环境浓度下DDT暴露对Wnt/β-catenin信号通路介导的大肠癌肿瘤学效应的影响

Colorectal cancer is one of the common malignant tumors, and Wnt/β-catenin signaling pathway lays a crucial role in the colorectal carcinogenesis. Epidemiological surveys discovered that colorectal cancer occurrence and development are related to DDT pollution, but its molecular mechanism remains unclear. Our previous studies indicated that DDT exposure promotes cancer cell proliferation and migration, and causes the Wnt/β-catenin signaling pathway activation. On this basis, this project intends to use p, p'-DDT as a target compound. We are firstly going to measure DDT concentrations in serum and the expression levels of Wnt signaling molecules in the colorectal cancer patients with different pathological staging. Combined with pathological staging, we shall analyze the relevance of Wnt/β-catenin signal pathway abnormal activation、 pollution characteristics of DDT with the incidence of colorectal cancer. Moreover, we are going to use the nude mice colorectal cancer model to validate the influences of Wnt/β-catenin signaling pathway mediated by DDT exposure on colorectal carcinogenesis. On this basis, the cancer cell lines will be hired to study the molecular mechanism of Wnt/β-catenin signaling pathway mediated by DDT exposure on colorectal carcinogenesis. This project aims to elucidate the molecular mechanisms of Wnt/β-catenin signaling pathway mediated by the environmental concentrations of DDT on colorectal cancer. This study will provide the scientific basis for prevention and control of colorectal cancer in the relevant population.

大肠癌是危害人民健康的常见恶性肿瘤之一，且Wnt/β-catenin信号通路激活在大肠癌进展中起决定性作用。流行病学调查发现大肠癌发生发展与DDT污染有关，但其分子机制尚不清楚。本项目前期研究表明，DDT暴露促进肠癌细胞增殖和迁移，且引起Wnt/β-catenin信号通路激活。在此基础上，本项目拟以p,p'-DDT为目标化合物，在大肠癌不同病理分期患者中分析Wnt/β-catenin信号通路异常激活和DDT污染特征与大肠癌的相关性；以肠癌裸鼠模型验证Wnt/β-catenin信号通路介导的DDT暴露对大肠癌发展的影响；以肠癌细胞系研究Wnt/β-catenin信号通路介导的DDT暴露促进肠癌细胞增殖及其引起大肠癌发展的分子机理。本项目旨在阐明环境浓度DDT暴露下，Wnt/β-catenin信号通路介导的大肠癌发展过程及其分子机制，为相关人群大肠癌预防和控制提供科学依据。

滴滴涕(Dichlorodiphenyltrichloroethane，DDT)是一种曾经被广泛使用的有机氯农药，对生态环境和人类健康带来极大危害。大肠癌是危害人类健康的一种的恶性肿瘤。流行病学调查表明，DDT及其代谢物DDE暴露与大肠癌发病有关，但两者间的具体作用机制并不清楚。本研究主要探讨p, p’-DDT及代谢物p, p’-DDE对大肠癌进展的影响及作用机制。研究内容包括以下几个部分：1）大肠癌患者血清中DDT负荷与大肠癌发病的相关性。以自然人群为基础，分别收集了山西省大肠癌和对照血清，分析比较样品DDT含量差异。取病例组和正常组织标本，比较Wnt/β-catenin信号通路主要成员β-catenin的表达情况。结果表明DDT的检出率为100%。总DDT的残留量高于对照组。高DDT残留患者组织中β-catenin表达水平较高。2）p, p’-DDT暴露对大肠癌细胞增殖的影响及作用机制。利用体内裸鼠成瘤模型和体外大肠癌细胞研究p,p’-DDT促大肠癌细胞增殖的效应。结果表明低浓度的p, p’-DDT在体内和体外均能促进大肠癌细胞增殖，其机制是通过氧化应激介导的Wnt/β-catenin信号通路激活进而促进大肠癌细胞增殖。3）p, p’-DDT暴露对大肠癌细胞凋亡的影响及作用机制。利用体内裸鼠成瘤模型和体外大肠癌细胞研究p,p’-DDT抑制大肠癌细胞凋亡的效应及分子机制。结果表明p,p’-DDT能抑制大肠癌细胞凋亡，其机制是通过激活PI3K/AKT和Hedgehog/Gli1信号通路进而抑制大肠癌细胞凋亡。4）代谢物p, p’-DDE暴露对大肠癌细胞增殖的影响及作用机制。利用体外大肠癌细胞系研究p,p’-DDE促大肠癌细胞增殖的效应。结果表明低浓度的p, p’-DDE具有促进大肠癌细胞增殖的效应，其机制是通过氧化应激介导的Wnt/β-catenin和Hedgehog/Gli1信号通路激活进而促进大肠癌细胞增殖。综上所述，低浓度的p, p’-DDT及代谢物p, p’-DDE具有促进大肠癌发展的效应。这一研究对于理解有机农药DDT及其类似物促大肠癌发展的机制提供了重要的理论数据。