长白山珍珠梅黄酮纳米粒诱导肝癌细胞凋亡的内质网应激作用机制

内质网应激在肝脏病变和肿瘤的发生过程中具有重要的作用。珍珠梅黄酮（5，2′，4′-三羟基-6，7，5′-三甲氧基黄酮，TTF1）是从长白山抗癌药珍珠梅中分离得到单体，珍珠梅黄酮纳米粒（TTF-NP）是采用乳化溶剂挥发法制备的新剂型。课题组前期报道TTF1具有抗肿瘤作用，能诱导肿瘤细胞凋亡；预实验结果提示TTF1-NP诱导肿瘤细胞凋亡与内质网应激（ERS）有关。本项目拟通过体外、体内实验，培养人肝癌细胞株，建立移植性裸鼠模型、DEN诱发原发性大鼠肝癌发生模型，观察TTF-NP 诱导肝癌细胞凋亡ERS机制中CHOP、JNK和Caspase三条通路中各种调控因子的亚细胞定位及mRNA、蛋白质表达水平变化，从亚细胞和分子水平阐明TTF1-NP诱导肝癌细胞凋亡的ERS作用机制，为肝癌的治疗提供新的思路与靶点，为长白山抗癌药材珍珠梅的开发提供理论和实验基础。

Endoplasmic reticulum stress (ERS) play an important role in hepatic lesion and tumorigenesis. The 5, 2′, 4′-trihydroxy-6, 7, 5′-trimethoxyflavone (TTF1) was the first monomeric compound identified from acetic ether extracts of anti-tumor herb Sorbaria sorbifolia, native to Changbai Mountain in China. TTF1 nanoparticle (TTF-NP) is a new dosage form prepared by the emulsion-solvent evaporation method. We previously reported that TTF1 showed anti-tumor activity, and is able to induce tumor cells apoptosis. Preliminary data suggest TTF1-NP induce cell apoptosis be related with ERS. This project plan in vitro and in vivo to establish human hepatocarcinoma cell model, transplanted nude mice model and diethylnitrosamine (DEN) induced rats hepatocarcinoma model. To observe the subcellular localization of each kinds of regulators and the expression levels of mRNA and protein in the pathways of CHOP, JNK and Caspase in hepatocarcinoma cell apoptosis ERS induced by TTF1-NP. Then to elucidate the subcellular and molecular mechanism of hepatocarcinoma cell apoptosis ERS induced by TTF1-NP. To provide new idea and target for the hepatocarcinoma treatment, and provide theoretical and experimental basis for the development of anti-tumor herb Sorbaria sorbifolia.