Zhou Yongxu, Yu Liang, Huang Peng, Zhao Xudong, He Risheng, Cui Yunfu, Pan Bo, Liu Chang
Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.
Front Pharmacol. 2023 May 9;14:1166454. doi: 10.3389/fphar.2023.1166454. eCollection 2023.
Afatinib is an irreversible epidermal growth factor receptor tyrosine kinase inhibitor, and it plays a role in hepatocellular carcinoma (LIHC). This study aimed to screen a key gene associated with afatinib and identify its potential candidate drugs. We screened afatinib-associated differential expressed genes based on transcriptomic data of LIHC patients from The Cancer Genome Atlas, Gene Expression Omnibus, and the Hepatocellular Carcinoma Database (HCCDB). By using the Genomics of Drug Sensitivity in Cancer 2 database, we determined candidate genes using analysis of the correlation between differential genes and half-maximal inhibitory concentration. Survival analysis of candidate genes was performed in the TCGA dataset and validated in HCCDB18 and GSE14520 datasets. Immune characteristic analysis identified a key gene, and we found potential candidate drugs using CellMiner. We also evaluated the correlation between the expression of ADH1B and its methylation level. Furthermore, Western blot analysis was performed to validate the expression of ADH1B in normal hepatocytes LO2 and LIHC cell line HepG2. We screened eight potential candidate genes (ASPM, CDK4, PTMA, TAT, ADH1B, ANXA10, OGDHL, and PON1) associated with afatinib. Patients with higher ASPM, CDK4, PTMA, and TAT exhibited poor prognosis, while those with lower ADH1B, ANXA10, OGDHL, and PON1 had unfavorable prognosis. Next, ADH1B was identified as a key gene negatively correlated with the immune score. The expression of ADH1B was distinctly downregulated in tumor tissues of pan-cancer. The expression of ADH1B was negatively correlated with ADH1B methylation. Small-molecule drugs panobinostat, oxaliplatin, ixabepilone, and seliciclib were significantly associated with ADH1B. The protein level of ADH1B was significantly downregulated in HepG2 cells compared with LO2 cells. Our study provides ADH1B as a key afatinib-related gene, which is associated with the immune microenvironment and can be used to predict the prognosis of LIHC. It is also a potential target of candidate drugs, sharing a promising approach to the development of novel drugs for the treatment of LIHC.
阿法替尼是一种不可逆的表皮生长因子受体酪氨酸激酶抑制剂，在肝细胞癌（LIHC）中发挥作用。本研究旨在筛选与阿法替尼相关的关键基因，并确定其潜在的候选药物。我们基于来自癌症基因组图谱、基因表达综合数据库和肝细胞癌数据库（HCCDB）的LIHC患者转录组数据，筛选出与阿法替尼相关的差异表达基因。通过使用癌症药物敏感性基因组学2数据库，我们利用差异基因与半数抑制浓度之间的相关性分析确定了候选基因。在TCGA数据集中对候选基因进行生存分析，并在HCCDB18和GSE14520数据集中进行验证。免疫特征分析确定了一个关键基因，我们使用CellMiner找到了潜在的候选药物。我们还评估了ADH1B的表达与其甲基化水平之间的相关性。此外，进行蛋白质免疫印迹分析以验证ADH1B在正常肝细胞LO2和LIHC细胞系HepG2中的表达。我们筛选出了八个与阿法替尼相关的潜在候选基因（ASPM、CDK4、PTMA、TAT、ADH1B、ANXA10、OGDHL和PON1）。ASPM、CDK4、PTMA和TAT表达较高的患者预后较差，而ADH1B、ANXA10、OGDHL和PON1表达较低的患者预后不佳。接下来，ADH1B被确定为与免疫评分呈负相关的关键基因。ADH1B的表达在泛癌的肿瘤组织中明显下调。ADH1B的表达与ADH1B甲基化呈负相关。小分子药物帕比司他、奥沙利铂、伊沙匹隆和塞利西利与ADH1B显著相关。与LO2细胞相比，HepG2细胞中ADH1B的蛋白水平显著下调。我们的研究提供了ADH1B作为一个与阿法替尼相关的关键基因，它与免疫微环境相关，可用于预测LIHC的预后。它也是候选药物的潜在靶点，为开发治疗LIHC的新型药物提供了一种有前景的方法。
