基于Nrf2信号通路探讨莱菔硫烷对结肠癌的化学预防作用及其机制

It is of great importance to develop efficient prevention measures of colon cancer due to the high incidence and the deficiency of effective treatments. Sulforaphane is a safe phytochemical with easy availability, which is proved to be able to increase the expression of UGT1A, a subfamily of phase II metabolic enzyme, in human colon cancer Caco-2 cells in our prior study and thus may have a chemopreventive effect on colon cancer. Through cell culture and animal model building, our project intends to further explore the chemopreventive effect of sulforaphane on colon cancer and elucidate its machanism. We will ascertain the role of Nrf2 signal transduction pathway in the UGT1A expression-inducing effect of sulforaphane by silencing Nrf2 gene expression with the application of RNA interference technique and further study the epigenetic mechanism and the upstream signal transduction pathway of the activation of Nrf2 pathway by sulforaphane. And then we will verify the induction of UGT1A expression by sulforaphane and its chemopreventive effect on colon cancer as well as its mechanism in vivo using Nrf2 gene knock-out mice and a mouse model of colon aberrant crypt foci. The study is expected to provide a theoretical basis for the marketing of sulforaphane and shed new light on the treatment of colon cancer.

由于结肠癌的高发病率及治疗的被动性，寻找有效的预防措施具有重要的公共卫生意义。莱菔硫烷是饮食中一种安全易得的植物化学素，我们的前期研究证实莱菔硫烷能够增加结肠癌Caco-2细胞II相代谢酶UGT1A的表达，因而可能具有对结肠癌的化学预防作用。本项目拟通过细胞培养和动物模型构建两大途径，进一步探讨莱菔硫烷对结肠癌的化学预防作用并深入阐明其作用机制:通过RNA干扰技术靶向沉默Nrf2基因表达，探明莱菔硫烷诱导作用中Nrf2信号通路的地位，进而深入研究莱菔硫烷激活Nrf2通路的表观遗传机制及上游信号转导通路机制；利用Nrf2基因敲除鼠和鼠结肠畸变隐窝模型，验证莱菔硫烷在体内诱导UGT1A表达及对结肠癌的化学预防作用并进一步探讨其作用机制。期望该研究能为莱菔硫烷早日市场化提供理论依据，将结肠癌的治疗引向化学预防这一全新领域。

由于结肠癌的高发病率及治疗的被动性，寻找有效的预防措施具有重要的公共卫生意义。莱菔硫烷是饮食中一种安全易得的植物化学素，我们的前期研究证实莱菔硫烷能够增加结肠癌Caco-2细胞II相代谢酶UGT1A的表达，因而可能具有对结肠癌的化学预防作用。本项目拟通过细胞培养和动物模型构建两大途径，进一步探讨莱菔硫烷对结肠癌的化学预防作用并深入阐明其作用机制:通过RNA干扰技术靶向沉默Nrf2基因表达，探明莱菔硫烷诱导作用中Nrf2信号通路的地位，进而深入研究莱菔硫烷激活Nrf2通路的表观遗传机制及上游信号转导通路机制；利用Nrf2基因敲除鼠和鼠结肠畸变隐窝模型，验证莱菔硫烷在体内诱导UGT1A表达及对结肠癌的化学预防作用并进一步探讨其作用机制。我们的研究结果显示，莱菔硫烷确实能够通过诱导Nrf2信号通路而上调UGT1A靶蛋白的表达，其在Nrf2基因敲除鼠中亦得到验证。本研究深入地探究了莱菔硫烷、Nrf2信号通路和UGT1A的关系，为莱菔硫烷早日市场化提供了必要的理论依据，将结肠癌的治疗中化学预防的领域做出了贡献。为莱菔硫烷的实际应用提供良好的研究基础，把莱菔硫烷与结肠癌的系列相关研究引向深入，有助于推进研究并达到国际先进乃至领先水平。