转化生长因子β诱导蛋白在胶质瘤中的表达及生物学功能

Expression and biological functions of TGFBI in glioma

目的:探讨转化生长因子β诱导蛋白(TGFBI)在胶质瘤中的表达及其生物学功能。方法:通过从癌症基因组图谱(TCGA)、中国脑胶质瘤图谱(CGGA)和脑肿瘤分子数据库(Rembrandt)下载胶质瘤的转录组数据和相应的临床资料,分析在不同级别胶质瘤中TGFBI mRNA的表达水平,及其表达变化与胶质瘤患者预后的关系。免疫组织化学染色法检测35例胶质母细胞瘤组织和5例正常脑组织中TGFBI蛋白的表达水平。通过用慢病毒转染U87和U373细胞株构建TGFBI表达下调的胶质母细胞瘤细胞系,检测TGFBI对胶质瘤细胞增殖、侵袭、凋亡和细胞周期的影响。通过基因集富集分析(GSEA)预测TGFBI在胶质瘤发生发展中可能参与并调控的相关通路。结果:TCGA、CGGA和Rembrandt数据库的结果分析显示随着胶质瘤级别的增加,TGFBI mRNA的表达水平升高(P<0.05)。此外,TGFBI m RNA的高表达与胶质瘤患者不良预后显著相关(P<0.01)。免疫组化检测结果显示,与正常脑组织相比,胶质母细胞瘤组织中TGFBI蛋白表达水平显著增加(P<0.05)。细胞学实验结果显示,TGFBI表达下调可显著抑制胶质母细胞瘤细胞增殖和侵袭能力,同时能够促进细胞凋亡,促使细胞从G1期转向S期。GSEA分析结果显示高表达TGFBI可能通过TOLL样受体信号通路、NOD样受体信号通路和JAK-STAT信号通路参与调控胶质瘤恶性生物学行为。结论:TGFBI在胶质母细胞瘤组织中表达升高,可促进肿瘤细胞的增殖、侵袭,抑制细胞凋亡并诱导细胞周期重排,推测其可能在胶质瘤发生发展中扮演着癌基因的角色。

OBJECTIVE:To investigate expression and biological function of the transforming growth factorβ-induced protein(TGFBI)in glioma.METHODS:The transcriptome data and the corresponding clinical information of tumor samples from glioma patients in the Cancer Genome Atlas(TCGA)、Chinese Glioma Genome Atlas(CGGA)and Rembrandt database were obtained to analyze potential associations between grades,subtypes,overall survival of glioma patients and TGFBI mRNA expression levels.Expression of TGFBI protein in 35 glioblastoma tissues and 5 normal brain tissues was analyzed using immunohistochemical method.Furthermore,the U87 and U373 cell lines were transfected with the constructed lentivirus vector containing shTGFBI target sequence to establish glioblastoma cell lines with low TGFBI expression and then to explore the effect of TGFBI on tumor proliferation、invasion、apoptosis and cell cycle.Finally,Gene set enrichment assay(GSEA)was used to predict the related pathways that TGFBI might participate in the occurrence and development of glioma.RESULTS:Results from TCGA、CGGA and Rembrandt databases showed that TGFBI expressions were positively correlated with the WHO grades(P<0.05).In addition,high expressions of TGFBI were correlated with inferior survival in glioma patients.Expressions of TGFBI in glioma tissues were significantly higher than that in normal brain tissues(P<0.05).The knockdown of TGFBI significantly inhibited proliferation and invasion of cancer cells、promoted cell apoptosis and promoted cell cycle progression from the G1 to the S phases.GSEA showed that high expressions of TGFBI were involved in activation of the TOLL-like receptors,NOD-like receptors and JAK-STAT signaling pathways.CONCLUSION:Overexpressions of TGFBI in gliomas promoted proliferation and invasion of tumor cells,inhibited cell apoptosis and induced cell cycle rearrangement.Thus,TGFBI might play an oncogene role in the occurrence and development of gliomas.