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

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 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 upregulation in both CPA and CPB cells. Omeprazole, but not famotidine, downregulated these genes induced by bile acids. In addition, omeprazole-induced downregulation of SOX9 and CDX2 was mediated by Hh signaling. To explore the mechanisms by which omeprazole inhibits Hh signaling, we performed luciferase assay but didn't find any effects of omeprazole on the activity of GLI1 promoter, the critical transcription factor of Hh signaling. Therefore， we used microRNA sequencing and a bioinformatic 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 downregulation of SOX9 and CDX2. Collectively, our data indicate omeprazole inhibits Hh signaling and subsequent...

Source: Clinical Science - January 31, 2019 Category: Biomedical Science Authors: Huang, J., Liu, H., Sun, T., Fang, J.-Y., Wang, J., Xiong, H. Tags: PublishAheadOfPrint Source Type: research