高EGCG绿茶对转基因小鼠肺癌预防与治疗的实验研究

It was shown that (-)-Epigallocatechin-3- gallate (EGCG) from green tea can inhibit the genesis and progress of different kinds of cancer in numerous studies, but it is still controversial whether the green tea consumption can reduce cancer risk according to the epidemiological studies. Using the transgenic mice harboring K-RAS or EGFR, which were often mutated in lung cancer patients, in this study we want to investigate the preventive and therapeutic effect of green tea with higher EGCG on lung caner. The cancer incidence, mortality, survival analysis, proliferation index and apoptosis in cancer tissues will be compared with and without continuous drink of green tea with higher EGCG content. Secondly, the exosome-based nanoparticles will be used to carry EGCG and will be modified by the antibodies targeted lung cancer stem cell markers such as CD133, CD44 or ALDH1 for target transportation. The effect of EGCG nanoparticles on lung cancer of transgenic mice and the underlying molecular mechanism will also be studied. The results of this study will provide solid data for the potential usage of green tea with higher content of EGCG as a protective drink of lung cancer and EGCG nanoparticles as a targeted therapy drug of lung cancer.

研究表明绿茶中EGCG对多种肿瘤的发生发展有明显的抑制作用，然而流行病学调查绿茶饮用对肿瘤的预防作用却存在很大的争议。本研究拟采用肺癌常见的突变基因K-RAS和EGFR的转基因小鼠为肺癌的动物模型，研究直接饮用高EGCG含量的绿茶提取物对小鼠肺癌发生率、肿瘤大小、荷瘤生存时间、肿瘤细胞增殖及凋亡的影响，探讨饮用绿茶在肺癌防治方面的可能作用及分子机制；同时采用肿瘤干细胞特异性标志物的抗体修饰的纳米颗粒携带纯化的EGCG，观察纳米颗粒对靶向输送的特异性、药物的稳定性和毒副作用的影响，研究EGCG纳米技术给药对肺癌的预防及治疗作用，并探讨其相应的分子机制，为EGCG预防和治疗肺癌的临床应用，提高药物的靶向输送能力及稳定性奠定实验基础。

很多研究表明绿茶中的EGCG对多种肿瘤的发生发展有明显的抑制作用，然而流行病学调查绿茶饮用对肿瘤的预防作用却存在比较大的争议，尤其是当机体已经发生了肿瘤相关的突变后饮用绿茶或者摄入EGCG是否可以预防或者延缓肿瘤的发生发展，目前还缺乏相应的实验数据。通过本课题的研究，揭示了EGCG可以通过与NF-kB蛋白直接结合从而抑制NF-kB活化的分子机制，阐明了NF-kB信号通路在EGCG抑制肺癌细胞增殖、侵袭、迁移中的作用，提示了EGCG与NF-kB抑制剂Bay11-7082联合运用治疗肺癌的可能性。同时优化了携带EGCG的PLGA纳米颗粒的制备条件，提高了EGCG的稳定性并降低了其有效作用浓度，并在PDX模型中得到验证，同时PLGA-EGCG纳米颗粒可以通过抑制NF-kB信号通路降低肺癌细胞对EGFR靶向药的耐药性，为PLGA-EGCG纳米颗粒应用于肺癌治疗奠定实验基础。利用KRas突变的转基因小鼠，发现了EGCG可以明显抑制KRas突变所导致的唇舌部肿瘤样病变，有效延长突变小鼠的生存期，并阐明了Notch信号通路在此过程中的促进作用，为绿茶EGCG预防和治疗肿瘤的临床应用，提高药物的稳定性和靶向性提供实验数据。