去泛素化酶BAP1在肝细胞癌发展中的功能研究

Study on the function of deubiquitinating enzyme BAP1 in the development of hepatocellular carcinoma

目的探索BAP1及其突变体参与调控肝癌细胞生长转移的功能,为发现肝癌治疗的新靶点奠定基础。方法从TCGA数据库中获得了375例肝细胞癌(HCC)样本,共44845例体细胞突变数据,并下载肝癌临床指标数据及术后生存期数据,利用软件具体数据分析,通过BAP1的RNA表达量进行数据分析,建立了BAP1稳定敲除和过表达的肝癌细胞系,分析BAP1生物学特性的影响,建立了裸鼠皮下移植瘤模型。结果BAP1为DUBs家族中突变率最高的基因,突变率约为5.31%,与正常肝组织相比,HCC组织中BAP1突变差异显著,BAP1突变与病人较好的预后密切相关,BAP1 mRNA高表达与病人较差的预后密切相关,BAP1敲低显著抑制肝癌细胞的生长和转移,BAP1G45R和W196G位点突变显著抑制肿瘤生长。结论BAP1突变与HCC病人较好的预后密切相关,BAP1敲低及其突变能够显著抑制肝癌细胞增殖、迁移以及裸鼠的成瘤能力。

Objective Explore the function and mechanism of BAP1 involved in regulating the growth and metastasis of liver cancer cells,and to find new targets for the treatment of liver cancer.Methods A total of 44,845 somatic mutation data in 375 cases of hepatocellular carcinoma samples were obtained from the TCGA database,and the clinical index data and postoperative survival data of liver cancer were downloaded,and the specific data of the software was used to analyze the data through the RNA expression of BAP1.A liver cancer cell line with stable knockout or overexpression of BAP1 was established,and the influence of the biological characteristics of BAP1 was analyzed,and a subcutaneous xenograft tumor model was established in nude mice.Results BAP1 was the gene with the highest mutation rate in the DUBs family.The mutation rate was about 5.31%.Compared with normal liver tissues,BAP1 mutations in HCC tissues were significantly different.BAP1 mutations were closely related to better prognosis of patients.High expression of BAP1 mRNA was closely associated with the patient's poor prognosis.BAP1 knockdown significantly inhibited the growth and metastasis of liver cancer cells,and mutations at BAP1G45R and W196G significantly inhibited tumor growth.Conclusion BAP1 mutation is closely related to the better prognosis of HCC patients.BAP1 knockdown and its mutation can significantly inhibit the proliferation and migration of liver cancer cells and the tumorigenic ability of nude mice.