The incidence of esophageal adenocarcinoma (EAC) has increased more than six fold over the past three decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts abnormally refluxate into the esophagus. leads to the development of Barrett's esophagus (BE), a premalignant condition that is the main risk factor for EAC. We and others have shown that chronic exposure of BE cells to acidic bile salts induces inflammation and is associated with a dramatic increase in the burden of reactive oxygen species and oxidative stress: believed to be the main driving forces for disruption of cellular signaling mechanisms and the development of EAC. Exposure to oxidative stress can alter the redox status of reactive cysteine residues, located within the DNA-binding domain of some transcription factors (TFs), thereby modulating their activity and DNA binding affinity. Therefore, the cellular redox capacity is paramount in protecting these redox-sensitive TFs. The exposure of cells to oxidative agents and oxidative stress also leads to formation of pre-mutagenic apurinic/apyrimidinic (AP) sites in DNA molecules, which if unrepaired, lead to the formation and accumulation of additional DNA damage lesions, up to lethal levels. It is unknown how Barrett's and EAC can escape the oxidative effects of acidic bile salts reflux and also become resistant to currently used chemotherapeutic agents. APE1 is the only known protein with dual functions; 1) base excision repair (BER) activity, an important function for repair of oxidative DNA lesions, 2) redox-dependent functions that protect the cellular transcription machinery. In this proposal, we plan to characterize the molecular function(s) of APE1, a frequently overexpressed gene in EAC, in order to identify its biological, diagnostic, prognostic, and possibly therapeutic significance. Based on our preliminary data, we hypothesize that APE1 can promote the oncogenic pro-survival properties of Barrett's cancer cells through redox-dependent and independent (BER) functions.
In aim 1, we will investigate the interplay between cellular localization, structure (BER and redox domains) and functions of APE1 in Barrett's carcinogenesis.
In aim 2, we will examine the APE1-dependent redox functions in Barrett's carcinogenesis. The clinical significance and therapeutic potential of APE1 in EAC will be determined in aim 3. Upon completion of our work, we expect to unveil a new paradigm for the protective molecular mechanisms against oxidative stress in Barrett's carcinogenesis.
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