基于多组学的毒作用模式对亚硝胺暴露致食管癌风险研究

Esophageal cancer is one of priority controlled malignant tumors with high incidence in China. The data in our recent study indicated that populations from the high incidence area of esophageal cancer were more highly exposed to N-nitrosamines. To systematically elucidate the carcinogenic effect of N-nitrosamines, multi-omics analysis technology and mode of action/adverse outcome pathway(MOA/AOP) will be applied to analyze the toxic phenotypes including metabolic disorders and protein expression differences in rat model of esophageal cancer by N-nitrosamines exposure in the study. The potential mechanisms and key molecules will be explored and recognized in the progression of esophageal carcinoma. Furthermore, the candidate biomarkers for esophageal cancer will be screened and confirmed in a case-control epidemiologic study and the association of N-nitrosamines exposure and the risk of esophageal cancer will be further verified in a cohort study. Finally, risk stratification model is to be established in attempt to identify the high-risk individuals in the screening of esophageal cancer, and to provide a scientific and rational strategy for comprehensive prevention and control of esophageal cancer.

食管癌是我国重点防控的高发恶性肿瘤之一。本项目拟在食管癌高发区人群亚硝胺高暴露水平前期研究发现的基础上，拟构建亚硝胺致食管癌大鼠模型，采用多组学技术和MOA/AOP分析策略，分析亚硝胺暴露所引起的代谢紊乱、蛋白表达差异等毒性表型，探讨亚硝胺诱导食管癌发生可能的分子机制，识别亚硝胺致食管癌的关键分子事件，探讨其与食管癌发生发展相关结局之间的关联强度，发现具有较高效应预测价值的候选生物标志；进一步结合人群病例-对照研究筛选食管癌预测生物标志，并在队列研究基础上进一步验证亚硝胺暴露与食管癌风险的关联性，构建亚硝胺暴露致食管癌风险评估模型，服务于高发区食管癌筛查，为食管癌综合防控提供科学依据。

食管癌是我国重点防控的高发恶性肿瘤之一。本项目拟在食管癌高发区人群亚硝胺高暴露水平前期研究发现的基础上，拟构建亚硝胺致食管癌大鼠模型，采用多组学技术和MOA/AOP分析策略，分析亚硝胺暴露所引起的代谢紊乱、蛋白表达差异等毒性表型，探讨亚硝胺诱导食管癌发生可能的分子机制，识别亚硝胺致食管癌的关键分子事件，探讨其与食管癌发生发展相关结局之间的关联强度，发现具有较高效应预测价值的候选生物标志；进一步结合人群病例-对照研究筛选食管癌预测生物标志，并在队列研究基础上进一步验证亚硝胺暴露与食管癌风险的关联性，构建亚硝胺暴露致食管癌风险评估模型，服务于高发区食管癌筛查，为食管癌综合防控提供科学依据。初步得出以下结论：.1. 食管癌高发区人群亚硝胺暴露水平高于低发区人群。.2. NMEA、NDBA和NPyr暴露与ESCC风险正相关，NMEA和NDBA暴露与RE/BCH风险正相关。.3. 炎性反应是低浓度亚硝胺共暴露的重要毒效应。亚硝胺既可诱导Cys和MET代谢介导组蛋白甲基化上调，促进炎症反应；也可以下调NAD+/NADH比值，抑制SIRT1介导的NF-кB p65去乙酰化，激活NF-кB信号通路，促进炎性因子释放。.4. NA和NAM代谢、鞘脂代谢和TRP代谢是NMBA诱导大鼠ESCC发生发展过程中的关键代谢通路，通过干扰能量代谢、炎性微环境和免疫抑制，促进食管上皮恶性转化。.5. TRP代谢以及鞘脂代谢改变是人ESCC的重要代谢特征。S1P、TRP、SPH/S1P、DH-S1P可能成为亚硝胺致ESCC的潜在效应生物标志。.6. 代谢组学分析表明，亚硝胺暴露主要引起富含脂质脂肪酸的代谢途径的显著改变。.7. 脂质组学分析表明亚硝胺暴露导致小鼠肝脏PA、PC、PE、LPC、LPE、DAG、TAG、Cer以及FA的分解和氧化。