The role of NRF2 in reflux-induced esophageal adenocarcinomas

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ABSTRACT/SUMMARY: 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 affects almost 20% of adult US population. GERD leads to the development of a glandular epithelium known as Barrett's esophagus (BE); the main risk factor for the development of neoplastic lesions; high-grade dysplasia (HGD) and progression to EAC. We and others have shown that chronic exposure of BE cells to acidic bile salts is associated with a dramatic increase in the burden of reactive oxygen species (ROS) and oxidative stress. We have found that several members of the glutathione family members that protect against oxidative stress in BE cells are silenced in neoplastic HGD and EAC. EAC cells are exposed to high levels of ROS and oxidative stress due to chronic acidic bile reflux and activation of oncogenes. Failure to control the cumulative levels of ROS and oxidative stress would be lethal to cancer cells, if they remain uncorrected. We hypothesize that; with the silencing of several antioxidant genes in progression from BE to HGD/EAC, cancer cells must develop an antioxidant network that prevents uncontrolled accumulation of ROS. These adaptive mechanisms are crucial in promoting their survival in response to high levels of ROS due to exposure to acidic bile salts, activation of oncogenes, and treatment with chemotherapeutics. Our preliminary data demonstrated constitutive high levels of expression of NRF2 in HGD/EAC, suggesting its role as an intrinsic adaptive molecular mechanism. We show for the first time that accumulation of NRF2 protein and its activation in EAC is mainly dependent on redox factor 1 (REF1); not on its physiological inhibitor KEAP1. In this proposal, we will investigate the biological relevance of NRF2 antioxidant functions in regulating ROS, oxidative stress, oxidative DNA damage, gene expression, and cell survival in response to acidic bile salts and chemotherapeutics. The regulation of NRF2 by REF1 and its transcription network will be investigated in Aim 1. In Aim 2, we will tackle previously unexplored roles of NRF2 in EAC tumorigenesis and identify the role of NRF2 in EAC cancer cell survival in response to acidic bile salts and chemotherapeutics. The clinico-pathological significance of NRF2 expression and its significance as a druggable target will be investigated alone and in combination with existing chemotherapeutics (Aim 3). In summary, this project addresses gaps in our knowledge and tackles etiology-based biologically relevant questions to uncover novel information regarding the role of NRF2 in regulating survival and chemotherapeutic resistance in EAC. The findings are especially important as several NRF2 activators are available over the counter and are also used to treat some clinical disorders such multiple sclerosis (MS). Treatments with NRF2 activators may need to be carefully monitored in patients with MS and BE, as they could be at higher risk for EAC because of NRF2 pro-tumorigenic effects in this setting. Our results could also support the development of NRF2 inhibitors and provide a novel window of therapeutic opportunity for EAC treatment.