Regulation of the JAK/STAT Signaling and Esophageal Tumorigenesis in Conditions of Esophageal Reflux Injury

摘要/摘要 食管腺癌(EAC)是美国上升最快的癌症之一。这个肿瘤还有待于 一种难以治疗的疾病，手术是目前治疗的主要方法，具有显著的发病率和 死亡率。EAC生物学与慢性胃食道反流病(GERD)密切相关，GERD是一种消化性疾病 胃酸和十二指肠胆盐进入食道引起强烈的组织损伤和破坏的疾病。 巴雷特化生(BE)的发生发展。BE是一种可进展到EAC的癌前状态。然而， 这种肿瘤形成过程背后的具体机制仍然知之甚少，限制了肿瘤的发展 EAC的新预防和治疗选择。 我们提出了一个创新的假说，解释了反流是如何在 反应性异uglandins的蛋白内吞和JAK/STAT的异常激活 信号通路。这一假说得到了动物研究产生的强大初步数据的支持 BE和GERD患者的人体组织标本分析 在目标1中，我们将定义调节JAK/STAT信号的新的、以前未描述的机制 在食道反流损伤的情况下通过蛋白质加成。在目标2中，我们将研究PRO-2的调节 使用EAC动物模型和人类临床标本研究Tein在食道壁龛中的加合物。在目标3中，我们 将测试在由慢性气体创造的促肿瘤环境中抑制蛋白质加成的各种选择- 食道反流，并研究其如何影响食道癌的发生。 我们的项目是P01项目的组成部分，重点是EAC肿瘤发生的机制研究 同时探索新的癌症化学预防和治疗方案。这次合作学习也将扩大 并通过探索等位基因的交叉点加深我们对食道癌发生的理解。 具有APE1-SOX9和SOX4信令网络的Leuglandins，在项目2和3中检查。我们的集体 该项目和P01计划的研究有望为新的治疗应用奠定基础。

ABSTRACT/ SUMMARY Esophageal adenocarcinoma (EAC) is one of the fastest rising cancers in the US. This tumor remains to be a poorly treatable disease with surgery that is the mainstay of current therapy, carrying significant morbidity and mortality. The EAC biology is tightly linked to chronic gastroesophageal reflux disease (GERD), a digestive disorder in which gastric acid and duodenal bile salts enter the esophagus causing strong tissue injury and de- velopment of Barrett’s metaplasia (BE). BE is a precancerous condition that can progress to EAC. Yet, the specific mechanisms underlying this tumorigenic process remain poorly understood limiting the development of new preventive and treatment options for EAC. We have developed an innovative hypothesis explaining how reflux induces carcinogenic alterations in the esophagus through protein adduction with reactive isolevuglandins and aberrant activation of the JAK/STAT signaling pathway. This hypothesis is supported by strong preliminary data generated by animal studies and analyses of human tissue specimens collected from patients with BE and GERD. In aim 1, we will define novel, previously uncharacterized mechanisms regulating the JAK/STAT signaling by protein adduction in conditions of esophageal reflux injury. In aim 2, we will investigate the regulation of pro- tein adducts in the esophageal niche using animal models of EAC and human clinical specimens. In aim 3, we will test various options to inhibit protein adduction in a pro-tumorigenic environment created by chronic gas- troesophageal reflux and investigate how it affects esophageal carcinogenesis. Our project is an integral part of the P01 program focused on the mechanistic studies of EAC tumorigenesis while exploring novel cancer chemopreventive and treatment options. This cooperative study will also expand and deepen our understanding of esophageal carcinogenesis by exploring the intersections of the iso- levuglandins with APE1-SOX9 and SOX4 signaling networks, examined in Projects 2 and 3. Our collective studies in this project and P01 program are expected to lay the groundwork for novel therapeutic applications.