解痉肽表达化生（SPEM）在Barrett食管胃、肠型分化中的作用及癌变潜能研究

The definition of Barrett’s esophagus （BE） is still controversial. The major issue underlying disagreement on histologic criteria for the diagnosis of BE is whether comprises intestinal metaplasia or not. Therefore，it is very important to clarify the mechanism of gastric and intestinal differentiation of BE and their potential for esophageal adenocarcinoma. Recent investigations have demonstrated a new metaplastic lineage, chief cells transdifferentiate into Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) which develops in the fundus in the setting of parietal cell loss following chronic inflammation. However, its molecule mechanism is still unclear.We hypothesize that Be epithelium cells can transdifferentiate into gastric and intestinal cells through SPEM pathway induced by acid and bile salt. To investigate that possibility, we want to study the effects of acid and bile salt on transdifferentiation of BE epithelium cells into gastric and intestinal epithelium and their potential for esophageal adenocarcinoma, to evaluate the role of SPEM in this course in vivo and in vitro. Our study may reveal the mechanism of gastric and intestinal differentiation of BE and explore a new way for prevention and treatment of BE.

目前国际上关于Barrett食管（BE）的定义仍有争论，争论的焦点是BE的诊断是否需要肠上皮化生的存在。研究BE黏膜胃型和肠型化生的机制及癌变潜能对BE的诊断和治疗均有重要的指导意义。新近研究发现，胃底黏膜在炎症因素作用下可引起壁细胞的缺失，由主细胞转分化为解痉肽表达化生（Spasmolytic Polypeptide-Expressing Metaplasia, SPEM），然后出现肠上皮化生，但其发生的分子机制仍不清楚。据此我们设想，在酸和胆盐等炎症因素的作用下，BE上皮可以可通过SPEM途径进一步分化为胃型和肠型上皮细胞。为证实以上设想，我们拟通过体内外实验研究胃酸、胆汁及混合反流物对BE黏膜向胃、肠黏膜上皮细胞分化的影响，探讨SPEM在BE上皮向胃型和肠型分化的作用和机制及癌变潜能，从全新的角度揭示BE胃型和肠型分化的分子机制及癌变潜能，并为BE的防治提供新的探索途径。

目前柱状非杯状细胞Barrett食管（BE）发育的分子机制仍是未知的。本项研究调查了胃食管反流介导的损伤对食管鳞状上皮细胞转化为解痉肽表达化生（SPEM）组织的影响以及柱状非杯状细胞BE和SPEM之间的关系。实验数据显示，在BE活检标本中，非杯状柱状上皮细胞中SPEM的出现频率高于带有杯状的柱状上皮细胞，胆汁酸反流可诱导SPEM标记物TFF2和MUC6的表达。胆汁酸处理主细胞会增加STAT3的表达，并且抑制Notch和STAT3通路会使食管鳞状上皮细胞转分化为SPEM。这些结果表明胃食管反流通过柱状非杯状细胞Barrett食管中的Notch和STAT3途径促进了SPEM。