FABP4通过TRIM21介导的非蛋白质降解途径促进宫颈癌上皮-间充质转化的功能及其机制研究

宫颈癌的转移和复发是造成其治疗失败的重要原因之一，研究表明上皮-间充质转化（EMT）与肿瘤的浸润转移密切相关。课题组预实验显示，脂肪酸结合蛋白4（FABP4）在宫颈癌中高表达且促进肿瘤细胞的EMT。我们也证实E3泛素连接酶TRIM21与FABP4存在蛋白相互作用，且TRIM21不会促进FABP4的降解，反而增加其蛋白水平。此外，TRIM21增加FABP4蛋白的泛素化水平，使得K63位泛素化显著增加，而K48位泛素化却减少。结合文献信息和预实验结果，我们提出研究假设：宫颈癌中高表达的TRIM21通过增强底物蛋白FABP4的K63位多泛素修饰，竞争性抑制K48泛素化介导的蛋白降解，导致肿瘤细胞中FABP4蛋白水平升高，促进EMT介导的癌细胞迁移和侵袭。本项目的完成，有助于阐明FABP4蛋白泛素化修饰在宫颈癌中调控EMT的分子机制，为宫颈癌的防治提供新策略。

Outcome for women diagnosed with metastatic or recurrent cervical cancer remains poor, and epithelial-mesenchymal transition (EMT) plays important role in the invasion and metastasis of cervical cancer. In our previous study, the elevated fatty acid binding protein 4 (FABP4) increased the migration and invasion of cervical cancer cells through EMT signaling pathway. Furthermore, we found a E3 ubiquitin ligase TRIM21 can interacted with FABP4 by Co-Immunoprecipitation/Mass assay. It is interesting that TRIM21 did not promote the degradation of FABP4, but increased the protein level of FABP4. TRIM21 increased the ubiquitination of FABP4 in cervical cancer cells, especially increased the K63-linked polyubiquitination, and decreased the K48-linked polyubiquitination at the same time. Therefore, we propose the hypothesis that the elevated TRIM21 in cervical cancer cells increases the K63-linked polyubiquitination of FABP4, which competes with the K48-linked polyubiquitination for the binding site to FABP4. The competing binding results in the decrease of FABP4 degradation and the increasing protein level of FABP4 in the cervical cancer cells, which finally promotes cell migration and invasion of cervical cancer cells through EMT signaling pathway. Our present study aims to investigate the underlying molecular mechanism for the role of FABP4 ubiquitination in regulating EMT in cervical cancer, and to explore new biomarker and therapeutic strategy for metastatic cervical cancer.