Identification of Hub Genes Associated With Immune Infiltration and Predict Prognosis in Hepatocellular Carcinoma via Bioinformatics Approaches.
Identification of Hub Genes Associated With Immune Infiltration and Predict Prognosis in Hepatocellular Carcinoma via Bioinformatics Approaches.
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DOI：
10.3389/fgene.2020.575762
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发表时间：
2020
影响因子：
3.7
通讯作者：
Xie L
中科院分区：
文献类型：
--
作者：
Chen H;Wu J;Lu L;Hu Z;Li X;Huang L;Zhang X;Chen M;Qin X;Xie L
在癌症相关研究领域，目前非常需要更多有价值的生物标志物来预测肝细胞癌（HCC）的预后。在本研究中，我们旨在筛选与免疫细胞浸润相关的中枢基因，并探讨其对 HCC 的预后价值。我们分析了 Gene Expression Omnibus 数据库中的五个数据集（GSE46408、GSE57957、GSE74656、GSE76427 和 GSE87630），以筛选差异表达基因（DEG）。使用相互作用基因检索搜索工具构建了 DEG 的蛋白质-蛋白质相互作用网络；然后，鉴定了中心基因。基因的功能富集在 Metascape 网站上进行。接下来，这些枢纽基因的表达在多个数据库中得到验证，包括 Oncomine、基因表达谱交互分析 2 (GEPIA2) 和人类蛋白质图谱。我们在TIMER2.0数据库中探索了中枢基因和浸润免疫细胞之间的相关性。在GEPIA2中生成生存曲线，并使用TIMER2.0进行单变量和多变量Cox回归分析。十大枢纽基因【DNA拓扑异构酶IIα（TOP2A）、细胞周期蛋白B2（CCNB2）、胞质分裂蛋白调节蛋白1（PRC1）、Rac GTP酶激活蛋白1（RACGAP1）、极光激酶A（AURKA）、细胞周期蛋白依赖性激酶抑制剂3（CDKN3）、核仁和纺锤体相关蛋白1（NUSAP1）、细胞分裂周期相关5在随后的分析中鉴定出异常纺锤体微管组装（CDCA5）、异常纺锤体微管组装（ASPM）和非SMC凝缩蛋白I复合物亚基G（NCAPG）。这些基因在细胞分裂中最为显着富集，表明它们与肿瘤发生密切相关。多数据库分析证实 HCC 组织中 hub 基因上调。所有 hub 基因均与多种类型的免疫浸润呈正相关，包括 B 细胞、CD4+ T 细胞、巨噬细胞和树突状细胞。此外，这些hub基因作为独立的预后因素，这些hub基因的表达与巨噬细胞水平相结合可以帮助预测HCC的不良预后。总之，这些中心基因（TOP2A、CCNB2、PRC1、RACGAP1、AURKA、CDKN3、NUSAP1、CDCA5、ASPM 和 NCAPG）可能是预后预测的关键标记，也可能作为 HCC 免疫干预策略的目标。
In the cancer-related research field, there is currently a major need for a greater number of valuable biomarkers to predict the prognosis of hepatocellular carcinoma (HCC). In this study, we aimed to screen hub genes related to immune cell infiltration and explore their prognostic value for HCC. We analyzed five datasets (GSE46408, GSE57957, GSE74656, GSE76427, and GSE87630) from the Gene Expression Omnibus database to screen the differentially expressed genes (DEGs). A protein–protein interaction network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes; then, the hub genes were identified. Functional enrichment of the genes was performed on the Metascape website. Next, the expression of these hub genes was validated in several databases, including Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and Human Protein Atlas. We explored the correlations between the hub genes and infiltrated immune cells in the TIMER2.0 database. The survival curves were generated in GEPIA2, and the univariate and multivariate Cox regression analyses were performed using TIMER2.0. The top ten hub genes [DNA topoisomerase II alpha (TOP2A), cyclin B2 (CCNB2), protein regulator of cytokinesis 1 (PRC1), Rac GTPase-activating protein 1 (RACGAP1), aurora kinase A (AURKA), cyclin-dependent kinase inhibitor 3 (CDKN3), nucleolar and spindle-associated protein 1 (NUSAP1), cell division cycle-associated 5 (CDCA5), abnormal spindle microtubule assembly (ASPM), and non-SMC condensin I complex subunit G (NCAPG)] were identified in subsequent analysis. These genes are most markedly enriched in cell division, suggesting their close association with tumorigenesis. Multi-database analyses validated that the hub genes were upregulated in HCC tissues. All hub genes positively correlated with several types of immune infiltration, including B cells, CD4+ T cells, macrophages, and dendritic cells. Furthermore, these hub genes served as independent prognostic factors, and the expression of these hub genes combing with the macrophage levels could help predict an unfavorable prognosis of HCC. In sum, these hub genes (TOP2A, CCNB2, PRC1, RACGAP1, AURKA, CDKN3, NUSAP1, CDCA5, ASPM, and NCAPG) may be pivotal markers for prognostic prediction as well as potentially work as targets for immune-based intervention strategies in HCC.