Increased TRIM5 is associated with a poor prognosis and immune infiltration in glioma patients
doi: 10.7507/1001-5515.202004064
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摘要: 三结构域蛋白家族 5（TRIM5）在自噬中起重要作用，并参与免疫和肿瘤进程，然而 TRIM5 在神经胶质瘤中的功能尚不清楚。本研究旨在通过生物信息学分析来评估 TRIM5 在胶质瘤中的作用。本研究神经胶质瘤数据库临床样本包括低级别神经胶质瘤（LGG）与多形性成胶质细胞瘤（GBM）。通过 Oncomine、基因表达谱交互分析（GEPIA）和癌症基因组图谱（TCGA）数据库探寻了 TRIM5 在胶质瘤组织中的表达。基于 TCGA 数据库，我们利用生存分析和多因素 Cox 回归分析评价 TRIM5 的预后作用。利用 STRING 数据库预测 TRIM5 相关蛋白网络，并通过 KEGG 富集分析预测 TRIM5 在胶质瘤中的潜在分子通路。此外，采用 CIBERSORT 和 TIMER 数据库进行免疫浸润分析。结果表明，与 Oncomine、GEPIA 和 TCGA 数据库中的正常样本相比，神经胶质瘤样本中的 TRIM5 表达明显上调。生存分析结果显示，较高的 TRIM5 表达与 LGG+GBM 患者以及 LGG 患者较差的总体生存（OS）有关，但与 GBM 患者 OS 无关。临床相关性分析结果显示，TRIM5 表达与年龄（χ2=44.31，P<0.001）、病理学分级（χ2=130.10，P<0.001）以及组织学类型（χ2=125.50，P<0.001）具有相关性。多因素 Cox 风险分析结果显示 TRIM5 表达（HR=1.48，95% CI=1.20～1.80，P<0.001）、年龄（HR=1.05，95% CI=1.03～1.10，P<0.001）以及病理学分级（HR=3.11，95% CI=2.30～4.20，P<0.001）是胶质瘤患者（LGG+GBM）预后的独立危险因素；TRIM5 表达（HR=1.82，95% CI=1.42～2.32，P<0.001）、年龄（HR=1.06，95% CI=1.05～1.08，P<0.001）、病理学分级（HR=1.92，95% CI=1.22～3.01，P=0.005）以及组织学类型（HR=0.71，95% CI=0.57～0.89，P=0.003）是 LGG 患者的独立预后因素。相互作用网络分析发现，IRF3、IRF7、OAS1、OAS2、OAS3、OASL、GBP1、PML、BTBD1 以及 BTBD2 蛋白与 TRIM5 具有相互作用。此外，KEGG 分析还发现细胞凋亡、肿瘤以及免疫相关通路在 TRIM5 升高时显著富集。免疫浸润分析显示，TRIM5 表达可以影响胶质瘤中活化 NK 细胞、单核细胞、活化肥大细胞、巨噬细胞等免疫细胞浸润水平。以上结果提示，TRIM5 在胶质瘤组织中显著上调，并与预后不良和免疫浸润相关。TRIM5 可能作为神经胶质瘤预后与指导免疫治疗的生物标志物。Abstract: Tripartite motif 5 (TRIM5) plays a significant function in autophagy and involves in immune and tumor processes. While the function of TRIM5 remains poorly understood in glioma. We purpose to evaluate the possible prognostic role of TRIM5 in glioma via bioinformatics analyses. The database clinical samples of glioma in this study included low grade glioma (LGG) and glioblastoma multiforme (GBM). TRIM5 expression in glioma tissues were explored in Oncomine, GEPIA and The Cancer Genome Atlas (TCGA) databases. Survival analysis and the multivariate Cox regression analysis of TRIM5 based on TCGA were used to evaluate the prognostic role of TRIM5. The protein networks of TRIM5 was detected by STRING database. KEGG enrichment analyses were performed to predict the potential molecular pathways of TRIM5 in glioma. In addition, immune infiltration analysis was conducted by CIBERSORT and TIMER databases. We found that TRIM5 was strongly increased in glioma samples compared with normal samples in Oncomine, GEPIA and TCGA databases. Higher TRIM5 was significantly contributed to worse overall survival (OS) in LGG+GBM patients and LGG patients, while was no correlated with OS of GBM patients. Interaction networks analysis identified that IRF3, IRF7, OAS1, OAS2, OAS3, OASL, GBP1, PML, BTBD1 and BTBD2 proteins were contacted with TRIM5. Moreover, KEGG revealed that apoptosis and cancer- and immune-related pathways were enriched with elevated TRIM5. Specifically, TRIM5 could influence the immune infiltration levels, such as activated NK cells, monocytes, activated mast cells and macrophages in glioma. In conclusion, our data indicated that TRIM5 was upregulated in glioma tissues and associated with poor prognosis and immune infiltration. TRIM5 may be acted as a biomarker in prognosis and immunotherapy guidance of glioma.
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Key words:
- TRIM5 /
- glioma /
- biomarker /
- prognosis /
- immune infiltration
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Figure 1. Elevated TRIM5 expression in glioma
a. TRIM5 expression between cancer and normal tissues of Brain and CNS cancer in Oncomine; b. meta-analysis of TRIM5 expression in 4 analyses; c-f. TRIM5 expression in Murat Brain, Sun Brain and TCGA Brain
Figure 2. TRIM5 expression based on GEPIA database
a. TRIM5 was notably increased in variety tumors; b. TRIM5 expression in LGG and GBM compared with normal control. *, P < 0.05
Figure 3. TRIM5 upregulation was associated with poor prognosis in glioma on TCGA database
a–d. OS of LGG+GBM patients; e–h. OS of LGG patients; i–l. OS of GBM patients
Figure 4. The potential interaction networks prediction of TRIM5
a. transcriptome prediction of TRIM5 in glioma in Oncomine database; b. TRIM5 protein interaction networks in STRING
Figure 6. The proportion of 22 immune cells effected by TRIM5 expression
a. the ratio of 22 immune cells in glioma in low (blue) and high (red) TRIM5 expression groups, * P < 0.05; b. heat map of 22 immune cells in glioma samples
Table 1. Correlations between TRIM5 expression and clinicopathological characteristics in glioma patients (LGG+GBM)
Parameters Cases (n=668) TRIM5 expression χ2 P value Low (n=334) High (n=334) Age/year 44.310 <0.001 ≤51 406 245 (73.35%) 161 (48.20%) >51 262 89 (26.65%) 173 (51.80%) Gender 2.930 1.711 Female 283 152 (45.51%) 131 (39.22%) Male 385 181 (54.19%) 204 (61.08%) Grade 130.100 <0.001 G2 247 170 (50.90%) 77 (23.05%) G3 262 145 (43.41%) 117 (35.03%) G4 159 19 (5.69%) 140 (41.92%) Histological 125.500 <0.001 Astrocytoma 192 107 (32.03%) 85 (25.45%) Oligoastrocytoma 317 208 (62.28%) 109 (32.63%) GBM 159 19 (5.69%) 140 (41.92%) Positive results were highlighted in bold 
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Table 2. Univariate and multivariate Cox analyses of OS in LGG+GBM patients
Characteristics Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value Age 1.073 1.061−1.084 <0.000 1.047 1.035−1.060 <0.000 Gender 1.124 0.858−1.471 0.396 Grade 4.702 3.784−5.843 <0.000 3.110 2.300−4.206 <0.000 Histological type 1.971 1.698−2.288 <0.000 0.886 0.754−1.041 0.140 TRIM5 expression 2.808 2.342−3.366 <0.000 1.481 1.201−1.824 0.000 Positive results were highlighted in bold
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Table 3. Univariate and multivariate Cox analyses of OS in LGG patients
Characteristics Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value Age 1.065 1.048−1.081 <0.000 1.064 1.047−1.082 <0.000 Gender 1.060 0.726−1.548 0.762 Grade 3.120 2.061−4.723 <0.000 1.915 1.219−3.009 0.005 Histological type 0.749 0.601−0.934 0.010 0.709 0.566−0.890 0.003 TRIM5 expression 2.400 1.839−3.132 <0.000 1.816 1.419−2.322 <0.000 Positive results were highlighted in bold
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Table 4. Results of part KEGG enrichment analyses
Gene set name NES NOM p-val FDR q-val KEGG_PATHWAYS_IN_CANCER 1.705 0.002 0.045 KEGG_SMALL_CELL_LUNG_CANCER 1.864 0.002 0.026 KEGG_APOPTOSIS 2.021 0.002 0.033 KEGG_LYSOSOME 1.958 0.004 0.025 KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION 1.965 0.002 0.047 KEGG_COMPLEMENT_AND_COAGULATION_CASCADES 1.926 0.000 0.022 KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY 1.745 0.032 0.038 KEGG_PRIMARY_IMMUNODEFICIENCY 1.882 0.006 0.028 Abbreviations: NES, normalized enrichment score
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