Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Korea.
Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Korea.
Genes Genomics. 2024 Aug;46(8):977-990. doi: 10.1007/s13258-024-01539-1. Epub 2024 Jul 8.
NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis.
We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods.
We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated.
Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-β dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer.
The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.
NR4A 家族基因在癌症中发挥着关键作用。然而，NR4A 家族基因在癌症中的作用是矛盾的，因为它们既促进又抑制肿瘤发生。
我们旨在通过生物信息学方法对 NR4A 家族基因的表达与肿瘤微环境（TME）之间的关联进行综合分析。
我们从 TCGA 和 GTEx 数据库中收集了 33 种癌症类型和 20 个正常组织部位的 RNA-seq 数据。研究了 NR4A 家族基因的表达模式及其与 DNA 甲基化、miRNA、总生存期、药物反应和肿瘤微环境的关系。
在 15 种癌症类型中，所有 NR4A 家族基因均显著下调。在五种癌症中，NR4A 家族基因的 DNA 启动子甲基化和表达呈负相关。靶向 NR4A 家族基因的 10 种 miRNA 的表达与 NR4A 家族基因的表达呈负相关。所有 NR4A 家族基因的高表达与胃腺癌的不良预后相关，NR4A2 和 NR4A3 的高表达与肾上腺皮质癌的不良预后相关。此外，我们发现 NR4A2 的表达升高，增强了对各种化疗药物的反应，而 NR4A3 降低了药物敏感性。有趣的是，在乳腺癌中，NR4A3 与 C2（IFN-γ 优势）、C3（炎症）和 C6（TGF-β 优势）免疫亚型和浸润免疫细胞类型显著相关，这表明 NR4A3 在乳腺癌中具有致癌和肿瘤抑制功能。
NR4A 家族基因有可能成为人类癌症的诊断、预后和免疫标志物。
