抑郁介导肿瘤免疫微环境诱导肝癌不良预后研究

Depression Induces Poor Prognosis of Liver Cancer Patients Through Tumor Immune Microenvironment

[目的]寻找抑郁影响肿瘤预后的相关基因,分析这些基因与肿瘤免疫微环境的相互作用,探讨抑郁影响肝癌预后的可能作用机制。[方法]选取倾向评分匹配临床及病理分期相一致的肝癌患者组织17例,其中抑郁组8例、无抑郁组9例,通过转录组基因芯片技术筛选两组间差异基因,采用基因互作网络作图分析肝癌抑郁相关的关键因子和相关信号通路。利用癌症基因图谱(The Cancer Genome Atlas,TCGA)数据库分析抑郁相关关键炎症因子的表达与肝癌肿瘤浸润淋巴细胞(tumor infiltrating lymphocytes,TILs)表型评分及预后的关系。[结果]比较两组组织标本基因表达谱,共有286个基因表达水平发生改变,其中上调基因131个、下调基因155个。将差异表达基因进行互作网络作图,发现主要存在两个主要的网络节点,CXCR4-CXCL12轴和ALDH2-DMGDH-ABAT,炎症因子CXCL13、TIMP2、FOS、CD40、CCL25都与CXCR4-CXCL12轴存在相互作用或调控的关系,抑郁相关的CXCR4-CXCL12轴差异基因表达与肝癌患者TILs表型评分相关。生存分析结果显示,TILs表型评分的低评分组生存时间短于中评分组(P<0.05)。Cox回归分析结果显示,FOS、CXCR4、CXCL13、CD40高表达及CXCL12低表达是影响肝癌患者总生存的危险因素。[结论]抑郁可介导激活肝癌组织中FOS、CXCR4、CXCL13、CD40表达、下调CXCL12表达调控TILs表型,影响肿瘤免疫微环境,抑制肿瘤免疫,从而影响预后。

[Purpose] To investigate the effect of depression on prognosis of liver cancer patients and its related mechanisms. [Methods] Seventeen liver cancer tissue samples matched with clinical and pathological stages by tendentious analysis were collected,including 8 from patients with depression and 9 from non-depression patients. The gene expression profiles were detected by the gene chip and bioinformatics analysis and compared between two groups,and the differentially expressed genes were identified. Gene interaction network was used to analyze the key factors and signaling pathways related to depression and liver cancer. The relationships between the expression of depression related key inflammatory genes and the score of tumor infiltrating lymphocytes(TILs) phenotype,the prognosis of liver cancer patients were analyzed with the Cancer Genome Atlas(TCGA). [Results]A total of 286 differentially expressed genes were identified(P<0.05),among which 131 genes were up-regulated and 155 genes were down-regulated. The network of the differentially expressed genes showed that there were two main network nodes,CXCR4-CXCL12 axis and ALDH2-DMGDH-ABAT. Inflammatory factors CXCL13,TIMP2,FOS,CD40 and CCL25 had an interaction or regulation relationship with the CXCR4-CXCL12 axis. The expression of differentially expressed genes related to CXCR4-CXCL12 axis was correlated with the TILs phenotype score in liver cancer patients. The overall survival time of the low TILs phenotype score group was shorter than that of the middle group(P<0.05).Cox regression analysis identified high expression of FOS,CXCR4,CXCL13,CD40 and low expression of CXCL12 as risk factors for liver cancer patients. [Conclusion] Depression may activate the expression of FOS,CXCR4,CXCL13 and CD40,and inhibit the expression of CXCL12 to regulate tumor immune microenvironment,inducing poor prognosis of liver cancer patients.