糖基化EpCAM通过L-FABP/mTOR调控脂代谢参与肝癌侵袭性转移的分子机制研究

Abnormal lipid metabolism in hepatocellular carcinoma (HCC) could provide biological macromolecules and energy for the invasive metastasis of HCC. Epithelial cell adhesion molecule (EpCAM) is a glycoprotein expressing on the cell membrane and participates in cell adhesion. EpCAM is highly glycosylated in hepatocellular carcinoma cells. In previous study, we found that glycosylated EpCAM promoted the migration of hepatocellular carcinoma cells and the level of EpCAM glycosylation is affected by exogenous fatty acids. Meanwhile, glycosylated EpCAM could activate the lipid metabolism-related mammalian target of rapamycin (mTOR) pathway and promote the expression of liver fatty acid binding protein(L-FABP).Thus, we proposed that glycosylated EpCAM might be involved in lipid metabolism to induce the metastasis of HCC. This study intends to carry out the followings: ①To identify glycosylated EpCAM on the regulation of HCC metastasis; ②To identify glycosylated EpCAM on lipid metabolism of HCC; ③To identify the regulatory mechanisms of glycosylated EpCAM on L-FABP/mTOR pathway; ④To identify the regulatory mechanisms of EpCAM glycosylation ,and analyzing patient tissue samples to clarify the relationship between glycosylated EpCAM and HCC metastasis. The study is the first to establish the basis for clarifying the mechanism of glycosylated EpCAM in regulating lipid metabolism-induced HCC metastasis, which provide a theoretical basis for preventing the metastasis of HCC by targeting glycosylated EpCAM.

肝癌脂代谢存在异常，能够为肝癌侵袭性转移提供生物大分子和能量。EpCAM是细胞膜表面糖蛋白，参与细胞间粘附。在肝癌细胞中，EpCAM高表达，且呈现较高糖基化水平。本项目预实验发现，糖基化EpCAM能够促进肝癌细胞迁移，且EpCAM的糖基化水平受到外源性脂肪酸的影响；此外，糖基化EpCAM能够激活脂代谢相关mTOR信号通路，并促进肝型脂肪酸结合蛋白L-FABP的表达。因此推测，糖基化EpCAM可能通过调控脂代谢参与肝癌侵袭性转移。本项目拟研究：①糖基化EpCAM对肝癌转移的调控作用；②糖基化EpCAM对肝癌脂代谢的调控作用；③糖基化EpCAM对L-FABP/mTOR的调控机制；④EpCAM糖基化的调控机制，以及收集临床病例样本，分析糖基化EpCAM与肝癌转移相关性。本项目首次明确糖基化EpCAM调控脂代谢参与肝癌侵袭性转移的分子机制，能够为以糖基化EpCAM为靶点防治肝癌转移提供理论依据。

肝细胞肝癌是危害人类健康的常见恶性肿瘤，其发病率和死亡率在全球处于较高水平。由于肝脏血供丰富，导致肝细胞肝癌出现高侵袭和高转移潜能，给治疗带来困难。研究表明， 脂代谢异常参与调控肿瘤侵袭性转移过程；同时，肝癌的发展、转移与脂肪代谢的紊乱直接相关。肝癌脂代谢存在异常，能够为肝癌侵袭性转移提供生物大分子和能量。EpCAM是细胞膜表面糖蛋白，参与细胞间粘附；研究表明，糖基化EpCAM可能调控肿瘤细胞侵袭性转移过程。本项目旨在研究糖基化EpCAM对肝细胞肝癌脂代谢的调控作用，从而明确其侵袭性转移的分子调控机制。本项目从以下几个方面研究：①糖基化EpCAM对肝癌转移的调控作用；②糖基化EpCAM对肝癌脂代谢的调控作用；③糖基化EpCAM对L-FABP/mTOR的调控机制。通过本项目的研究，得到以下重要结果：第一部分：糖基化EpCAM与肝癌侵袭性转移的相关性研究：①在肝癌细胞中，EpCAM高表达，呈现较高糖基化水平；②EpCAM与肝细胞肝癌的上皮间质转化过程高度相关，可能调控肝癌侵袭性转移过程；③EpCAM与脂肪酸代谢高度相关，且EpCAM的糖基化水平受到外源性脂肪酸的影响；综上所述，糖基化EpCAM可能能够促进肝癌细胞侵袭性转移过程，且这一过程可能与EpCAM对脂代谢的调控作用相关。第二部分：糖基化EpCAM对肝癌侵袭性转移的调控机制研究：①糖基化EpCAM能够激活脂代谢相关Akt、mTOR等信号通路活性；②肝型脂肪酸结合蛋白L-FABP在肝癌中呈现较高水平表达，且与脂代谢高度相关；③糖基化EpCAM能够调控L-FABP的表达水平。因此推测，糖基化EpCAM可能通过调控L-FABP介导脂代谢参与肝癌侵袭性转移过程。本项目首次明确糖基化EpCAM调控脂代谢参与肝癌侵袭性转移的分子机制，能够为以糖基化EpCAM为靶点防治肝癌转移提供理论依据。