Rpb3调控Lgr5+肝干细胞向肝癌干细胞转化的作用和机制研究

Hepatocellular carcinoma(HCC), one of the most common cancers of digestive tract, is a serious threat to human health. Liver cancer stem cells (LCSCs) are closely related to the development of hepatocellular carcinoma, while the origin of liver cancer stem cells is unknown. Previous studies had shown that Rpb3 was highly expressed in Lgr5+ liver cancer stem cells and promoted the development of hepatocellular carcinoma. Therefore, in this project, we firstly detect the expression of Rpb3 and Lgr5 in hepatocellular carcinoma, and analyze the correlation between Rpb3 and Lgr5, combining with clinicopathological data to reveal its clinical significance. Secondly, we take advantage of Lgr5+ liver stem cells, liver cancer stem cells and hepatocellular carcinoma animal model to discuss the regulatory effect of Rpb3 on the malignant transformation of Lgr5+ liver stem cells. In the end, the study of Wnt/β-catenin signal pathway elucidate the regulatory mechanism that Rpb3/TCF4 promotes the transformation of Lgr5+ liver stem cells into liver cancer stem cells. This project may contribute to illuminate the origin of liver cancer stem cells and lay a theoretical foundation for the treatment of hepatocellular carcinoma.

肝癌是最常见的消化道肿瘤之一，严重威胁着人类健康。肝癌干细胞与肝瘤的发生发展密切相关，而肝癌干细胞的来源不明。前期研究提示Rpb3在Lgr5+肝癌干细胞中高表达，促进肝癌的发生发展。因此在本项目中，我们首先通过检测Rpb3与Lgr5的表达，分析Rpb3与Lgr5之间相关性，并结合临床病理资料，揭示其临床意义。其次，利用Lgr5+肝干细胞、肝癌干细胞以及肝癌动物模型，探讨Rpb3对Lgr5+肝干细胞恶性转化的调控作用；最后通过对Wnt/β-catenin信号通路研究，阐明Rpb3/TCF4促进Lgr5+肝干细胞向肝癌干细胞转化的调控机制。本项目研究有助于揭示肝癌干细胞的来源，为肝癌的治疗奠定理论基础。

本项目主要研究肝癌的发生发展机制，在前期研究基础上，深入研究了Rpb3调控Wnt/β-catenin信号通路促进肝癌肿瘤干细胞转化抵抗放射线损伤的作用和机制。发现了新的肝癌调控因子VOPP1、POLA2并探索其调控肝癌进展的作用和机制，探索了低压脉冲冲洗和钕激光碎石去除肝内胆管结石的技术方法和人类白细胞抗原HLA-E水平在肿瘤中的意义。本研究揭示肝癌发生发展的调控新机制，为肝癌诊断、治疗提供了新靶点。在本项目资助下，项目负责人以第一作者（含共同）发表SCI论文2篇，以共同作者发表SCI论文1篇。项目负责人及参与人作为第一发明人申请国内专利4项。