通过加权基因共表达网络分析探索肝硬化的免疫景观。
Exploring the Immune Landscape of Cirrhosis through Weighted Gene Co-expression Network Analysis.
机构信息
Department of Gastroenterology, Lhasa People's Hospital, Lhasa, China.
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
出版信息
Cell Mol Biol (Noisy-le-grand). 2023 Jun 30;69(6):168-174. doi: 10.14715/cmb/2023.69.6.25.
Cirrhosis is a persistent hepatic ailment that emerges from a range of causes, including viral infections, alcoholic liver disease, and non-alcoholic fatty liver disease. It is distinguished by the replacement of normal liver parenchyma with fibrous scar tissue, culminating in the development of hepatic insufficiency, portal hypertension, and eventual liver collapse. Several molecular and cellular mechanisms contribute to cirrhosis' pathogenesis, including activation of immune cells and dysregulation of immune-related pathways. Weighted Gene Co-expression Network Analysis (WGCNA) is a powerful data mining application used to identify gene modules and hub genes that are closely associated with specific phenotypes or conditions of interest. In this study, we performed WGCNA on publicly available gene expression datasets and subsequently assessed the roles of immune-related genes in the etiology and progression of cirrhosis, intending to explore potential therapeutic targets for this disease. GSE36411 gene expression profiling was extracted from the Gene Expression Omnibus repository (GEO). The transcriptomic data were submitted to Weighted Gene Co-expression Network Analysis (WGCNA) to screen for the presence of key genes, and immune-related genes were filtered by comparison to the InateDB database. Cancer Genome Atlas (TCGA) was included in the study to validate the significant modules generated from WGCNA. The key gene interaction network was constructed using GeneMANIA and Metascape. Kaplan-Meier method and Spearman correlation were used to evaluate the correlation of immune-related genes with prognosis, tumor microenvironment, and immune cell infiltration. Finally, we explored a possible mechanism using gene set enrichment (GSEA) analyses. In total, 2,102 differentially expressed genes (DEGs) were identified from the gene expression profile dataset. A weighted gene co-expression network analysis was performed, resulting in the classification of genes into 3 modules. Among these modules, the turquoise module was found to be most closely associated with cirrhosis. By comparing the turquoise module genes with an InateDB immune-related gene set, we identified 157 immune-associated genes. In addition, our study found that many hub genes are strongly associated with the number of immune-related genes in liver cirrhosis, in addition to a few modules associated with immune infiltration. It turns out that these hub genes were engaged in migration, activation, and immune cell regulation, as well as in the signaling pathways that drive the immune response to infection. Our research offered a deeper understanding of the underlying processes of immune infiltration in cirrhosis and also suggested potential treatment options for this troublesome condition. Our results demonstrate the effectiveness of WGCNA in uncovering new knowledge regarding the biology of cirrhosis and the function of the immune system in this disease. More studies ought to focus on the validation of the identified hub genes and the determination of their clinical relevance. These results could serve as the basis for the creation of more potent therapies for those with liver cancer linked to cirrhosis.
肝硬化是一种由多种原因引起的持续性肝脏疾病,包括病毒感染、酒精性肝病和非酒精性脂肪性肝病。其特征是正常的肝实质被纤维疤痕组织所取代,最终导致肝功能不全、门静脉高压和肝衰竭。几种分子和细胞机制导致肝硬化的发病机制,包括免疫细胞的激活和免疫相关途径的失调。加权基因共表达网络分析(WGCNA)是一种强大的数据挖掘应用程序,用于识别与特定表型或感兴趣的条件密切相关的基因模块和枢纽基因。在这项研究中,我们对公开的基因表达数据集进行了 WGCNA 分析,随后评估了免疫相关基因在肝硬化的病因和进展中的作用,旨在探索这种疾病的潜在治疗靶点。从基因表达综合数据库(GEO)中提取了 GSE36411 基因表达谱。将转录组数据提交给加权基因共表达网络分析(WGCNA),以筛选关键基因,并通过与 InateDB 数据库比较筛选免疫相关基因。癌症基因组图谱(TCGA)也被纳入研究,以验证 WGCNA 产生的显著模块。使用 GeneMANIA 和 Metascape 构建关键基因互作网络。使用 Kaplan-Meier 方法和 Spearman 相关性评估免疫相关基因与预后、肿瘤微环境和免疫细胞浸润的相关性。最后,我们使用基因集富集(GSEA)分析探讨了一种可能的机制。从基因表达谱数据集中共鉴定出 2102 个差异表达基因(DEGs)。进行了加权基因共表达网络分析,结果将基因分为 3 个模块。在这些模块中,发现绿松石模块与肝硬化最密切相关。通过将绿松石模块基因与 InateDB 免疫相关基因集进行比较,我们鉴定出 157 个免疫相关基因。此外,我们的研究发现,许多枢纽基因与肝硬化中免疫相关基因的数量密切相关,除了一些与免疫浸润相关的模块。事实证明,这些枢纽基因参与了迁移、激活和免疫细胞调节,以及驱动免疫反应的感染信号通路。我们的研究提供了对肝硬化中免疫浸润的潜在过程的更深入了解,并为这种棘手的疾病提出了潜在的治疗选择。我们的结果表明,WGCNA 在揭示肝硬化生物学和免疫系统在该疾病中的功能的新知识方面是有效的。应该进行更多的研究来验证所鉴定的枢纽基因及其临床相关性。这些结果可以为那些与肝硬化相关的肝癌患者创建更有效的治疗方法提供基础。