以肝癌发生及生长必需基因Bmi1为靶点的叶酸靶向纳米脂质体治疗肝癌的实验研究

肝癌严重威胁人民健康且治疗手段缺乏，针对病因开发靶向药物是目前肝癌治疗研究的重要方向。我们前期研究发现，Bmi1基因是驱动肝癌发生的重要癌基因。在体外沉默Bmi1可以促使细胞凋亡，抑制肝癌细胞生长。在小鼠体内，关闭Bmi1的表达可以逆转肿瘤生长，使其萎缩。我们还发现，Bmi1基因缺失不仅能够限制肝脏卵圆细胞增殖，还可以抑制肝癌干细胞形成。这些都表明Bmi1基因是肝癌治疗的一个极好靶点。我们前期研究还证实，叶酸靶向脂质体可以将药物有效递送到癌组织中并抑制肿瘤生长。本研究中，我们尝试利用叶酸靶向脂质体递送Bmi1 siRNA治疗肝癌，来克服核内转录因子（Bmi1）难以被小分子化合物靶向的问题。本研究将通过体内体外研究，考察靶向Bmi1的siRNA叶酸纳米脂质体的制备方法、稳定性、及其治疗肝癌的有效性和安全性，进而探索以Bmi1基因为靶点治疗肝癌的可行性。

Hepatocellular carcinoma (HCC) is a worldwide malignancy rusulted in millions of deaths and lack of effective therapeutic medications. In previous study, we found Bmi1 is overexpressed in human HCC samples. When Bmi1 expression is knocked down in human HCC cell lines, it significantly inhibits cell proliferation and perturbs cell cycle regulation. In the mouse model, Bmi1 silencing by shRNA through tet-on system could significantly suppress the growth of hepatoma xenografts in nude mice. In past study, we also found that Bmi1 is required for the proliferation of oval cell(one type of liver projenitor or stem cell), as well as the hepatic cancer stem cell. Hence, we believe that Bmi1 is ideal target for HCC treatment. To test the efficacy and safety of HCC treatment by inhibiting Bmi1, we disined a folat conjugated liposomes to diliver Bmi1 siRNA,which facilitate the efficient delivery of drugs to the livers. We expect that the gene therapy targeting Bmi1 can inhibit liver cancer malignant properties more effectively and safely, which may benefit the patients with unresectable HCC. In conclusion, here we propose a study by applying the folate conjugated Bmi1 siRNA liposome nanoparticles to treat HCC both in vitro and in vivo, and hence to determine its safety and efficacy.