TRIM21与胰腺癌临床病理特征及免疫浸润的相关性分析

Correlation analysis of TRIM21 expression with clinicopathological features and immune infiltration of pancreatic cancer

摘要:

目的：探讨三结构域蛋白家族成员21（tripartite motif 21，TRIM21）在胰腺癌中的表达及其与临床病理特征、预后及免疫浸润的关系。方法：应用Oncomine与GEPIA数据库分析TRIM21在胰腺癌中的mRNA表达水平；利用基因富集分析（gene set enrichment analysis，GSEA）预测TRIM21可能参与的信号通路；TIMER数据库分析TRIM21在胰腺癌中的表达水平与免疫细胞浸润丰度的相关性，并通过Kaplan-Meier Plotter数据库进行验证；免疫组织化学染色（immunohistochemistry，IHC）检测TRIM21在87例胰腺癌组织及36例癌旁组织中的蛋白水平，并分析其与临床病理特征、预后的关系。结果：TRIM21在胰腺癌组织中明显高表达，且与患者无复发生存时间负相关（P=0.041）；GSEA分析证实TRIM21参与胰腺癌患者免疫相关信号通路；TIMER数据库分析显示胰腺癌中TRIM21表达水平与B细胞（P=7.87e-06）、CD8+T细胞（P=1.18e-04）、巨噬细胞（P=1.43e-02）、中性粒细胞（P=2.01e-07）和树突状细胞（P=9.52e-09）的浸润程度明显正相关；Kaplan-Meier Plotter数据库分析显示，在免疫细胞高度富集的胰腺癌患者中，TRIM21高表达者较低表达者具有更低的总体生存率；IHC分析显示胰腺癌组织中TRIM21明显高表达，且TRIM21高表达者较低表达者预后更差（HR=1.725，P=0.033）；胰腺癌患者中TRIM21高表达与低表达者相比，其血清CEA水平（P=0.000）、CA-199水平（P=0.002）、AJCC病理分期（P=0.004）、N分期（P=0.010）、M分期（P=0.006）和组织分化程度（P=0.000）均具有统计学差异；多因素回归分析表明CA-199水平（P=0.008）、N分期（P=0.028）和肿瘤大小（P=0.049）均是影响胰腺癌患者术后总体生存时间的独立因素。结论：TRIM21在胰腺癌中高表达标志着更差的临床预后，并可能通过调控免疫浸润影响肿瘤微环境，促进胰腺癌的发生发展。

Abstract:

Objective：To investigate the expression of tripartite motif 21（TRIM21） in pancreatic cancer and its relations with clinico－pathological features，prognosis and immune infiltration. Methods：Oncomine and GEPIA databases were applied to analyze the mRNA expression level of TRIM21 in pancreatic cancer. Gene set enrichment analysis（GSEA） was used to predict the possible signaling pathways that TRIM21 may be involved in. TIMER database was used to analyze the correlation between TRIM21 expression level in pancreatic cancer and the infiltration abundance of immune cells，and the results were validated by Kaplan-Meier Plotter database. Immunohistochemistry（IHC） test was used to detect the protein level of TRIM21 in 87 cases of pancreatic cancer tissues and 36 cases of para-carcinoma tissues，and to analyze its relations with clinicopathological features and prognosis. Results：TRIM21 was signifi－cantly overexpressed in pancreatic cancer and negatively correlated with relapse-free survival（P=0.041）. GSEA analysis confirmed that TRIM21 was involved in immune-related signaling pathways in patients with pancreatic cancer. TIMER database analysis showed that the expression level of TRIM21 in pancreatic cancer was positively associated with B cells（P=7.87e-06），CD8+ T cells（P=1.18e-04），macrophages（P=1.43e-02），neutrophils（P=2.01e-07） and dendritic cells（P=9.52e-09） infiltration levels. Kaplan-Meier Plotter database analysis showed that pancreatic cancer patients with high concentration of immune cells with high expression of TRIM21 had lower overall survival than those with low expression of TRIM21. IHC analysis indicated that TRIM21 was significantly overexpressed in pancreatic cancer tissues，and the prognosis was lower in patients with high expression of TRIM21 than those with low expression of TRIM21（HR=1.725，P=0.033）. Compared with low expression of TRIM21，there were significant differences in the serum CEA level（P=0.000），CA-199 level（P=0.002） and AJCC pathological stage（P=0.004），N stage（P=0.010），M stage（P=0.006），and tissue differentiation（P=0.000） in the pancreatic cancer patients with high expression of TRIM21. The multivariate regression analysis showed that CA-199 level（P=0.008），N stage（P=0.028） and tumor size（P=0.049） were independent factors affecting the overall survival in patients with pancreatic cancer after surgery. Conclusion：TRIM21 is highly expressed in pancreatic cancer and marks a poorer clinical prognosis and promotes the development of pancreatic cancer by modulating immune infiltration affecting the tumor microenvironment.