去泛素化酶OTUD6B调控VHL/HIF-1α信号抑制肝癌转移的作用和机制

转移和复发是肝癌患者死亡率居高不下的主要原因,深入揭示肝癌转移的分子机制,对于提高肝癌患者生存率具有重要意义。泛素蛋白酶体系统是细胞内主要的蛋白质稳态调控机器,泛素化途径的失调与恶性肿瘤的发生发展密切相关。去泛素化酶(DUB)能够通过特异性的剪切泛素链来控制底物蛋白的稳定性和生物活性，参与机体的生理和病理过程。我们的研究发现OTU亚家族DUB分子OTUD6B能够特异抑制肝癌细胞迁移,机制研究发现抑癌蛋白VHL可能作为其去泛素化底物介导其抑制肝癌转移的作用。本课题一方面利用细胞模型和基因敲除小鼠模型，验证OTUD6B抑制HCC转移的作用,另一方面阐明OTUD6B与VHL相互作用并调控其泛素化的分子机理。最后,结合临床样本分析,明确OTUD6B/VHL与肝癌的临床相关性。该研究的结果一方面为揭示肝癌转移的分子机制提供线索，同时也为我们完善对OTU家族DUB功能和作用机制的认识奠定基础。

Metastasis and recurrence are the main reasons for the high mortality of Hepatocellular carcinoma (HCC) patients. It is of great significance to reveal the molecular mechanism of HCC metastasis. The ubiquitin proteasome system is a main pathway regulating protein homeostasis, and its dysregulation is closely related to the occurrence and development of malignant tumors. Deubiquitinating enzyme (DUB) can control the stability and biological activity of substrate proteins via shearing ubiquitin chains, and participate in the physiological and pathological processes. Our previous study found that the OTU subfamily DUB member OTUD6B can specifically inhibit HCC cell migration, and the tumor suppressor protein VHL act as the substrate of OTUD6B and mediate its inhibitory effect on HCC metastasis. In this study, on the one hand, we plan to use cell model and gene knockout mouse model to verify the functional role of OTUD6B in suppressing HCC metastasis, and on the other hand, to elucidate the molecular mechanism underlying OTUD6B interacting with VHL and regulating its ubiquitination. Finally, combined with clinical sample analysis, the clinical correlation of OTUD6B/VHL and liver cancer will be determined. The results of this study would provide clues to reveal the molecular mechanism of liver cancer metastasis, and also lay the foundation for us to improve the understanding of the function and mechanism of OTU subfamily DUB.