Lin28A特异性调控具有抑癌特性的let-7的生成，形成Lin28A-let-7信号轴。研究表明，Lin28A-let-7信号轴的失衡与多种肿瘤的发生发展密切相关。在前期研究中，我们鉴定了Lin28A的SUMO化修饰及其位点，并发现SUMO化修饰显著增强Lin28A对let-7生成的负向调控作用，最终促进肿瘤发生发展。本项目的研究将深入阐明SUMO化修饰调控Lin28A抑制let-7生成的全新分子机制：即Lin28A的SUMO修饰促进其与pre-let-7的相互作用，一方面形成空间位阻效应，阻碍DICER对pre-let-7的加工剪切，另一方面形成了招募平台，促进TUT4对pre-let-7进行寡尿苷化修饰。我们还将深入解析Lin28A的SUMO化修饰的生物学功能，包括Lin28A的SUMO化修饰可调控因素及其分子机理；Lin28A的SUMO化修饰在肿瘤发生发展、转移和化疗抵抗中的作用。

Let-7 is a classic tumor suppressor gene, which can suppress tumorigenesis by targeting multiple oncogenes, such as Ras, c-Myc and HMGA2. The let-7 family miRNAs are specifically down regulated by Lin28A and form Lin28A-let-7 signal axis. It is reported that the imbalance of lin28a-let-7 signal axis is closely related to the development of various kinds of tumors. In our preliminary work we have identified the SUMOylation of Lin28A and its site, and found that Lin28A SUMOylation significantly enhanced its negative regulatory effect on let-7 biogenesis and ultimately promoted cancer progression. This project will further elucidate the novel molecular mechanism of SUMOylation of Lin28A regulates its inhibition of let-7 biogenesis: SUMOylation promotes the interaction of Lin28A with pre-let-7, which on the one hand forms stereo-hindrance effect, inhibits pre-let-7 cleaved by DICER; on the other hand, it forms a recruitment platform, enhances the interaction of pre-let-7 with TUT4 Uridine transferase, and then the uridylated pre-let-7 by TUT4 is following degraded. Combined with biochemistry experiments, crystal structure mimicry, mouse model and clinical sample analysis, we will further explore the biological function of Lin28A SUMOylation, including the regulatory factors of Lin28A SUMOylation and its underlying molecular mechanisms, and the functions of Lin28A SUMOylation in tumorigenesis, metastasis and chemoresistance.