剪接体组分蛋白USP39及其动态修饰在肝癌发生发展中的作用和机制研究

探究肝癌的发生发展机制，寻找有效治疗靶标是目前肝癌诊治的迫切需要。可变剪接已成为肿瘤研究领域的前沿和热点，然而剪接体组分蛋白在肝癌中的具体功能和作用机理还有待阐明。由于剪接体蛋白在肿瘤中经常有表达或动态修饰异常的现象，我们对TCGA、GEO等数据库中的肝癌病例进行分析，发现USP39在癌组织中广泛高表达且与临床病理进程相关联。应激状态下，USP39受到乙酰化及SUMO化修饰，进而调节其功能与活性。随后，我们通过构建条件性敲除小鼠模型证明抑制USP39表达可减缓肝癌发生发展。对这些组织样品进行RNA-seq后分析发现，USP39敲除广泛影响可变剪接。在此基础上，本项目拟进一步明确USP39在不同诱因的转基因小鼠肝癌模型中的作用；深入研究USP39表达异常或动态修饰异常对mRNA可变剪接的分子调控机制。从而明确USP39作为肝癌干预新靶点的临床意义，为肝癌的有效治疗和药物开发提供理论基础。

In order to improve the clinical diagnosis and treatment for hepatocellular carcinoma (HCC), it’s urgently needed to explore the mechanism of HCC carcinogenesis as well as develop effective therapeutic targets. Research on alternative splicing (AS) has become hotspot and frontier in cancer research. However, the functional roles of spliceosome proteins and their underlying mechanisms in HCC development remain unclear. As the expression and modification of spliceosome proteins are frequently deregulated during tumorigenesis, we started to analyze HCC cases in TCGA and GEO databases. The result showed that USP39 was frequently over-expressed in HCC tumor samples and its expression correlated with clinical pathological progression. Under cellular stresses, USP39 was post-translationally acetylated and SUMOylated, which modulated its function and activity. Using conditional knock-out mice model, we showed that USP39 suppression could inhibit HCC development. Transcriptome sequencing analysis on these mice tissues showed that USP39 knock-out had widespread influence on AS. In current project, we intend to further identify the roles of USP39 using various transgenic mice HCC models. The effects of USP39 expression and modification deregulation in AS modulation and its underlying mechanisms will be further elucidated. The results would testify the possibility of clinically targeting USP39, and hopefully pave the way for HCC treatment and drug development.