SCF复合物是环指类E3泛素连接酶家族，其关键组分F-box蛋白负责底物蛋白的特异性识别和招募。FBXO43是F-box蛋白家族成员，目前报道的其功能主要局限于生殖发育，而该蛋白在肿瘤发生发展中的作用和可能机制尚无任何报道。我们前期结果提示，FBXO43在肝癌临床样本中显著高表达。敲低FBXO43后，人肝癌细胞出现显著生长抑制，伴随p27、p21的表达升高。结合SCF复合物与CDKIs关系的研究进展，我们推测以p27和p21代表的CDKIs可能是SCF-FBXO43复合物作为E3泛素连接酶调节的底物蛋白。本项目拟以人肝癌细胞为主要研究对象，系统研究FBXO43在促进肿瘤细胞增殖中的确切作用，并重点从泛素化降解方面明确FBXO43调节可能底物蛋白p27和/或p21稳定性的分子机制。本项目属于国内外首次对FBXO43蛋白在肿瘤中的作用和机制进行系统深入研究，有望为难治性肝癌提供新型诊治靶标。

F-box proteins are subunit recruiting modules of SCF (SKP1-Cullin 1-F-box protein) E3 ligase complexes, and determine the substrate specificity of the complexes. FBXO43 is a member of FBXO sub-family of F-box proteins. While it is reported that FBXO43 is involved in the regulation of meiosis and embryonic development, little is known about the biological function of the protein, especially its role during human malignancies. Our preliminary results indicated both FBXO43 gene and protein levels are significantly highly expressed in the clinical samples of liver cancer, as compared with normal tissues. Also, knockdown of FBXO43 caused significant growth inhibition in human hepatocellular carcinoma cells. These data suggest FBXO43 may play a tumorigenic role during cancer development. We also observed the expression of p27 and p21 proteins, both of which belong to CDKIs family, were simultaneously increased upon FBXO43 depletion. As some SCF complexes have been reported to be capable of modulating CDKIs protein stability, we speculated that p27 and/or p21 may be the substrate proteins regulated by the SCF-FBXO43 complex as an E3 ubiquitin ligase. In this project, we aim to thoroughly study the effect of FBXO43 on the proliferation and survival of human liver cancer cells by altering the protein level of FBXO43. Mechanistically, the role of FBXO43 in regulating p27 and/or p21 protein stability through ubiquitin degradation will be systematically examined. This novel project will provide first evidence to demonstrate the function of FBXO43 in human malignancies, which may serve as a potential biomarker as well as therapeutic target for human hepatocellular carcinoma.