Department of Neurosurgery, Chongqing Medical University, Chongqing, China.
Chongqing University Three Gorges Hospital, Wanzhou, Chongqing, China.
Aging (Albany NY). 2022 Apr 29;14(9):3856-3873. doi: 10.18632/aging.204048.
Glioblastoma in the brain is the most malignant solid tumor with a poor prognosis. Screening critical targets and exploring underlying mechanisms will be a benefit for diagnoses and treatment. IDH1 mutation (R132) was used to distinguish glioblastoma grade and predict prognosis as a significant marker. However, the manner of IDH1 mutation regulating glioblastoma development was still unclear.
To study the function of IDH1 mutation, multi-type sequencing data (transcriptome, methylation and copy number variation) from the GEO and TCGA database were analyzed using bioinformatics techniques. The biological functions of IDH1 mutation (R132) would be comprehensively evaluated from the regulatory networks, tumor immune microenvironment and clinical relevance. Then the analysis result would be validated by experimental techniques.
Compared with adjacent tissues, IDH1 was up-regulated in glioblastoma, which also positively correlated with the malignant degree and a poor prognosis. To further study the mechanism of mutated IDH1 (R132) function, 5 correlated genes (FABP5, C1RL, MIR155HG, CSTA and BCL3) were identified by different expression gene screening, enrichment analysis and network construction successively. Among them, the BCL3 was a transcription factor that may induce IDH1expression. Through calculating the correlation coefficient, it was found that in IDH1 glioblastoma, the dendritic cell infiltration was reduced which may result in a better prognosis. In addition, the level of IDH1, FABP5, C1RL, MIR155HG, CSTA and BCL3 might also influence lymphocytes infiltration (eg. CD4+ T cell) and chemokine expression (CXCL family).
IDH1 may participate in pathological mechanisms of glioblastoma via expression alteration or gene mutation. Furthermore, IDH1 mutation might improve prognosis via suppressing the expression of FABP5, C1RL, MIR155HG, CSTA and BCL3. Meanwhile, it was identified that BCL3 might perform similar immunomodulatory functions with IDH1 as an upstream transcript factor.
脑胶质瘤是最恶性的实体肿瘤，预后不良。筛选关键靶点和探索潜在机制将有助于诊断和治疗。IDH1 突变（R132）被用于区分胶质瘤的分级并预测预后，作为一个重要的标志物。然而，IDH1 突变调节胶质瘤发生的方式仍不清楚。
为了研究 IDH1 突变的功能，使用生物信息学技术分析了来自 GEO 和 TCGA 数据库的多类型测序数据（转录组、甲基化和拷贝数变异）。从调控网络、肿瘤免疫微环境和临床相关性等方面综合评价 IDH1 突变（R132）的生物学功能。然后通过实验技术验证分析结果。
与邻近组织相比，IDH1 在脑胶质瘤中上调，且与恶性程度和预后不良呈正相关。为了进一步研究突变 IDH1（R132）功能的机制，通过差异表达基因筛选、富集分析和网络构建，先后鉴定出 5 个相关基因（FABP5、C1RL、MIR155HG、CSTA 和 BCL3）。其中，BCL3 是一种可能诱导 IDH1 表达的转录因子。通过计算相关系数，发现在 IDH1 脑胶质瘤中，树突状细胞浸润减少，可能导致预后较好。此外，IDH1、FABP5、C1RL、MIR155HG、CSTA 和 BCL3 的水平也可能影响淋巴细胞浸润（如 CD4+T 细胞）和趋化因子表达（CXCL 家族）。
IDH1 可能通过表达改变或基因突变参与脑胶质瘤的病理机制。此外，IDH1 突变可能通过抑制 FABP5、C1RL、MIR155HG、CSTA 和 BCL3 的表达来改善预后。同时，鉴定出 BCL3 可能作为一个上游转录因子，发挥与 IDH1 相似的免疫调节功能。
