[CD40配体是浸润性乳腺癌肿瘤微环境中一种新型的免疫和基质相关预后生物标志物]
[CD40LG is a novel immune- and stroma-related prognostic biomarker in the tumor microenvironment of invasive breast cancer].
作者信息
Guo L, Ma Y, Li T, Li J
机构信息
Ningxia Medical University, Yinchuan 750000, China.
General Hospital of Ningxia Medical University, Yinchuan 750000, China.
出版信息
Nan Fang Yi Ke Da Xue Xue Bao. 2022 Sep 20;42(9):1267-1278. doi: 10.12122/j.issn.1673-4254.2022.09.01.
OBJECTIVE
To identify tumor microenvironment (TME)- related genes associated with the occurrence of invasive breast cancer as potential prognostic biomarkers and therapeutic targets.
METHODS
RNA transcriptome data and clinically relevant data were retrieved from TCGA database, and the StromalScore and ImmuneScore were calculated using the ESTIMATE algorithm. The differentially expressed genes (DEGs) were screened by taking the intersection. A protein- protein interaction network was established, and univariate COX regression analysis was used to identify the core genes among the DEGs. A core gene was selected for GSEA and CIBERSORT analysis to determine the function of the core gene and the proportion of tumor-infiltrating immune cells, respectively. Western blotting and qRT-PCR were performed to verify the expression level of CD40LG in breast cancer cell lines and clinical specimens.
RESULTS
A total of 1222 samples (124 normal and 1098 tumor samples) were extracted from TCGA for analysis, from which 487 DEGs were identified. These genes were mainly enriched in immune-related pathways, and crossover analysis identified 11 key genes (CD40LG, ITK, CD5, CD3E, SPN, IL7R, CD48, CCL19, CD2, CD52, and CD2711) associated with breast cancer TME status. CD40LG was selected as the core gene, whose high expression was found to be associated with a longer overall survival of breast cancer patients (=0.002), and its expression level differed significantly with TNM stage and tumor size ( < 0.05). GSEA and CIBERSORT analyses indicated that CD40LG expression level was associated with immune activity in the TME. Western blotting and qRT-PCR showed that the protein and mRNA expression of CD40LG were significantly lower in breast cancer cells and cancer tissues than in normal breast cells and adjacent tissues.
CONCLUSIONS
The high expression of CD40LG in TME is positively correlated with the survival of patients with invasive breast cancer, suggesting its value as a potential new biomarker for predicting prognosis of the patients.
目的
鉴定与浸润性乳腺癌发生相关的肿瘤微环境（TME）相关基因，作为潜在的预后生物标志物和治疗靶点。
方法
从TCGA数据库中检索RNA转录组数据和临床相关数据，使用ESTIMATE算法计算基质评分和免疫评分。通过取交集筛选差异表达基因（DEG）。建立蛋白质-蛋白质相互作用网络，采用单因素COX回归分析鉴定DEG中的核心基因。选择一个核心基因进行GSEA和CIBERSORT分析，分别确定核心基因的功能和肿瘤浸润免疫细胞的比例。进行蛋白质印迹和qRT-PCR以验证CD40LG在乳腺癌细胞系和临床标本中的表达水平。
结果
从TCGA中提取了总共1222个样本（124个正常样本和1098个肿瘤样本）进行分析，从中鉴定出487个DEG。这些基因主要富集在免疫相关途径中，交叉分析确定了11个与乳腺癌TME状态相关的关键基因（CD40LG、ITK、CD5、CD3E、SPN、IL7R、CD48、CCL19、CD2、CD52和CD2711）。选择CD40LG作为核心基因，发现其高表达与乳腺癌患者较长的总生存期相关（=0.002），并且其表达水平在TNM分期和肿瘤大小方面有显著差异（<0.05）。GSEA和CIBERSORT分析表明，CD40LG表达水平与TME中的免疫活性相关。蛋白质印迹和qRT-PCR显示，CD40LG的蛋白质和mRNA表达在乳腺癌细胞和癌组织中明显低于正常乳腺细胞和相邻组织。
结论
TME中CD40LG的高表达与浸润性乳腺癌患者的生存呈正相关，表明其作为预测患者预后的潜在新生物标志物的价值。
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