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

摘要： 食管鳞状细胞癌（ESCC）主要影响非洲裔美国人，而不是白人 美国人的比例约为4：1。患有ESCC的非洲裔美国人的预后比他们的预后差得多。 白人同行因此，更好地理解ESCC的分子机制是重要的， 为这种致命疾病开发靶向治疗，以减少种族差异。最近的NextGen测序 研究已经确定了人类ESCC中的多种驱动突变，其中Nrf 2和Keap 1突变是 已知激活Nrf 2信号。然而，Nrf 2相关致癌作用的分子机制已经被证实， 还没有被清楚地理解，特别是在体内。根据我们的初步数据，我们假设Nrf 2 激活通过EGFR/PI 3 K/Akt途径诱导食管过度增殖和过度角化， 代谢重编程使用食管过度增殖和过度角化的Keap 1-/-小鼠模型， 我们计划用两个具体的目的来检验我们的假设：（1）为了检验Keap 1-/- 食管通过转录激活EGFR/PI 3 K/Akt通路和代谢重编程 EGFR/PI 3 K/Akt通路和能量代谢的基因调控。(2)To测试是否遗传或 EGFR/PI 3 K/Akt通路的化学抑制或代谢重编程可以抑制食管癌的发生。 Keap 1-/-小鼠中的表型，以及两种事件的抑制是否可能具有协同效应。这一试点项目 目的：探讨食管鳞状细胞Nrf 2激活的致癌机制 体内致癌作用如果成功，将为Nrf 2-high的转化研究奠定坚实的基础 ESCC，并有助于减少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.