Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Department of Clinical Medicine, The Second Clinical School of Guangzhou Medical University, Guangzhou 510182, China.
Aging (Albany NY). 2023 Jun 24;15(12):5798-5825. doi: 10.18632/aging.204841.
TRIM family molecules have been identified as being involved in the tumor progression of various cancer types. Increasingly, experimental evidence indicates that some of TRIM family molecules are implicated in glioma tumorigenesis. However, the diverse genomic changes, prognostic values and immunological landscapes of TRIM family of molecules have yet to be fully determined in glioma.
In our study, employing the comprehensive bioinformatics tools, we evaluated the unique functions of 8 TRIM members including TRIM5/17/21/22/24/28/34/47 in gliomas.
The expression levels of 7 TRIM members (TRIM5/21/22/24/28/34/47) were higher in glioma as well as its diverse cancer subtypes than in normal tissues, whereas the expression level of TRIM17 was the opposite, lower in the former than in the latter. In addition, survival analysis revealed that the high expression profiles of TRIM5/21/22/24/28/34/47 were associated with poor overall survival (OS), disease-specific survival (DSS) and progress-free interval (PFI) in glioma patients, whereas TRIM17 displayed adverse outcomes. Moreover, the 8 TRIM molecules expression as well as methylation profiles remarkably correlated with different WHO grades. And genetic alterations, including mutations and copy number alterations (CNAs), in the TRIM family were correlated with longer OS, DSS and progress-free survival (PFS) in glioma patients. Furthermore, through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results of these 8 molecules and their related genes, we found that these molecules may change the immune infiltration of the tumor microenvironment and regulate the expression of immune checkpoint molecules (ICMs), affecting the occurrence and development of gliomas. The correlation analyses between the 8 TRIM molecules and TMB (tumor mutational burden)/MSI (microsatellite instability)/ICMs discovered that as the expression level of TRIM5/21/22/24/28/34/47 increased, the TMB score also increased significantly, while TRIM17 showed an opposite outcome. Further, a 6-gene signature (TRIM 5/17/21/28/34/47) for predicting overall survival (OS) in gliomas was built by using the least absolute shrinkage and selection operator (LASSO) regression, and the survival and time-dependent ROC analyses all were found to perform well in testing and validation cohorts. Results of multivariate COX regression analysis showed that TRIM5/28 are both expected to become independent risk predictors to guide clinical treatment.
In general, the results indicate that TRIM5/17/21/22/24/28/34/47 might exert a crucial influence on gliomas tumorigenesis and might be putative prognostic markers and therapeutic targets for glioma patients.
TRIM 家族分子已被确定参与各种癌症类型的肿瘤进展。越来越多的实验证据表明，TRIM 家族的某些分子参与了神经胶质瘤的发生。然而，TRIM 家族分子的不同基因组变化、预后价值和免疫景观尚未在神经胶质瘤中得到充分确定。
在我们的研究中，我们使用全面的生物信息学工具，评估了 8 种 TRIM 成员（TRIM5/17/21/22/24/28/34/47）在神经胶质瘤中的独特功能。
与正常组织相比，7 种 TRIM 成员（TRIM5/21/22/24/28/34/47）在神经胶质瘤及其多种癌症亚型中的表达水平更高，而 TRIM17 的表达水平则相反，前者的表达水平低于后者。此外，生存分析显示，TRIM5/21/22/24/28/34/47 的高表达谱与神经胶质瘤患者的总生存（OS）、疾病特异性生存（DSS）和无进展间隔（PFI）不良相关，而 TRIM17 则显示出不良结果。此外，8 种 TRIM 分子的表达和甲基化谱与不同的世卫组织分级显著相关。TRIM 家族的遗传改变，包括突变和拷贝数改变（CNAs），与神经胶质瘤患者的 OS、DSS 和无进展生存（PFS）延长相关。此外，通过对这 8 种分子及其相关基因的基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析结果，我们发现这些分子可能改变肿瘤微环境的免疫浸润，并调节免疫检查点分子（ICMs）的表达，影响神经胶质瘤的发生和发展。8 种 TRIM 分子与 TMB（肿瘤突变负荷）/MSI（微卫星不稳定性）/ICMs 的相关性分析发现，随着 TRIM5/21/22/24/28/34/47 表达水平的升高，TMB 评分也显著升高，而 TRIM17 则呈现相反的结果。进一步，通过最小绝对收缩和选择算子（LASSO）回归构建了一个用于预测神经胶质瘤总生存（OS）的 6 基因特征（TRIM5/17/21/28/34/47），并在测试和验证队列中进行了生存和时间依赖性 ROC 分析，均表现良好。多变量 COX 回归分析结果表明，TRIM5/28 均有望成为指导临床治疗的独立风险预测因子。
总的来说，这些结果表明 TRIM5/17/21/22/24/28/34/47 可能对神经胶质瘤的发生具有重要影响，并且可能是神经胶质瘤患者的潜在预后标志物和治疗靶点。
