肿瘤的主要死因是转移，上皮间质化(Epithelial-Mesenchymal Transition，EMT)是肿瘤转移的起始和限速步骤。最近，我们发现，一种在结肠癌中高度表达的孤儿核受体Nur77会诱导结肠癌细胞丧失上皮标签（E-cadherin），并获得间质细胞表型（N-cadherin），与结肠癌的迁移和浸润有密切关系，其机制可能是通过Nur77-mTORC1信号转导。mTORC1在许多肿瘤中过度激活，是肿瘤最常发生异常的信号转导通路之一，我们前期初步的结果表明，Nur77可通过与FKBP38和Rheb相互作用影响mTORC1的活性，本项目将重点研究其调控机制，并利用我们新近发现的Nur77调控物和厚朴酚（honokoil）及衍生物，系统阐述Nur77-mTORC1信号转导在结肠癌EMT和转移中的作用，为发展结肠癌新的治疗方法奠定重要理论基础。

Most cancer deaths result from tumor metastasis, and understanding the underlying mechanisms is of obvious importance. Epithelial-mesenchymal transition (EMT) is a first and rate-limiting step in the metastatic cascade. Recently, we show for the first time a role for Nur77 in the loss of E-cadherin expression and acquisition of N-cadherin expression that promotes EMT and colon cancer cell metastasis. Interestingly, Nur77-dependent EMT is possibly mediated through a novel Nur77-mTORC1 signaling. mTORC1 is frequently activated in a variety of tumors and represents one of the most common dysregulated signaling in cancers. Our pilot experiments show that Nur77 may regulate mTORC1 activity through interaction with FKBP38 and Rheb, which can be regulated by honokiol and its derivatives. In this proposal, we will employ honokiol and its derivatives to investigate the role and regulation of Nur77-mTORC1 signaling axis in EMT and tumor metastasis. This study will provide an important understanding of the novel mechanisms of Nur77 involved in tumor metastasis, and also insight on the development of new and more efficacious therapeutic targets.