State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China.
State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
Clin Sci (Lond). 2019 Feb 12;133(3):483-495. doi: 10.1042/CS20180828. Print 2019 Feb 14.
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 and , 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.
hedgehog（Hh）信号的激活有助于 Barrett 食管（BE）的进展，从而增加食管腺癌的风险。最近的临床研究表明，质子泵抑制剂（PPIs）而非 H2 受体拮抗剂（H2RAs）与食管腺癌风险降低相关。我们想知道 PPIs 是否会在 BE 治疗期间干扰 BE 的进展。在这里，我们探讨了奥美拉唑对 Hh 信号传导和 BE 的两个关键生物标志物 SOX9 和 CDX2 的表达的作用。我们证明了胆汁酸会升高 Hh 通路靶基因的表达，例如 和 ，并诱导 CP-A 和 CP-B 细胞中 SOX9 和 CDX2 的上调。奥美拉唑而非法莫替丁可下调胆汁酸诱导的这些基因。此外，奥美拉唑诱导的 SOX9 和 CDX2 下调是由 Hh 信号传导介导的。为了探索奥美拉唑抑制 Hh 信号传导的机制，我们进行了荧光素酶测定，但未发现奥美拉唑对 Hh 信号传导的关键转录因子 GLI1 启动子活性有任何影响。因此，我们在研究中使用 miRNA 测序和生物信息学工具来鉴定用或不用奥美拉唑处理的 BE 类器官中差异表达的 miRNAs，我们发现 miR-2116-3p 参与了奥美拉唑介导的 Hh 信号抑制以及随后的 SOX9 和 CDX2 下调。总之，我们的数据表明奥美拉唑通过上调 miR-2116-3p 抑制 Hh 信号传导及其随后的 SOX9 和 CDX2 表达。我们已经证明了奥美拉唑的一种新的酸非依赖性机制，这可能为临床管理 BE 进展提供有价值的见解，而与酸反流症状无关。
