Nikonezhad Behnoosh, Lotfian Maryam, Manavi Nadia, Zamani Atefeh, Mahdevar Mohammad
Genius Gene, Genetics and Biotechnology Company, Isfahan, Iran.
Department of Medical Laboratory Science, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Cancer Cell Int. 2025 Jun 6;25(1):203. doi: 10.1186/s12935-025-03839-2.
BACKGROUND: E2F transcription factors are crucial in various biological processes, including cell proliferation, differentiation, and apoptosis. However, the exact role of E2F target genes in breast cancer (BC), as well as their influence on survival and immune response, remains poorly understood. METHODS: To investigate the differential expression of E2F target genes and their relationship with patient prognosis and immune cell infiltration, transcriptomic data from the Cancer Genome Atlas database were analyzed. A risk model was developed to identify genes associated with survival. BC samples were clustered into high-expression (C1) and low-expression (C2) groups of E2F target genes. The correlation between gene expression and factors such as survival, immune cell infiltration (CD4 + and CD8 + T cells), and immune checkpoint inhibitors (PD-L1 and PD-L2) was analyzed. We analyzed the link between clusters and clinical characteristics using the chi-squared test. For further investigation, single-cell data from GSE243526 were utilized. For validation, the expression levels of JPT1 and TBRG4 were assessed using RT-qPCR in clinical samples. RESULTS: Genes targeting E2F, such as AURKB, JPT1, TBRG4, and KIF4A, showed increased expression linked to poor patient prognosis, regardless of clinical features. Kaplan-Meier survival analysis revealed that elevated expression of these genes correlated significantly with decreased survival rates and heightened mortality risk. Single-cell data confirmed that candidate genes exhibited higher expression in tumor-associated epithelial cells than healthy ones. Furthermore, samples from group C1 exhibited a lower survival rate than C2. Immune cell infiltration analysis determined that high expression of E2F target genes in the C1 subgroup was associated with diminished T cell infiltration and increased PD-L1 and PD-L2 expression. A strong and significant association was also identified between triple-negative breast cancer and the C1 cluster. RT-qPCR validation confirmed a significant elevation of JPT1 and TBRG4 expression levels relative to adjacent healthy tissues in BC. CONCLUSION: These findings suggest that E2F target genes, including JPT1 and TBRG4, may act as prognostic biomarkers and contribute to immune evasion in BC. E2F target genes can also offer good potential for classifying and treating patients.
背景：E2F转录因子在包括细胞增殖、分化和凋亡在内的各种生物学过程中至关重要。然而，E2F靶基因在乳腺癌（BC）中的具体作用及其对生存和免疫反应的影响仍知之甚少。 方法：为了研究E2F靶基因的差异表达及其与患者预后和免疫细胞浸润的关系，分析了来自癌症基因组图谱数据库的转录组数据。建立了一个风险模型来识别与生存相关的基因。将BC样本聚类为E2F靶基因的高表达（C1）和低表达（C2）组。分析了基因表达与生存、免疫细胞浸润（CD4 +和CD8 + T细胞）以及免疫检查点抑制剂（PD-L1和PD-L2）等因素之间的相关性。我们使用卡方检验分析了聚类与临床特征之间的联系。为了进一步研究，利用了来自GSE243526的单细胞数据。为了进行验证，在临床样本中使用RT-qPCR评估了JPT1和TBRG4的表达水平。 结果：靶向E2F的基因，如AURKB、JPT1、TBRG4和KIF4A，无论临床特征如何，其表达增加都与患者预后不良有关。Kaplan-Meier生存分析显示，这些基因的表达升高与生存率降低和死亡风险增加显著相关。单细胞数据证实，候选基因在肿瘤相关上皮细胞中的表达高于健康细胞。此外，C1组样本的生存率低于C2组。免疫细胞浸润分析确定，C1亚组中E2F靶基因的高表达与T细胞浸润减少以及PD-L1和PD-L2表达增加有关。三阴性乳腺癌与C1聚类之间也发现了强烈且显著的关联。RT-qPCR验证证实，BC中JPT1和TBRG4的表达水平相对于相邻健康组织显著升高。 结论：这些发现表明，包括JPT1和TBRG4在内的E2F靶基因可能作为预后生物标志物，并有助于BC中的免疫逃逸。E2F靶基因在对患者进行分类和治疗方面也具有良好的潜力。
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