“LXR-lncRNA HULC-FOXM1通路”的鉴定及其在抗肝细胞癌中的作用机制研究

HULC (up-regulated in liver cancer) is an important long non coding RNA (lncRNA) in promoting hepatocellular carcinoma (HCC). However, it is not well known about the mechanisms by which HULC promotes HCC and HULC itself is regulated. According to our preliminary innovative discoveries (see the 'background section'for this project), we hypothesize that LXR may downregulate the expression of HULC, which results in the release of miR-134 (a tumor suppressive micro RNA), and then the released miR-134 may play anti-HCC function by suppressing the expression of FOXM1(a tumor promoting molecule). In the present project, we will explore the mechanisms by which LXR downregulates HULC and HULC upregulates FOXM1 via the 'sponge' interaction with miR-134, and verify that FOXM1 is a novel target gene of miR-134. By performing the above studies, we hope to identify the 'LXR-HULC-miR-134-FOXM1 pathway'. Subsequently, we will do the in vitro experiments to investigate the effects of the pathway on the proliferation, migration and invasion of HCC cells. Finally, we will perform the in vivo experiments in HCC-bearing mice to observe the effects of the pathway on the growth and metastasis of HCC. This project aims to reveal that the pathway is a novel mechanism by which LXR protects against HCC and HULC promotes HCC, which may provide a new sight for developing novel therapeutic strategy for HCC by targeting this pathway.

HULC是发挥促肝细胞癌（HCC）作用的重要lncRNA，但关于其促HCC的机理以及其自身表达调控机制均亟待阐明。我们在前期进行探索性研究并获得创新性发现（见工作基础部分）的基础上提出假设：核受体LXR可通过下调HULC而使后者吸附的miR-134（抑癌microRNA）释放，继而miR-134通过抑制促癌分子FOXM1的表达而发挥抗HCC作用。本项目将解析LXR下调HULC表达的分子机制以及HULC通过吸附miR-134而上调FOXM1的分子机制，确定FOXM1是miR-134的新靶基因，从而证实"LXR-HULC-miR-134-FOXM1通路"的存在；随后在体外探讨上述通路对HCC细胞增殖、迁移和侵袭能力的影响；最后利用荷瘤小鼠体内探讨该通路对HCC生长和转移的影响，旨在揭示该通路是LXR抗HCC以及HULC促HCC作用的新机制，为探索以该通路为靶点的HCC防治新策略提供科学依据。

HULC是发挥促肝细胞癌（HCC）作用的重要lncRNA，但关于其促HCC的机理以及其自身表达调控机制均亟待阐明。LXR属核受体超家族成员,作为一种多功能转录因子。研究显示，配体活化的LXR可抑制多种肿瘤细胞的增殖，从而发挥抗肿瘤的功能。我们前期的研究发现，LXR可以直接抑制FOXM1的表达，从而抑制HCC细胞增殖，发挥抗HCC功能。鉴于肿瘤的发生发展通常是受到多因素、多通路，复杂的网络调控，因此，除了上述LXR直接抑制FOXM1而抗HCC外，是否同时存在其他间接的调节通路，而该间接调节通路是否与调节LncRNA HULC有关，进而发挥与直接通路同样重要的抗HCC的功能。因此，本项目将解析LXR下调HULC表达的分子机制以及HULC通过吸附miR-134而上调FOXM1的分子机制，确定FOXM1是miR-134的新靶基因，从而证实“LXR-HULC-miR-134-FOXM1通路”的存在；随后在体外探讨上述通路对HCC细胞增殖、迁移和侵袭能力的影响；旨在揭示该通路是LXR抗HCC以及HULC促HCC作用的新机制，为探索以该通路为靶点的HCC防治新策略提供科学依据。