Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma

摘要/摘要 食管腺癌(EAC)的发病率在过去增加了6倍多。 三十年了。慢性胃食道反流病(GERD)，酸性胆盐异常反流 进入食道，导致巴雷特食道(BE)的发展，这是一种癌前状态，是 EAC的主要危险因素。我们和其他人已经证明，长期暴露在酸性胆盐中会导致 炎症，与氧化应激负担的急剧增加有关；据信是 细胞信号机制的破坏和EAC的发展的主要驱动力。这是未知的 致瘤的食道细胞如何逃脱酸性胆盐反流的氧化作用 对目前使用的化疗药物产生抗药性。反应性半胱氨酸氧化还原状态的变化 位于氧化还原敏感转录因子(TF)DNA结合域内的残基可以抑制 TFS的DNA结合亲和力和转录活性。因此，细胞的氧化还原能力在 促进致癌转录因子的活性，保护致瘤细胞，促进其存活 和扩张。这个项目建立在三个项目之间的集体交互之上，这些项目产生了几个 新的初步发现。我们已经证明，AP核酸内切酶1(APE1)的氧化还原活性是 SOX9等致癌转录因子的激活对反流和 化疗药物。作为P01中科学整合的一部分，在项目2和3的工作中，我们还发现 高水平的反应性异uglandins(IsLGs)蛋白加合物促进了SOX9的稳定性。由于…… 在这些分子事件中，EACS对标准化疗药物产生内在和获得性耐药性。基座 根据我们的初步结果，我们的目标是研究APE1-reodx功能在促进SOX9激活中的作用 在EACS中。在目标1中，我们将研究APE1和等LG加合物在调节SOX9稳定性和 活动。目的2研究APE1-SOX9网络的功能结果。临床意义和 靶向APE1氧化还原活性的治疗潜力将在目标3中确定。 相关分子功能是本P01和本项目的重点，是发展证据的关键一步-- 以EAC的生物学和分子基础为基础的治疗方法。vt.在.的基础上 我们的工作完成后，我们希望发现一种新的范式来理解EAC的生物学 促进针对这种致命癌症的新医疗疗法的开发。

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.