缺氧环境下，肝癌细胞“驯化”巨噬细胞成为M2型是缺氧促肝癌转移的关键因素之一。但肝癌细胞如何在缺氧环境中获得更强的“驯化”能力尚不清楚，是该领域亟需解决的问题。申请人前期研究发现肝癌细胞中YAP通路的缺氧异常激活可能是其促巨噬细胞M2型极化的关键，而缺氧下YAP蛋白Neddylation修饰水平的变化是导致YAP通路异常激活的关键因素。本课题将在此全新发现的基础上，进一步研究Neddylation修饰如何调控YAP通路的异常激活，发现调控该修饰的关键分子，探索缺氧YAP激活后肝癌细胞“驯化”巨噬细胞的关键分泌蛋白，探讨通过调控YAP蛋白Neddylation修饰从而干预巨噬细胞M2型极化成为抗肝癌转移新策略的可能性。本课题将阐明YAP缺氧异常激活的全新机制，发现YAP蛋白“驯化”巨噬细胞的新生物学功能，揭示缺氧促肿瘤转移的新分子机制，为抗肝癌转移的药物研究和临床治疗提供新靶点和新策略。

Macrophages are educated by tumor cells to be M2-like phenotype, which is critical for hypoxia drived metastasis of heptocarcinoma. How the heptocarcinoma cells obtain stronger ability of education in hypoxia remains exclusive, which is a pressing problem to be solved. Our previous studies have found for the first time that the aberrant activation of YAP by hypoxia plays a key role in hypoxia triggered M2 polarization of macrophages. NEDD8 is involved in hypoxia drived activation of YAP. Based on these previous studies, we will further clarify the relationship between neddylation and YAP activation in hypoxia, discover the key regulators during the modification, find the downstream secretory protein that participate in M2 polarization stimulated by hypoxia. We will also discuss the feasibility of anti-metastasis by targeting M2 polarization through interfere neddylation of YAP in heptocarcinoma. Our study will elucidate the underlying mechanisms responsible for YAP activation in hypoxia, discover the new biological functions of YAP in macrophages education, and enrich the molecular mechanisms of hypoxia drived metastasis, in the hope to provide new targets for the design and discovery of novel anti-metastasis drugs and potential therapeutic targets for anti-metastasis therapy.