钠钙交换体亚型1介导CDX2上调促进Barrett食管发生发展的研究

Previous study indicated that the long acid exposure and bile reflux up-regulation the expression of CDX2, which a marker for intestinal differentiation, and promote the development of Barrett's esophagus . However, the specific mechanism was not clear. The Literatures and our study have found that the intracellular calcium increase in the normal esophageal epithelial cells after application of hydrochloric acid and deoxycholic acid. This results indicated that the ion channel plan an important role in the process, and the activition of intracellular calcium signaling involved in the regulation of CDX2. Based on our previous studies demonstrating that the sodium and calcium exchange type 1(NCX1) is critical for the regulation of the intracellular calcium signaling after acid exposure and bile reflux. We hypothesis that the acid exposure and bile reflux induced intracellular calcium increase via the activity of NCX1, and activate P65 and STAT3. The binding site of STAT3 and P65 existed in the promoter region of CDX2 and up-regulate of the transcriptional expression of CDX2. We believe this project has scientific and clinical significance because successful execution of the project

研究证实酸暴露及胆汁反流能够上调肠型分化标志物尾型同源盒转录因子-2（CDX2）的表达，从而促进Barrett食管的发生发展，但具体机制不清。文献及前期实验均发现盐酸或脱氧胆酸刺激正常食管上皮细胞的过程中通常伴随着细胞内钙的增高，表明细胞内钙的变化有可能参与上述CDX2的调控，而介导钙变化的离子通道在这一事件中则起着举足轻重的作用。预实验结果发现一种胞膜上的Ca2+双向调节通道—NCX1（钠钙交换体亚型1），可能在酸暴露及胆汁刺激的细胞内钙调控过程中具有重要的作用。因此我们提出下述假设：酸暴露或者胆汁通过激活NCX1通道介导食管上皮细胞内Ca2+增加，进而活化下游转录因子P65及STAT3入核增多，结合于CDX2的启动子区域上调CDX2的表达。本课题从分子和功能调控两方面阐明NCX1在Barrett食管发生发展中的重要作用，以期为以NCX1为靶点的Barrett食管的防治提供新的依据。

Barrett's 食管是发生于食管下段鳞柱状交界区的鳞状上皮被单层柱状上皮所替代的一种病理现象， 常伴有肠上皮化生, 是一种公认的食管腺癌的癌前病变。研究证实胆汁反流能够上调CDX2的表达， 从而促进 Barrett's 食管的发生、 发展，但具体机制不清。本项目通过研究脱氧胆酸诱导细胞内钙离子平衡在Barrett’s食管发生发展中的作用及其分子机制的研究。初步揭示了离子通道介导的钙信号在脱氧胆酸刺激下调控食管细胞肠化的潜在机制。通过本研究首次证实了NCX1 在 BE 发生、发展中的作用及其机制，脱氧胆酸通过活化 TGR5/PLC/PKC 信号通路进而激活 NCX1 通道，促进食管细胞内钙活化，激活下游 NF-KB (P65) 信号通路上调食管细胞 CDX2 的表达。我们的结果不仅阐述了胆汁酸触发 BE 发生、发展的新机制，同时也为以 TGR5、NCX1 为靶点的 Barrett 食管的防治提供了新的理论依据。