Pilot Project 2: Nrf2 Activation in Esophageal Squamous Cell Carcinogenesis In Vivo

摘要： 食道鳞状细胞癌(ESCC)主要影响非裔美国人而非高加索人 美国人的比例约为4：1。患有ESCC的非裔美国人的预后比他们的 高加索人的同行。因此，更好地了解ESCC和ESCC的分子机制具有重要意义。 为这一致命疾病开发有针对性的治疗方法，以减少种族差异。最新的下一代测序 研究发现人类ESCC中存在多种驱动突变，其中Nrf2和Keap1突变是 已知可激活Nrf2信号。然而，Nrf2相关致癌的分子机制有 尤其是在活体内，还没有被清楚地理解。根据我们的初步数据，我们假设NRF2 激活通过EGFR/PI3K/Akt途径诱导食道过度增殖和角化过度 代谢重新编程。使用Keap1/-小鼠的食道过度增殖和过度角化病模型， 我们计划用两个具体的目标来验证我们的假设：(1)检查Keap1-/-中Nrf2的激活 食道通过转录激活EGFR/PI3K/Akt途径和代谢重编程 EGFR/PI3K/Akt通路基因调控与能量代谢(2)检测基因或 化学抑制EGFR/PI3K/Akt通路或代谢重编程可能抑制食道 Keap1-/-小鼠的表型，以及对这两种事件的抑制是否具有协同效应。这一试点项目 目的是了解Nrf2在食道鳞状细胞中激活的致癌机制。 体内致癌作用。如果成功，将为NRF2-HIGH的翻译研究奠定坚实的基础 并有助于缩小非裔美国人的癌症健康差距。

Abstract: Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their Caucasian counterparts. Therefore it is important to better understand molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 activation induces esophageal hyperproliferation and hyperkeratosis through the EGFR/PI3K/Akt pathway and metabolic reprogramming. Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- esophagus activates the EGFR/PI3K/Akt pathway and metabolic reprogramming through transcriptional regulation of genes of the EGFR/PI3K/Akt pathway and energy metabolism. (2)To test whether genetic or chemical inhibition of the EGFR/PI3K/Akt pathway or metabolic reprogramming may suppress esophageal phenotype in Keap1-/- mice, and whether inhibition of both events may have synergistic effect. This Pilot Project is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high ESCC and contribute to reduction of cancer health disparity in the African American population.