肝细胞的恶性增殖是肝细胞癌发生发展的病理基础。致癌基因AEG-1的过量表达显著促进肿瘤细胞的增殖与存活，但其具体的调节机制仍待完善。近些年的研究表明蛋白质的棕榈酰化修饰水平异常与癌症密切相关。申请人前期实验发现AEG-1能被ZDHHC6进行棕榈酰化修饰，其棕榈酰化修饰水平在肝细胞癌细胞中显著升高且随着AEG-1蛋白表达量的增加而显著上升。进一步研究发现突变AEG-1棕榈酰化修饰位点能够显著抑制细胞增殖。基于此，本项目拟开展以下研究：①探索AEG-1的棕榈酰化修饰调控细胞增殖的具体分子机制；②明确AEG-1棕榈酰化修饰酶ZDHHC6表达水平与患者生存期的相关性；③利用AEG-1棕榈酰化修饰位点突变小鼠及ZDHHC6敲除小鼠验证能否阻断肝细胞癌的发生。本项目的开展有助于揭示ZDHHC6介导的AEG-1棕榈酰化修饰调控肝细胞癌发生发展的作用机制，可能为治疗肝细胞癌提供新思路。

The malignant proliferation of hepatocytes is the pathological basis for the occurrence and development of hepatocellular carcinoma (HCC). Overexpression of the oncogene AEG-1 can significantly promote the proliferation and survival of tumor cells, but its regulation mechanism is far from illumination. Studies in recent years have shown that abnormal levels of palmitoylation of proteins are closely related to cancer. Our preliminary data demonstrated that AEG-1 was palmitoylated by ZDHHC6, and its modification level was significantly increased in HCC cells and was positively correlated with AEG-1 expression. Further research found that mutated AEG-1 palmitoylation site can significantly inhibit cell proliferation. Therefore, our current study will focus on the following points: (1) explore the molecular mechanism of AEG-1 palmitoylation on cell proliferation regulating, (2) determine the correlation between the expression level of ZDHHC6 and patient survival, (3) AEG-1 palmitoylation site-mutated mice and ZDHHC6 knockout mice were used to verify whether they can block the occurrence of HCC. The understanding of these questions would help us to peek into the mechanisms of ZDHHC6-mediated palmitoylation of AEG-1 in regulating the occurrence and development of HCC, and may provide novel insights into innovative therapeutics for HCC.