去泛素化酶OTUB1在肝癌索拉非尼耐药中的潜在作用及其靶向化合物筛选

The Potential Role of Deubiquitinating Enzyme OTUB1 in Sorafenib Resistance of Hepatocellular Carcinoma and Screening of Targeting Compounds

摘要: 目的：探讨去泛素化酶基因OTUB1在肝癌索拉非尼耐药中的潜在作用，并筛选下调OTUB1表达的潜在小分子化合物。方法：基于肝癌索拉非尼耐药及敏感样本的转录组数据，分析去泛素化酶家族基因的差异表达；通过GEPIA数据库评估差异表达基因在肝癌组织与配对癌旁组织中的表达水平差异；利用Kaplan-Meier Plotter数据库评估差异表达基因的预后价值；进一步对核心基因(OTUB1)进行甲基化分析、临床病理特征相关性分析及生存预后分析；借助CTD数据库预测靶向OTUB1的潜在化合物，并运用分子对接解析其与OTUB1蛋白的潜在相互作用。结果：共筛选出20个差异表达的去泛素化酶基因，其中OTUB1在耐药样本中显著高表达，且与患者不良预后相关(p < 0.05)。数据库筛选获得10种下调OTUB1的候选化合物，分子对接提示SB431542与OTUB1蛋白对接活性最好。

Abstract: Purpose: To investigate the potential mechanism of the deubiquitinating enzyme gene OTUB1 in sorafenib resistance in hepatocellular carcinoma (HCC) and to screen potential small-molecule compounds capable of downregulating OTUB1 expression. Methods: Differential expression of deubiquitinating enzyme family genes was analyzed based on transcriptome data from sorafenib-resistant and sorafenib-sensitive HCC samples. The GEPIA database was used to evaluate the expression levels of differentially expressed genes in HCC tissues versus adjacent non-tumor tissues. The Kaplan-Meier Plotter database was employed to evaluate the prognostic value of differentially expressed genes. Further analyses, including methylation, clinicopathological features correlation analysis, and survival prognosis, were conducted on the core gene (OTUB1). Potential compounds targeting OTUB1 were predicted via the CTD database, and molecular docking was performed to analyze their potential interactions with the OTUB1 protein. Results: A total of 20 differentially expressed deubiquitinating enzyme genes were screened. Among these, OTUB1 was significantly overexpressed in resistant samples and correlated with poor patient prognosis (p < 0.05). Ten candidate compounds capable of targeting and downregulating OTUB1 were screened through databases, and molecular docking suggested that SB431542 has the best docking activity with OTUB1 protein.