Department of Otorhinolaryngology Head and Neck Surgery, Xuanwu Hospital Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing 100053, China.
Dis Markers. 2022 May 26;2022:2561673. doi: 10.1155/2022/2561673. eCollection 2022.
This study is aimed at investigating the regulating mechanisms of the interferon regulatory factor (IRF) family genes in head and neck squamous cell carcinoma.
Based on the HNSC data in the 'The Cancer Genome Atlas (TCGA)' database, the expression pattern of IRF family genes was investigated. The association of IRFs family genes and survival outcomes were analyzed by Kaplan-Meier plotter web portal. The relation of IRF genes and tumor stages was evaluated by using stage plots and based on GEPIA portal. 50 genes interacting with IRFs were identified using the NetworkAnalyst's protein-protein interaction (PPI) network construction tool. The top 200 correlated genes with similar expression patterns in HNSC were obtained by the similar gene detection module of GEPIA. Furthermore, functional enrichment analysis was performed to determine the biological functions enriched by the interacting and correlated genes. The potential implication of IRFs in tumor immunity was investigated in terms of tumor-infiltrating immune cells, a pair of immune checkpoint genes (CD274 and PDCD1), and ESTIMATE-Stromal-Immune score.
The unpaired sample analysis shows that all of the IRF family genes were highly expressed in HNSC tumor samples compared to control samples. The survival analysis results showed that the overexpression of IRF1, IRF4, IRF5, IRF6, IRF8, and IRF9 was associated with better overall survival in HNSC, while the other IRFs genes (IRF2, IRF3. and IRF7) did not show prognostic values for overall survival outcome of HNSC. Four genes (STAT1, STAT2, FOXP3, and SPI1) were overlapping among 50 interacted genes in the PPI network and top 200 correlated genes identified by GEPIA. The 50 interacting genes in the PPI network and top 200 correlated genes were integrated into 246 genes. These 246 genes were found to be overrepresented in multiple KEGG pathways, e.g., Th17 cell differentiation, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, natural killer (NK) cell-mediated cytotoxicity, FOXO signaling, PI3K-Akt signaling, and ErbB signaling. Most correlations between IRF gene members and TIICs were positive. The strongest positive correlation was identified between IRF8 and T cells ( = 0.849, < 0.001). The majority of correlation between IRF family genes and ESTIMATE-Stromal-Immune score was found to be positive. The highest positive correlation was found to be between IRF8 and Immune score ( = 0.874, = 1.09 - 158). Most correlations between IRFs and two immunoinhibitor genes (CD274 and PDCD1) were positive. IRF1 and PDCD1 were found to show the highest positive correlation ( = 0.764, < 2.2 - 16).
The current analysis showed IRFs were differentially expressed in HNSC, indicated significant prognostic values, were involved in tumor immunity-related signaling pathways, and significantly regulated tumor-infiltrating immune cells. IRF family genes could be potential therapeutic biomarkers in targeting tumor immunity of head and neck cancer.
本研究旨在探讨干扰素调节因子（IRF）家族基因在头颈部鳞状细胞癌中的调控机制。
基于“癌症基因组图谱（TCGA）”数据库中的 HNSC 数据，研究了 IRF 家族基因的表达模式。通过 Kaplan-Meier 绘谱器网络门户分析了 IRFs 家族基因与生存结局的关联。使用 GEPIA 门户中的阶段图评估了 IRF 基因与肿瘤分期的关系。使用 NetworkAnalyst 的蛋白质-蛋白质相互作用（PPI）网络构建工具鉴定了 50 个与 IRFs 相互作用的基因。使用 GEPIA 的相似基因检测模块获得了与 HNSC 中相似表达模式相关的前 200 个相关基因。此外，进行了功能富集分析，以确定相互作用和相关基因富集的生物学功能。根据肿瘤浸润免疫细胞、一对免疫检查点基因（CD274 和 PDCD1）和 ESTIMATE-Stromal-Immune 评分，研究了 IRFs 在肿瘤免疫中的潜在意义。
未配对样本分析表明，与对照样本相比，所有 IRF 家族基因在 HNSC 肿瘤样本中均高度表达。生存分析结果显示，IRF1、IRF4、IRF5、IRF6、IRF8 和 IRF9 的过表达与 HNSC 的总体生存率改善相关，而其他 IRFs 基因（IRF2、IRF3 和 IRF7）与 HNSC 的总体生存率预后无关。在 PPI 网络和通过 GEPIA 鉴定的前 200 个相关基因中，有 4 个重叠基因（STAT1、STAT2、FOXP3 和 SPI1）。PPI 网络中的 50 个相互作用基因和通过 GEPIA 鉴定的前 200 个相关基因被整合到 246 个基因中。这些 246 个基因在多个 KEGG 途径中过度表达，例如 Th17 细胞分化、T 细胞受体信号通路、细胞因子-细胞因子受体相互作用、自然杀伤（NK）细胞介导的细胞毒性、FOXO 信号通路、PI3K-Akt 信号通路和 ErbB 信号通路。IRF 基因成员与 TIICs 之间的大多数相关性为正相关。IRF8 与 T 细胞之间的最强正相关为 = 0.849（<0.001）。IRF 家族基因与 ESTIMATE-Stromal-Immune 评分之间的大多数相关性为正相关。IRF8 与免疫评分之间的最高正相关为 = 0.874（= 1.09-158）。IRFs 与两个免疫抑制剂基因（CD274 和 PDCD1）之间的大多数相关性为正相关。IRF1 和 PDCD1 显示出最高的正相关性（= 0.764，<2.2-16）。
目前的分析表明，IRFs 在 HNSC 中差异表达，具有显著的预后价值，参与肿瘤免疫相关信号通路，并显著调节肿瘤浸润免疫细胞。IRF 家族基因可能是头颈部癌症靶向肿瘤免疫的潜在治疗生物标志物。
