目的：通过检索挖掘多个肿瘤公共数据库中肝细胞癌（hepatocellular carcinoma，HCC）的相关数据，从转录本、蛋白质、基因突变、蛋白相互作用及相应的信号通路和功能富集等不同层面，揭示BRD（bromodomain）蛋白家族与HCC的相关性，探索BRD蛋白家族作为HCC的肿瘤进展及预后判断的潜在生物标志物价值。方法：从UALCAN数据库中获取BRD蛋白家族所有成员在HCC患者组织样本中的mRNA表达数据和患者临床信息并进行相关性分析。从TCGA数据库中获取BRD蛋白家族mRNA表达水平与HCC患者预后的数据并进行相关性分析。从The Human Protein Atlas数据库中获取BRD蛋白家族在HCC组织和正常肝组织中的免疫组化结果并进行对比分析。使用 STRING 数据库获取 BRD 蛋白家族的相互作用蛋白网络，并利用CYTOSCAPE软件对获取的相互作用蛋白进行KEGG和GO分析。结果：BRD家族7个成员均在HCC组织中高表达（P<0.01），并且与HCC患者肿瘤分级和临床分期正相关（P<0.01）,同时BRD8和BRD9的低表达提示HCC患者预后较好（P<0.05）。BRD相互作用蛋白主要参与组蛋白乙酰化修饰，并高度富集于HCC相关的信号通路。TP53基因突变HCC患者的BRD1、BRD3、BRD4、BRD7、BRD8和BRD9表达水平显著高于非突变患者（P<0.05）。结论：BRD蛋白家族分子能够作为HCC患者肿瘤分级、临床分期和预后判断的潜在靶标。

Objective: To reveal the correlation between BRD (bromodomain)-containing protein family and hepatocellular carcinoma (HCC) from different perspectives such as transcripts, protein levels, gene mutations, protein interactions, corresponding signaling pathways and functional enrichment by searching and mining HCC-related data in multiple tumor public databases, and to explore the potential of BRDs as biological markers for tumor progression and prognosis prediction of HCC. Methods: The mRNA expression profile of all BRD-containing proteins and clinical information of HCC patients were obtained from UALCAN database, and their correlation was subsequently analyzed. The relationship between mRNA expression of BRDs and prognosis of HCC patients was analyzed by using TCGA database. The immunohistochemical results of BRDs in HCC tissues and normal liver tissues were obtained from The Human Protein Atlas, and the differential expression was compared. The STRING database was used to analyze the PPI (protein-protein interaction) network of BRDs, and the CYTOSCAPE software was used for the KEGG and GO analyses of the interacting molecules. Results: All the 7 BRD family members were highly expressed in HCC tissues (P<0.01) and were positively correlated with tumor grade and clinical stage in HCC patients (P<0.05); moreover, HCC patients with low BRD8 and BRD9 expression had better prognosis (P<0.01). In addition, BRD interacting proteins were mainly involved in histone acetylation modification and were highly enriched in HCC signaling pathways. The expressions of BRD1, BRD3, BRD4, BRD7, BRD8 and BRD9 in HCC patients with TP53 mutation were significantly higher than those in patients without TP53 mutation (P<0.05). Conclusion: The BRD-containing proteins might be used as potential biomarkers for tumor grade, clinical stage, and prognosis prediction of HCC patients.

国家自然科学基金委面上项目资助（No. 81871229）