结缔组织生长因子作为一个不利的预后标志物，促进了胶质瘤的增殖、迁移和侵袭。
Connective tissue growth factor as an unfavorable prognostic marker promotes the proliferation, migration, and invasion of gliomas.
机构信息
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
The First Clinical Medical Institute of Southern Medical University, Guangzhou, Guangdong 510515, China.
出版信息
Chin Med J (Engl). 2020 Mar 20;133(6):670-678. doi: 10.1097/CM9.0000000000000683.
BACKGROUND
In consideration of the difficulty in diagnosing high heterogeneous glioma, valuable prognostic markers are urgent to be investigated. This study aimed to verify that connective tissue growth factor (CTGF) is associated with the clinical prognosis of glioma, also to analyze the effect of CTGF on the biological function.
METHODS
In this study, glioma and non-tumor tissue samples were obtained in 2012 to 2014 from the Department of Neurosurgery of Nanfang Hospital of Southern Medical University, Guangzhou, China. Based on messenger RNA (mRNA) data from the Cancer Genome Atlas (TCGA) and CCGA dataset, combined with related clinical information, we detected the expression of CTGF mRNA in glioma and assessed its effect on the prognosis of glioma patients. High expression of CTGF mRNA and protein in glioma were verified by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. The role of CTGF in the proliferation, migration, and invasion of gliomas were respectively identified by methylthiazoletetrazolium assay, Transwell and Boyden assay in vitro. The effect on glioma cell circle was assessed by flow cytometry. For higher expression of CTGF in glioblastoma (GBM), the biological function of CTGF in GBM was investigated by gene ontology (GO) analysis.
RESULTS
In depth analysis of TCGA data revealed that CTGF mRNA was highly expressed in glioma (GBM, n = 163; lowly proliferative glioma [LGG], n = 518; non-tumor brain tissue, n = 207; LGG, t = 2.410, GBM, t = 2.364, P < 0.05). CTGF mRNA and protein expression in glioma (86%) was significantly higher than that in non-tumor tissues (18%) verified by collected samples. Glioma patients with higher expression of CTGF showed an obviously poorer overall survival (35.4 and 27.0 months compared to 63.3 and 55.1 months in TCGA and Chinese Glioma Genome Atlas (CGGA) databases separately, CGGA: χ = 7.596, P = 0.0059; TCGA: χ = 10.46, P = 0.0012). Inhibiting CTGF expression could significantly suppress the proliferation, migration, and invasion of gliomas. CTGF higher expression had been observed in GBM, and GO analysis demonstrated that the function of CTGF in GBM was mainly associated with metabolism and energy pathways (P < 0.001).
CONCLUSIONS
CTGF is highly expressed in glioma, especially GBM, as an unfavorable and independent prognostic marker for glioma patients and facilitates the progress of glioma.
背景
考虑到高级别胶质瘤诊断困难，急需寻找有价值的预后标志物。本研究旨在验证结缔组织生长因子（CTGF）与胶质瘤的临床预后相关，并分析 CTGF 对生物学功能的影响。
方法
本研究于 2012 年至 2014 年从南方医科大学南方医院神经外科获取胶质瘤和非肿瘤组织样本。基于癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）数据集的信使 RNA（mRNA）数据，并结合相关临床信息，检测 CTGF mRNA 在胶质瘤中的表达情况，并评估其对胶质瘤患者预后的影响。通过逆转录-聚合酶链反应、免疫组织化学和 Western blot 验证 CTGF mRNA 和蛋白在胶质瘤中的高表达。体外甲基噻唑基四唑比色法、Transwell 和 Boyden 检测分别鉴定 CTGF 在胶质瘤增殖、迁移和侵袭中的作用。通过流式细胞术评估对胶质瘤细胞周期的影响。对于胶质母细胞瘤（GBM）中 CTGF 高表达，通过基因本体（GO）分析研究 CTGF 在 GBM 中的生物学功能。
结果
对 TCGA 数据的深入分析表明，CTGF mRNA 在胶质瘤（GBM，n=163；低增殖性胶质瘤[LGG]，n=518；非肿瘤脑组织，n=207；LGG，t=2.410，GBM，t=2.364，P<0.05）中高表达。通过收集的样本验证，胶质瘤中 CTGF mRNA 和蛋白表达（86%）明显高于非肿瘤组织（18%）。TCGA 和中国胶质瘤基因组图谱（CGGA）数据库中 CTGF 高表达的胶质瘤患者总生存期明显缩短（分别为 35.4 和 27.0 个月与 63.3 和 55.1 个月，CGGA：χ²=7.596，P=0.0059；TCGA：χ²=10.46，P=0.0012）。抑制 CTGF 表达可显著抑制胶质瘤的增殖、迁移和侵袭。GBM 中观察到 CTGF 高表达，GO 分析表明 CTGF 在 GBM 中的功能主要与代谢和能量途径相关（P<0.001）。
结论
CTGF 在胶质瘤中高度表达，尤其是在 GBM 中，作为胶质瘤患者不利的独立预后标志物，促进胶质瘤的进展。
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