FBXO28通过降解Slug蛋白抑制肿瘤细胞上皮-间质转化和侵袭转移的作用机制研究

F-box蛋白是SCF(SKP1-Cullin1-F-box)复合物这一类E3泛素连接酶家族的重要组成部分，很多F-box蛋白与肿瘤侵袭转移的关系尚不清楚。本项目前期筛选发现F-box家族成员之一FBXO28能够抑制肝癌细胞侵袭转移。初步研究发现FBXO28蛋白可结合Slug这一重要的上皮-间质转化转录因子并促进其降解，因此推测Slug可能是SCFFBXO28复合物新的特异性底物蛋白。本项目拟以人肝癌和乳腺癌为主要研究对象，系统研究FBXO28在抑制肿瘤生长和转移中的确切作用，并重点围绕Slug蛋白降解和功能来深入研究FBXO28调控肿瘤转移的分子机制，同时将FBXO28表达水平与肿瘤临床样本的进展和预后进行关联分析。本项目属于国内外首次对FBXO28在肿瘤转移中的作用机制进行系统深入的研究，有助于全面理解SCF复合物中F-box蛋白在肿瘤中的作用特点，更有望为抗肿瘤治疗提供新诊治靶标。

F-box proteins are a family of a key component of the SCF (SKP1-Cullin1-F-box) E3 ubiquitin ligase complexes, which function to specifically recruit specific substrates for regulating their protein homeostasis. The relevance of a large portion of F-box proteins in the progression and metastasis of human malignances remains largely unknown. In a preliminary functional screening, we for the first time identified FBXO28, a member of the FBXOs sub-family in F-box proteins, to have the potential to inhibit the growth, invasion and metastasis of human hepatocellular carcinoma cells. Further analysis indicated that FBXO28 could specifically bind to, and promote, the degradation of Slug protein, a pivotal transcriptional factor in the regulation of epithelial mesenchymal transition (EMT) and metastasis in cancer. Thus we reason that Slug may be a novel identified substrate of the SCFFBXO28 complex that may mediate its proteosomal degradation. In this project, we aim to address the biological functions of FBXO28 in proliferation, invasion and metastasis in human cancer (especially liver and breast cancer) as well as the underlying mechanisms, based on the regulation of Slug protein level and stabilty by FBXO28. We will also perform the bioinformatics analysis to determine the correlation of FBXO28 expression with the progression and prognosis in clinical cancer specimens. The project will help understand the novel functions of FBXO28 in the F-box family in cancer, and identify a novel molecular target for potential intervention of cancer EMT and metastasis.