Omeprazole prevents CDX2 and SOX9 expression by inhibiting hedgehog signaling in Barrett's esophagus cells
Omeprazole prevents CDX2 and SOX9 expression by inhibiting hedgehog signaling in Barrett's esophagus cells
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DOI：
10.1042/cs20180828
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发表时间：
2019-02-14
期刊：
影响因子：
6
通讯作者：
Xiong, Hua
中科院分区：
文献类型：
--
作者：
Huang, Jiao;Liu, Hua;Xiong, Hua
刺猬（Hh）信号的激活有助于巴雷特食管（BE）的进展，这增加了食管腺癌的风险。最近的临床研究表明，质子泵抑制剂（PPI）而不是H2受体拮抗剂（H2 RA）与食管腺癌风险降低相关。我们想知道在BE治疗期间PPI是否会干扰BE进展。在这里，我们探讨了奥美拉唑对Hh信号传导和BE，SOX 9和CDX 2的两个关键生物标志物表达的作用。我们证明，胆汁酸升高Hh通路靶基因的表达，如GLI 1和PTCH 1，并诱导SOX 9和CDX 2在CP-A和CP-B细胞中上调。奥美拉唑，而不是法莫替丁，下调这些基因诱导的胆汁酸。此外，奥美拉唑诱导的SOX 9和CDX 2下调由Hh信号转导介导。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，但没有发现奥美拉唑对Hh信号传导的关键转录因子GLI 1启动子活性的任何影响。因此，我们在我们的研究中使用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类器官中不同表达的miRNA，并且我们鉴定了miR-2116- 3 p参与奥美拉唑介导的Hh信号传导抑制以及随后的SOX 9和CDX 2下调。总的来说，我们的数据表明奥美拉唑通过上调miR-2116- 3 p抑制Hh信号传导和随后的SOX 9和CDX 2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，这可能会对BE进展的临床管理产生有价值的见解，无论酸反流症状如何。
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.