THBS1 在胶质母细胞瘤中的表达及功能研究
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国家自然科学基金 (81972816);北京市科技新星计划 (20220484029);国家蛋白质科学基础设施(北京)北大分中心开放课题 (KF-202301)


Expression and function of THBS1 in glioblastoma
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    摘要:

    目的 研究THBS1在胶质母细胞瘤(GBM)中的表达水平及功能。方法 在癌症基因组 图谱计划(TCGA)和中国脑胶质瘤基因组图谱计划(CGGA)_693、CGGA_325 和 CGGA_301 数据集中提取 数据,对基因表达数据进行标准化处理后,分析THBS1在低级别胶质瘤和 GBM 中的表达差异以及与异 柠檬酸脱氢酶(IDH)突变、1p/19q 共缺失状态和生存预后的关系。基于单细胞测序数据、空间转录组数 据,分析THBS1在胶质瘤组织中的主要分布。采用 CellCall 算法和 MAGIC 算法进一步分析THBS1在细 胞相互作用网络之中的功能和THBS1相关基因及其功能,采用 CIBERSORTx 算法分析THBS1与免疫细 胞浸润的关系。结果 THBS1在 GBM 组织中的表达水平高于正常组织,差异有统计学意义(P< 0.05)。 在 CGGA 和 TCGA 数据集中,THBS1在 GBM 患者中的表达水平高于低级别胶质瘤,差异有统计学意义 (P< 0.01);THBS1在IDH野生型和非 1p/19q 共缺失型患者中的表达水平分别高于IDH突变型和 1p/19q 共缺失型,差异均有统计学意义(均P< 0.01)。在 CGGA_693 和 CGGA_325 数据集中,THBS1基因高表 达患者的生存率低于低表达患者,差异有统计学意义(P< 0.01)。单细胞测序数据分析显示,THBS1主 要在胶质瘤组织的单核 / 巨噬细胞中表达。空间转录组数据分析显示,表达THBS1的单核/巨噬细胞在 空间方面与星形胶质细胞、肿瘤细胞、神经元、少突细胞、少突胶质细胞前体细胞存在共定位。THBS1 阴性的单核/巨噬细胞和THBS1阳性的单核 / 巨噬细胞与肿瘤细胞、神经元之间细胞通信的通路活性及 所依赖的配体 - 受体途径不同。功能富集分析显示,THBS1相关基因参与囊泡介导的转运、自噬、DNA 结合转录因子活性的调节等生物过程。在 4 个数据集中,THBS1高表达组的巨噬细胞 M0 丰度高于低表 达组,差异有统计学意义(P< 0.05)。结论 THBS1在GBM中高表达,与患者较差的预后相关;THBS1 调控巨噬细胞M0浸润,表达THBS1的单核/巨噬细胞可能调控GBM的微环境,进而调控肿瘤发生。

    Abstract:

    Objective To explore the expression level and function of THBS1 in glioblastoma (GBM). Methods The data was extracted from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA)_693、CGGA_325 and CGGA_301 datasets. Gene expression data were normalized to analyze the differential expression of THBS1 in low-grade gliomas and GBM, as well as its relationship with isocitrate dehydrogenase (IDH) mutations, 1p/19q codeletion, and survival prognosis. Based on single-cell sequencing data and spatial transcriptomic data, the distribution of THBS1 in glioma tissue was analyzed. The CellCall algorithm and MAGIC algorithm were used to explore the function of THBS1 in the cell-cell communication, THBS1 related genes and their functions. The CIBERSORTx algorithm was used to analyze the relationship between THBS1 and immune cell infiltration. Results The expression level of THBS1 in GBM tissue was higher than that in normal tissue, and the difference was statistically significant (P < 0.05). In the CGGA and TCGA datasets, the expression level of THBS1 in GBM patients was higher than that in low-grade gliomas, and the difference was statistically significant (both P < 0.01). The expression levels of THBS1 in IDH wild-type and 1p/19q non-codeletion patients were higher than those in IDH mutant and 1p/19q codeletion patients, respectively, and the differences were statistically significant (both P < 0.01). In the CGGA_693 and CGGA-325 datasets, the survival rate of patients with high expression of THBS1 gene was lower than that of patients with low expression, and the difference was statistically significant (P < 0.01). Single-cell sequencing data analysis showed that THBS1 was mainly expressed in monocyte/ macrophages of glioma tissue. Spatial transcriptome data analysis indicated that monocyte/ macrophages expressing THBS1 were spatially co-localized with astrocytes, tumor cells, neurons, oligodendrocytes, and oligodendrocyte precursor cells. The pathway activity and dependent ligand-receptor pathways of cell-cell communication between THBS1 negative and THBS1 positive monocytes/macrophages and tumor cells and neurons were different. Functional enrichment analysis showed that THBS1 related genes were involved in biological processes such as vesicle mediated transport, autophagy, and regulation of DNA-binding transcription factor activity. In the four datasets, the abundance of macrophage M0 in the high expression group of THBS1 was higher than that in the low expression group, and the difference was statistically significant (P< 0.05). Conclusions THBS1 is highly expressed in GBM and is associated with poor prognosis in patients. THBS1 regulates macrophage M0 infiltration, and monocytes/macrophages expressing THBS1 may regulate the microenvironment of GBM, thereby regulating oncogenesis.

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胡慧敏,李泽生,刘博涵,陈彦坤,彭大钊. THBS1 在胶质母细胞瘤中的表达及功能研究[J].神经疾病与精神卫生,2024,(5).
DOI :10.3969/j. issn.1009-6574.2024.05.003.

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  • 在线发布日期: 2024-05-31