利用CRISPR技术探索Nrf2抗氧化通路在低氧诱导肺癌转移中的作用及机制

项目名称： 利用CRISPR技术探索Nrf2抗氧化通路在低氧诱导肺癌转移中的作用及机制

项目编号： No.81502480

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 成兴华

作者单位： 复旦大学

项目金额： 18.5万元

中文摘要： 低氧通过升高细胞内氧化应激水平诱导肺癌细胞上皮间质转化，使其侵袭迁移能力增加从而促进肿瘤转移。转录因子Nrf2是细胞内最重要的抗氧化机制，但迄今对Nrf2在低氧诱导的肿瘤转移中的作用仍知之甚少。我们前期研究结果发现低氧可以抑制Nrf2相关抗氧化物表达使氧化应激水平增加，而含NRF2基因激活突变的早期非小细胞肺癌患者手术后预后较好。因此我们提出假说：Nrf2抑制可能是低氧促进肿瘤转移的机制之一，而NRF2激活突变可以减轻低氧诱导的肿瘤转移。本项目旨在进一步验证这一假说，并利用CRISPR/CAS9基因修改工具在肺癌细胞内引入NRF2基因激活突变，以探索通过基因修改上调内源性抗氧化物水平抑制肿瘤侵袭及转移的可行性，为未来针对这一机制的基因治疗寻找初步依据。

中文关键词： C05_气管；支气管；肺肿瘤；肿瘤转移；低氧；Nrf2抗氧化信号通路

英文摘要： Relative hypoxia may induce tumor metastasis by increasing intracellular oxidative stress and subsequent epithelial mesenchymal transition (EMT), thus facilitating tumor invasion and migration. Nrf2 transcription factor mediated antioxidant signaling pathway is the most important endogenous protective mechanism against oxidative stress and Nrf2 gene silencing may induce tumor metastasis as a result of elevated intracellular oxidative stress. Our previous results show that Nrf2 mediated antioxidant signaling is inhibited by hypoxia, which may work as another underlying mechanism of the hypoxia induced tumor metastasis. Moreover, NRF2 activating mutation is associated with improved survival in early stage non-small cell lung cancer patients after curative surgery. In the present study we aim to further verify the role of Nrf2 associated antioxidant signaling in tumor metastasis induced by hypoxia and test the feasibility of upregulating endogenous antioxidant by introducing NRF2 activating mutation through CRIPSR/CAS9 gene editing tool to suppress lung cancer metastasis, which may contribute to the development of targeted gene therapy against this pathway in future.

英文关键词： lung cancer;tumor metastasis;hypoxia;Nrf2 antioxidant signalling pathway