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects)