Table_3_Analysis of Genes Involved in Ulcerative Colitis Activity and Tumorigenesis Through Systematic Mining of Gene Co-expression Networks.xls

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colon, characterized by continuous mucosal inflammation. Recently, some studies have considered it as part of an inflammatory bowel disease-based global network. Herein, with the aim of identifying the underlying potential genetic mechanisms involved in the development of UC, multiple algorithms for weighted correlation network analysis (WGCNA), principal component analysis (PCA), and linear models for microarray data algorithm (LIMMA) were used to identify the hub genes. The map of platelet activation, ligand-receptor interaction, calcium signaling pathway, and cAMP signaling pathway showed significant links with UC development, and the hub genes CCR7, CXCL10, CXCL9, IDO1, MMP9, and VCAM1, which are associated with immune dysregulation and tumorigenesis in biological function, were found by multiple powerful bioinformatics methods. Analysis of The Cancer Genome Atlas (TCGA) also showed that the low expression of CCR7, CXCL10, CXCL9, and MMP9 may be correlated with a poor prognosis of overall survival (OS) in colorectal cancer (CRC) patients (all p < 0.05), while no significance detected in both of IDO1 and VCAM1. In addition, low expression of CCR7, CXCL10, CXCL9, MMP9, and IDO1 may be associated with a poor prognosis in recurrence free survival (RFS) time (all p < 0.05), but no significant difference was identified in VCAM1. Moreover, the NFKB1, FLI1, and STAT1 with the highest enrichment score were detected as the master regulators of hub genes. In summary, these results indicated the central role of the hub genes of CCR7, CXCL10, CXCL9, IDO1, VCAM1, and MMP9, in response to UC progression, as well as the development of UC to CRC, thus shedding light on the molecular mechanisms involved and assisting with drug target validation.

溃疡性结肠炎（Ulcerative colitis, UC）是一种特发性慢性结肠炎症性疾病，以连续性黏膜炎症为典型特征。近期有研究将其纳入炎症性肠病相关的全球疾病网络范畴。本研究旨在揭示UC发生发展潜在的遗传机制，采用加权基因共表达网络分析（weighted correlation network analysis, WGCNA）、主成分分析（principal component analysis, PCA）以及微阵列数据线性模型算法（linear models for microarray data algorithm, LIMMA）等多种算法筛选枢纽基因。研究发现，血小板活化、配体-受体相互作用、钙信号通路及cAMP信号通路均与UC的发生发展存在显著关联；通过多种高效生物信息学方法，最终筛选得到CCR7、CXCL10、CXCL9、IDO1、MMP9、VCAM1等枢纽基因，其生物学功能涉及免疫失调与肿瘤发生。对癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据集的分析显示，CCR7、CXCL10、CXCL9及MMP9低表达与结直肠癌（colorectal cancer, CRC）患者的总生存期（overall survival, OS）不良预后显著相关（所有p值均<0.05），而IDO1与VCAM1的表达水平未体现此类统计学关联。此外，CCR7、CXCL10、CXCL9、MMP9及IDO1低表达可能与结直肠癌患者的无复发生存期（recurrence free survival, RFS）不良预后相关（所有p值均<0.05），但VCAM1未发现此类显著差异。进一步分析发现，富集得分最高的NFKB1、FLI1及STAT1为上述枢纽基因的主调控因子。综上，本研究结果表明CCR7、CXCL10、CXCL9、IDO1、VCAM1及MMP9这些枢纽基因在UC进展以及UC向CRC转化的过程中发挥核心作用，为阐明相关分子机制及验证药物靶点提供了新的理论依据与研究方向。