去泛素化酶BAP1调控肝细胞癌发生发展的作用和机制研究

Deubiquitinase (DUB) is an important regulatory enzyme in the ubiquitin-proteasome system (UPS), which can control the stability and bioactivity of substrate proteins by specific shear or processing of ubiquitin chains and play roles in carcinogenesis. However, the functional roles and mechanism of DUB family members in hepatocellular carcinoma (HCC) are still unclear. In previous research, we analyzed somatic mutation from 375 cases of liver cancer tissue samples in TCGA datasets and found that compared with the normal liver tissues, there is a significant difference in BAP1 mutation. BAP1 is a member of UCH ubiquitinases, and its function on HCC growth and metastasis has not been reported. Our preliminary study suggests that BAP1 mutations and expression may be associated with survival and pathological staging of HCC patients and can influence the biological characteristics of HCC cells in vitro. In this study, we will study the clinical relationship between BAP1 expression or mutation and HCC, and elucidate the functional role of BAP1 in regulating the biological characteristics of HCC cells. On the other hand, we plan to explore the molecular mechanism of BAP1 binding to KDM1B in HCC cells.

去泛素化酶（DUB）作为泛素-蛋白酶体系统（UPS）中的一类重要调控酶，能够通过特异性的剪切或加工泛素链来控制底物蛋白的稳定性和生物活性，进而参与机体的生理和病理过程。DUB家族成员参与肝细胞癌（HCC）发生发展的研究不多，对其调控HCC生物特性的功能和机制的了解仍很不清楚。我们前期利用TCGA数据库中375例肝癌组织样本体细胞突变结果分析发现，与对照组织相比，BAP1突变存在显著性差异。BAP1是一个UCH亚家族的去泛素化酶，其调控HCC生长转移的作用和机制还未见报道。我们初步研究提示，BAP1突变和表达可能与HCC病人预后和分期相关，且能够影响HCC的生物学特性。本课题拟一方面深入研究BAP1表达及突变与HCC的临床相关性，阐明BAP1调控肝癌细胞生物学特性的功能作用，另一方面探索肝癌细胞中BAP1结合KDM1B的功能和调节的分子机制，为理解肝癌发病的分子机制提供线索。

去泛素化酶（DUB）作为泛素-蛋白酶体系统（UPS）中的一类重要调控酶，能够通过特异性的剪切或加工泛素链来控制底物蛋白的稳定性和生物活性，进而参与机体的生理和病理过程。DUB家族成员参与肝细胞癌（HCC）发生发展的研究不多，对其调控HCC生物特性的功能和机制的了解仍很不清楚。BAP1是一个UCH亚家族的去泛素化酶，其调控HCC生长转移的作用和机制还未见报道。我们利用TCGA数据库中375例肝癌组织样本体细胞突变结果分析发现，与对照组织相比，BAP1突变存在显著性差异。BAP1突变和表达与HCC病人预后和分期相关，且能够影响HCC的生物学特性。本项目从分子、细胞、动物模型及临床样本等水平揭示了BAP1调节细胞生长和迁移的作用，阐明了BAP1点突变对其生物学功能的影响，揭示了BAP1调节低氧信号通路促进肝癌发生发展的机制。我们发现去泛素化酶OTUD6B能够通过增强CBCVHL复合体的稳定性，加速低氧环境下HIF-1α的降解，进而调节肝癌细胞的特性。项目成果分别发表在Cell Death & Disease，Advanced Science和中国生物医药技术杂志，申请中国发明专利1项，培养博士研究生1名，硕士研究生3名。