Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma

摘要/总结 食管腺癌（EAC）的发病率比过去增加了6倍多 三十年了慢性胃食管反流病（GERD），其中酸性胆汁盐异常反流 进入食管，导致巴雷特食管（BE）的发展，这是一种癌前病变， EAC的主要风险因素。我们和其他人已经表明，慢性暴露于酸性胆汁盐诱导 炎症，并与氧化应激负担的急剧增加有关;被认为是 破坏细胞信号传导机制和发展EAC的主要驱动力。尚不清楚 致瘤食管细胞如何逃避酸性胆汁盐反流的氧化作用， 对目前使用的化疗剂有抗性。活性半胱氨酸氧化还原状态的改变 位于氧化还原敏感性转录因子（TF）DNA结合结构域内的残基可以抑制 转录因子的DNA结合亲和力和转录活性。因此，细胞的氧化还原能力是至关重要的， 促进致癌转录因子的活性，保护致瘤细胞并促进其存活 和扩张。该项目建立在三个项目之间的集体互动的基础上， 新的初步发现。我们已经表明AP内切核酸酶1（APE 1）的氧化还原活性是必需的， 致瘤性转录因子如SOX 9响应于暴露于反流而活化， 化疗药物作为本P01科学整合的一部分，与项目2和项目3合作，我们还发现 高水平的反应性异evuglandins（isoLG）蛋白加合物促进SOX 9的稳定性。的结果 在这些分子事件中，EAC对标准化疗产生内在和获得性抗性。基于 基于我们的初步结果，我们旨在研究APE 1-reodx功能在促进SOX 9活化中的作用。 在EAC。在目标1中，我们将研究APE 1和异LG加合物在调节SOX 9稳定性中的作用， 活动目的2中研究了APE 1-SOX 9网络的功能结果。的临床意义及 靶向APE 1氧化还原活性的治疗潜力将在目标3中确定。理解生物学- 相关的分子功能，这个P01和这个项目的重点，是发展证据的关键一步- 基于EAC的生物学和分子基础的治疗方法。后 我们的工作完成后，我们希望发现一个新的范式，了解EAC的生物学， 促进了针对这种致命癌症的新型医学治疗的发展。

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, 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 to acidic bile salts induces inflammation and is associated with a dramatic increase in the burden of oxidative stress; believed to be the main driving forces for disruption of cellular signaling mechanisms and the development of EAC. It is unknown how tumorigenic esophageal cells escape the oxidative effects of acidic bile salts reflux and also become resistant to currently used chemotherapeutic agents. Alterations in the redox status of reactive cysteine residues, located within the DNA-binding domain of redox-sensitive transcription factors (TFs), can suppress TFs’ DNA binding affinity and transcription activity. Therefore, the cellular redox capacity is paramount in promoting activity of oncogenic transcription factors, protecting tumorigenic cells and promoting their survival and expansion. This project builds upon collective interaction among the three projects generating several novel preliminary findings. We have shown that AP endonuclease 1 (APE1) redox activity was required for activation of tumorigenic transcription factors such as SOX9 in response to exposure to reflux and chemotherapeutics. As part of scientific integration in this P01, working with Projects 2 and 3, we also found that high levels of reactive isolevuglandins (isoLGs) protein adducts promote stability of SOX9. As a result of these molecular events, EACs develop intrinsic and acquired resistance to standard chemotherapeutic. Based on our preliminary results, we aim to investigate the role of APE1-reodx function in promoting SOX9 activation in EACs. In Aim 1, we will investigate the role of APE1 and isoLG adducts in regulating SOX9 stability and activity. The functional outcome of APE1-SOX9 network is investigated in Aim 2. The clinical significance and therapeutic potential of targeting APE1 redox activity will be determined in Aim 3. Understanding biology- relevant molecular functions, the focus of this P01 and this project, is a key step for developing evidence- based therapeutic approaches that are founded on the biology and molecular underpinning of EAC. Upon completion of our work, we expect to uncover a new paradigm for understanding the biology of EAC to facilitate the development of novel medical treatments for this deadly cancer.