C-C 基序趋化因子配体 5（CCL5）：骨肉瘤的潜在生物标志物和免疫治疗靶点。

C-C Motif Chemokine Ligand 5 (CCL5): A Potential Biomarker and Immunotherapy Target for Osteosarcoma.

作者信息

Zheng Heng, Wang Yichong, Li Fengfeng

机构信息

The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

出版信息

Curr Cancer Drug Targets. 2024;24(3):308-318. doi: 10.2174/1568009623666230815115755.

DOI:10.2174/1568009623666230815115755

PMID:37581517

Abstract

BACKGROUND

Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue, which has an insidious onset and is difficult to detect early, and few early diagnostic markers with high specificity and sensitivity. Therefore, this study aims to identify potential biomarkers that can help diagnose OS in its early stages and improve the prognosis of patients.

METHODS

The data sets of GSE12789, GSE28424, GSE33382 and GSE36001 were combined and normalized to identify Differentially Expressed Genes (DEGs). The data were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) and Disease Ontology (DO). The hub gene was selected based on the common DEG that was obtained by applying two regression methods: the Least Absolute Shrinkage and Selection Operator (LASSO) and Support vVector Machine (SVM). Then the diagnostic value of the hub gene was evaluated in the GSE42572 data set. Finally, the correlation between immunocyte infiltration and key genes was analyzed by CIBERSORT.

RESULTS

The regression analysis results of LASSO and SVM are the following three DEGs: FK501 binding protein 51 (FKBP5), C-C motif chemokine ligand 5 (CCL5), complement component 1 Q subcomponent B chain (C1QB). We evaluated the diagnostic performance of three biomarkers (FKBP5, CCL5 and C1QB) for osteosarcoma using receiver operating characteristic (ROC) analysis. In the training group, the area under the curve (AUC) of FKBP5, CCL5 and C1QB was 0.907, 0.874 and 0.676, respectively. In the validation group, the AUC of FKBP5, CCL5 and C1QB was 0.618, 0.932 and 0.895, respectively. It is noteworthy that these genes were more expressed in tumor tissues than in normal tissues by various immune cell types, such as plasma cells, CD8+ T cells, T regulatory cells (Tregs), activated NK cells, activated dendritic cells and activated mast cells. These immune cell types are also associated with the expression levels of the three diagnostic genes that we identified.

CONCLUSION

We found that CCL5 can be considered an early diagnostic gene of osteosarcoma, and CCL5 interacts with immune cells to influence tumor occurrence and development. These findings have important implications for the early detection of osteosarcoma and the identification of novel therapeutic targets.

摘要

背景

骨肉瘤（OS）是最常见的原发性骨组织恶性肿瘤，其发病隐匿，早期难以发现，特异性和敏感性高的早期诊断标志物较少。因此，本研究旨在寻找有助于早期诊断 OS 的潜在生物标志物，改善患者预后。

方法

合并 GSE12789、GSE28424、GSE33382 和 GSE36001 数据集，通过基因本体论（GO）、京都基因与基因组百科全书（KEGG）和疾病本体论（DO）进行差异表达基因（DEG）分析。应用最小绝对收缩和选择算子（LASSO）和支持向量机（SVM）两种回归方法，对共同 DEG 进行分析，筛选出枢纽基因。然后在 GSE42572 数据集评估枢纽基因的诊断价值。最后，通过 CIBERSORT 分析免疫细胞浸润与关键基因的相关性。

结果

LASSO 和 SVM 的回归分析结果为以下三个 DEG：FK501 结合蛋白 51（FKBP5）、C-C 基序趋化因子配体 5（CCL5）、补体成分 1 Q 亚基 B 链（C1QB）。我们使用接受者操作特征（ROC）分析评估了三种生物标志物（FKBP5、CCL5 和 C1QB）对骨肉瘤的诊断性能。在训练组中，FKBP5、CCL5 和 C1QB 的曲线下面积（AUC）分别为 0.907、0.874 和 0.676。在验证组中，FKBP5、CCL5 和 C1QB 的 AUC 分别为 0.618、0.932 和 0.895。值得注意的是，这些基因在肿瘤组织中的表达水平明显高于正常组织，在多种免疫细胞类型中表达，如浆细胞、CD8+T 细胞、调节性 T 细胞（Tregs）、活化自然杀伤细胞、活化树突状细胞和活化肥大细胞。这些免疫细胞类型也与我们鉴定的三个诊断基因的表达水平相关。