Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People's Liberation Army, Shenyang, China.
Department of Radiation, Affiliated Central Hospital of Shenyang Medical College, Shenyang, China.
Am J Physiol Cell Physiol. 2024 Jan 1;326(1):C252-C268. doi: 10.1152/ajpcell.00234.2023. Epub 2023 Nov 20.
We elucidated the molecular mechanism of cancer-associated fibroblast (CAF)-associated gene insulin-like growth factor binding protein-2 (IGFBP2)-induced M2 macrophage polarization in the tumor microenvironment involved in glioma progression. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) provided bulk RNA-sequencing datasets, ESTIMATE scores for glioma stromal cells, and overall survival-clinicopathological correlation analyses. TIMER provided CAF abundance in the TCGA glioma-related dataset, differential gene analysis was performed for high- and low-CAF groups, and weighted gene coexpression network analysis identified CAF-related genes. Univariate and multifactorial cyclooxygenase (COX) regression analyses created the CAF risk models single sample gene set enrichment analysis, CIBERSORT, and GSE84465. Mice were implanted with gliomas, and Western blot and RT-quantitative PCR showed IGFBP2 in tumor tissues. Adeno-associated virus (AAV) decreased IGFBP2, flow cytometry measured M1 and M2 macrophage ratios, and immunohistochemistry detected markers. TCGA and CGGA transcriptome data showed malignant gliomas had higher stromal cell scores and worse prognoses. Low- and high-CAF TCGA gliomas were detected, and differential expression, WGCNA, and multifactorial COX identified 132 CAF-related genes and seven high-risk genes (CPQ, EFEMP2, IGFBP2, RAB42, TNFRSF12A, and VASN). Neither CAF risk score, grade, nor 1p/19q affected glioma prognosis. CAF only enriched EFEMP2 and IGFBP2. Gene Expression Profiling Interactive Analysis compared EFEMP2 and IGFBP2 expression in normal brain tissue and gliomas. Low-grade glioma and malignant glioblastoma highly expressed IGFBP2 and EFEMP2. GSEA raised IGFBP2. CIBERSORT linked M2 macrophage infiltration to TCGA glioma immune cell subpopulation IGFBP2 expression. IGFBP2 knockdown stopped mouse glioma and M2 macrophage polarization. CAF plays a procarcinogenic role in glioma, and the CAF-related gene IGFBP2 could promote glioma progression by inducing M2 macrophage polarization. The cancer-associated fibroblast (CAF)-related gene insulin-like growth factor binding protein-2 (IGFBP2) is highly expressed in gliomas and is associated with poor prognosis. CAF-related gene IGFBP2 promotes glioma progression by inducing polarization of M2 macrophages. This study provides a new basis for an in-depth investigation of the functional mechanisms of the glioma tumor microenvironment and the search for key genes involved in immune regulation in CAF.
我们阐明了癌症相关成纤维细胞（CAF）相关基因胰岛素样生长因子结合蛋白-2（IGFBP2）诱导肿瘤微环境中 M2 巨噬细胞极化的分子机制，该机制涉及胶质瘤的进展。癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）提供了批量 RNA 测序数据集、用于胶质瘤基质细胞的 ESTIMATE 评分以及整体生存-临床病理相关性分析。TIMER 提供了 TCGA 相关胶质瘤数据集的 CAF 丰度，对高 CAF 和低 CAF 组进行了差异基因分析，并进行了加权基因共表达网络分析以确定 CAF 相关基因。单变量和多因素环氧化酶（COX）回归分析创建了 CAF 风险模型单样本基因集富集分析、CIBERSORT 和 GSE84465。用小鼠植入脑肿瘤，Western blot 和 RT-定量 PCR 显示肿瘤组织中的 IGFBP2。腺相关病毒（AAV）降低 IGFBP2，流式细胞术测量 M1 和 M2 巨噬细胞比值，免疫组织化学检测标记物。TCGA 和 CGGA 转录组数据显示恶性胶质瘤的基质细胞评分更高，预后更差。检测到低 CAF 和高 CAF TCGA 脑肿瘤，差异表达、WGCNA 和多因素 COX 鉴定出 132 个 CAF 相关基因和 7 个高危基因（CPQ、EFEMP2、IGFBP2、RAB42、TNFRSF12A 和 VASN）。CAF 风险评分、分级或 1p/19q 均不影响胶质瘤的预后。CAF 仅富集 EFEMP2 和 IGFBP2。基因表达谱交互式分析比较了正常脑组织和脑肿瘤中 EFEMP2 和 IGFBP2 的表达。低级别胶质瘤和恶性胶质母细胞瘤高度表达 IGFBP2 和 EFEMP2。GSEA 提出 IGFBP2。CIBERSORT 将 TCGA 胶质瘤免疫细胞亚群 IGFBP2 表达与 M2 巨噬细胞浸润联系起来。IGFBP2 敲低阻止了小鼠脑肿瘤和 M2 巨噬细胞极化。CAF 在胶质瘤中起致癌作用，CAF 相关基因 IGFBP2 可通过诱导 M2 巨噬细胞极化促进胶质瘤的进展。癌症相关成纤维细胞（CAF）相关基因胰岛素样生长因子结合蛋白-2（IGFBP2）在脑肿瘤中高表达，与预后不良相关。CAF 相关基因 IGFBP2 通过诱导 M2 巨噬细胞极化促进脑肿瘤的进展。本研究为深入研究胶质瘤肿瘤微环境的功能机制以及寻找 CAF 中涉及免疫调节的关键基因提供了新的依据。
