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

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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.