EpCAM-丹参酮ⅡA纳米粒靶向肝癌干细胞调控Wnt/β-catenin信号通路抗肝癌侵袭转移的机制

肿瘤干细胞是肝癌复发转移的重要根源之一，Wnt/β-catenin信号转导参与了肿瘤干细胞的发生发展，在肝癌复发转移中起重要作用。申请人承担青年基金时成功构建丹参酮IIA纳米能靶向肝癌，并发现丹参酮IIA能抑制Wnt/β-catenin信号通路激活，下调VEGF表达，抑制肝癌侵袭转移。.本研究在前期研究基础上，利用EpCAM McAb的免疫特异性与肝癌干细胞表面EpCAM抗原结合，构建新型EpCAM修饰的丹参酮ⅡA纳米粒，使其特异性地识别肝癌干细胞。测定载药纳米粒对肝癌干细胞的靶向性；利用Q-RT-PCR、WB 及CHIP等技术研究EpCAM-丹参酮ⅡA纳米在肝癌干细胞β-catenin的激活作用及与转录因子TCF、相关靶基因的结合能力，揭示该纳米粒通过Wnt/β-catenin信号通路抑制LCSCs的激活，靶向阻断EpCAM抗肝癌侵袭转移的机制，为中医药治疗肝癌提供新的途径和理论依据。

Cancer stem cells (CSC) are one of the main resources for liver cancer (LC) relapse and metastasis. Wnt/beta-catenin signaling pathway plays an important role in the origination and development of CSC. Funded by the Youth Grant, we have already successfully generated TanshinoneIIA-nanoparticles (TSIIA-NPs), which inhibited LC cell invasion and metastasis by repressing wnt/beta-catenin/VEGF signaling. In the current application, we propose to first modify TSIIA-NPs by adding EpCAM McAb (EpCAM-TSIIA-NPs) to direct the particles to EpCAM expressing LCSC. We then will study the CSC targeting capability of these particles using laser confocal and LC-MC technologies, as well as their effect on beta-catenin signaling using Q-RT-PCR, western blot and CHIP. This study of ours will elucidate the mechanisms by which EpCAM-TSIIA-NPs inhibit LC metastasis through blocking beta-catenin activation in LCSC, and identify novel therapeutical targets for TCM to treat LC.