Role of Acid in the Development of Barrett's Esophagus

描述(申请人提供)：胃食道反流病(GERD)已被确定为食管腺癌的强烈危险因素。GERD可并发食管炎，或以Barrett‘s食管化生黏膜(BE)取代食道鳞状黏膜。在持续消化性损伤的情况下，BE可导致食管腺癌。目前尚不清楚为什么只有少数GERD患者发展为BE，或者为什么只有少数BE患者发展为食管腺癌。这一空白的原因之一是酸反流引发的分子事件，介导了BE的发展和肿瘤进展，但特征不佳。我们实验室的初步数据表明，酸激活了BE患者化生黏膜中的丝裂原活化蛋白激酶(MAPK)通路，并激活了正常人和未发展为BE的GERD患者的鳞状黏膜中的MAPK通路。相反，我们发现酸不能激活BE患者鳞状黏膜中的MAPK通路。我们推测，酸激活了MAPK依赖的信号转导通路，增加了细胞周期蛋白D1的表达，并引发了正常食管鳞状上皮和BE化生上皮细胞增殖的增加和凋亡的减少。根据我们的初步数据，这一基本假设对BE的发展和肿瘤进展具有临床意义。在正常和未发生BE的患者的食管鳞状上皮中，MAPK依赖通路的酸激活可能促进酸损伤的食道黏膜的修复；在BE患者中，酸不能激活MAPK通路可能会阻止酸损伤的鳞状上皮的再生，并易于通过化生修复。然而，一旦发生BE，对MAPK依赖通路的酸刺激可能更容易导致食管腺癌的发生。本研究的目的是利用体内和体外实验系统，评价酸对Barrett化生和食管鳞状上皮细胞中ERK、p38和JNK的MAP-K通路、AP-1转录因子家族、细胞周期蛋白D1表达的影响及其对细胞增殖和凋亡的影响。我们的长期目标是确定BE的分子标志物和分子靶点，以指导BE和食管腺癌患者的化学预防和化疗药物。

DESCRIPTION (provided by applicant): Gastroesophageal reflux disease (GERD) has been established as a strong risk factor for esophageal adenocarcinoma. GERD can be complicated by esophagitis, and by replacement of esophageal squamous mucosa with the metaplastic mucosa of Barrett's esophagus (BE). In the setting of continued peptic injury, BE can give rise to esophageal adenocarcinoma. It is not known why only a minority of individuals with GERD develop BE, or why only a minority of individuals with BE develop esophageal adenocarcinoma. One reason for this void is that the molecular events triggered by acid reflux which mediate the development and neoplastic progression of BE are poorly characterized. Preliminary data from our laboratory demonstrate that acid activates the mitogen activated protein kinase (MAPK) pathways in the metaplastic mucosa of patients with BE, and in the squamous mucosa of normal subjects and of patients with GERD who do not develop BE. In contrast, we found that acid fails to activate the MAPK pathways in the squamous mucosa of patients with BE. We hypothesize that acid activates the MAPK-dependent signal transduction pathways which increase expression of cyclin D1, and trigger an increase in cell proliferation and a decrease in apoptosis in normal esophageal squamous epithelium and in the metaplastic epithelium of BE. Based on our preliminary data, this basic hypothesis has clinical implications for both the development and neoplastic progression of BE. In the esophageal squamous epithelium from normal patients and patients who do not develop BE, acid activation of MAPK-dependent pathways may promote repair of the acid damaged esophageal mucosa; in patients who develop BE, failure of acid to activate MAPK pathways may prevent regeneration of the acid damaged squamous mucosa and predispose to repair through metaplasia. However, once BE develops, acid stimulation of MAPK-dependent pathways may predispose to the development of esophageal adenocarcinoma. The aims of our study are to evaluate the acid induced effects on the ERK, p38, and JNK MAP kinase pathways, the AP-1 family of transcription factors, cyclin D1 expression, and its effect on cell proliferation and apoptosis in Barrett's metaplasia and esophageal squamous mucosa using in vivo and in vitro systems. Our long term goals are to identify molecular markers of BE and molecular targets at which to direct chemopreventive and chemotheapeutic agents for patients with BE and esophageal adenocarcinoma.