FBXO22通过泛素化PDK1抑制结直肠癌发生发展的机制研究

泛素-蛋白酶体系统在肿瘤发生发展中发挥重要作用。申请人前期报道E3泛素连接酶SCF(FBXO22)通过降解Mdm2抑制肿瘤细胞转移。但FBXO22在基因敲除小鼠体内的功能和机制尚不清楚。因此，我们构建了肠上皮特异性敲除FBXO22小鼠。研究发现FBXO22缺失促进小鼠结直肠癌发生发展。质谱检测发现FBXO22与PDK1结合。文献报道PDK1能够磷酸化AKT进而激活mTORC1。我们也发现FBXO22缺失引起AKT-mTORC1磷酸化激活。在此基础上提出假说：以FBXO22为中心形成SCF(FBXO22)复合物，FBXO22与PDK1发生特异性结合，调控PDK1泛素化，进而影响PI3K-AKT-mTORC1通路激活，最终抑制结直肠癌发生发展。本课题拟利用我们构建的多种动物、细胞和人群模型阐明FBXO22抑制结直肠癌发生发展的分子机制。本研究的成功将为结直肠癌的基因治疗和分子诊断提供新靶点。

The ubiquitin-proteasome system plays an important role in tumorigenesis. We have previously reported that E3 ubiquitin ligase SCF(FBXO22) inhibits tumor cell metastasis by ubiquitinating Mdm2. However, the function and mechanism of FBXO22 in the knockout mice are unclear. The ubiquitin-proteasome system plays an important role in tumorigenesis. We have previously reported that E3 ubiquitin ligase SCF(FBXO22) inhibits tumor cell metastasis by ubiquitinating Mdm2. However, the function and mechanism of FBXO22 in the knockout mice are unclear. Using the constructed conditional knockout mice, we found that intestinal epithelium-specific knockout of FBXO22 promotes the development of colorectal cancer in mice. Mass spectrometry revealed that FBXO22 binds to PDK1. And the literature reports that PDK1 can phosphorylate AKT and activate mTORC1. We also found that deletion of FBXO22 caused AKT-mTORC1 phosphorylation activation. On the basis of these findings, we propose the hypothesis that FBXO22 is formed in the center of SCF complex. This complex regulates PDK1 ubiquitination, thereby affecting the activation of PI3K-AKT-mTORC1 pathway, and ultimately inhibits the progression of colorectal cancer. This project intends to clarify the mechanism that SCF(FBXO22) inhibits colorectal cancer progression via a variety of cell and animal models we constructed. The success of this study will provide new targets for gene therapy and molecular diagnosis of colorectal cancer.