The role of NRF2 in reflux-induced esophageal adenocarcinomas

摘要/摘要：食管腺癌(EAC)的发病率增加了6倍以上。 在过去的三十年里折叠起来。慢性胃食道反流病(GERD)，酸性胆盐 反常的食道反流影响了近20%的美国成年人口。GERD通向 发展的腺上皮称为巴雷特的食道(BE)；主要危险因素 肿瘤病变的发展；高度不典型增生(HGD)和进展为EAC。我们和其他人有 研究表明，BE细胞长期暴露在酸性胆盐中与负荷的急剧增加有关 活性氧物种(ROS)和氧化应激。我们发现该委员会的几名成员 保护BE细胞免受氧化应激的谷胱甘肽家族成员在肿瘤性HGD和 EAC。EAC细胞暴露在高水平的ROS和氧化应激下，这是由于慢性酸性胆汁反流和 癌基因的激活。如果不能控制ROS的累积水平和氧化应激，将对 癌细胞，如果它们不被纠正的话。我们假设，随着几个抗氧化基因的沉默 在从BE发展到HGD/EAC的过程中，癌细胞必须形成一个抗氧化网络，以防止 ROS的不受控制的积累。这些适应机制对于促进它们在 对暴露于酸性胆盐、癌基因激活和治疗引起的高水平ROS的反应 用化疗药物。我们的初步数据显示，NRF2在卵巢癌中有结构性的高水平表达 HGD/EAC，提示其作为一种内在的适应性分子机制发挥作用。我们第一次展示了 NRF2蛋白在EAC中的积累及其激活主要依赖于氧化还原因子1(REF1)，而不是依赖于 其生理抑制因子Keap1。在这项提案中，我们将研究NRF2的生物学相关性 抗氧化剂在调节ROS、氧化应激、DNA氧化损伤、基因表达和细胞中的作用 对酸性胆盐和化疗药物的反应存活。REF1对NRF2的调控及其作用机制 在目标1中，我们将研究转录网络。在目标2中，我们将解决以前未探索的NRF2的角色 在EAC肿瘤发生中的作用及确定NRF2在酸性胆盐反应EAC癌细胞存活中的作用 和化疗药物。NRF2表达的临床病理意义及其临床意义 将单独和与现有化疗药物联合研究可药物靶标(目标3)。在……里面 总结，这个项目解决了我们知识上的差距，并解决了基于病因学的生物学相关问题 关于NRF2在调节生存和化疗中的作用的新信息的问题 EAC中的抗性。这一发现尤其重要，因为有几种NRF2激活剂在 该药也用于治疗多发性硬化症(MS)等临床疾病。治疗 对于患有MS和BE的患者，可能需要仔细监测NRF2激活剂，因为他们可能在 在这种情况下，由于NRF2的促肿瘤作用，EAC的风险更高。我们的结果也可以支持 NRF2抑制剂的开发，为EAC的治疗提供了新的治疗机会之窗。

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.