MAGEA4在非小细胞肺癌中的表达以及与患者预后的关系

MAGEA4 expression in NSCLC cancer and its correlation with patient’s prognosis

目的探讨MAGEA4基因在非小细胞肺癌(NSCLC)患者中的表达、相关生物学功能及其与患者生存期的关系。方法检索肿瘤基因表达谱数据库(TCGA)中MAGEA4基因在NSCLC患者癌组织和癌旁组织中的表达情况;应用STRING数据构建MAGEA4基因编码蛋白-蛋白相互作用网络,并对网络中的蛋白进行基因本体论(GO)和KEGG信号通路富集;应用linkedomics在线分析软件,分析TCGA数据中与MAGEA4正负相关表达基因。同时回顾性分析我院手术治疗的68例NSCLC患者组织标本,采用免疫组织化学法(IHC)检测患者癌和癌旁组织中MAGEA4蛋白表达水平并分析其与患者临床病理特征的关系,对前述生物信息分析结果进行验证。结果 MAGEA4基因mRNA在NSCLC患者癌组织中的表达水平明显高于癌旁组织(P<0.05);与MAGEA4蛋白相互作用网络中,区域聚类指数为0.90,蛋白相互作用网络富集明显(P<0.05);与MAGEA4正相关表达最为显著的基因为MAGEA410(r=0.80,P<0.05),而负相关表达最为显著的基因为DE4D (r=-0.37,P<0.05);功能富集分析显示,MAGEA4生物学过程、细胞成分及分子功能分别主要富集于磷脂酰肌醇3激酶结合、细胞粘附的蛋白质复合物和核苷酸受体活性;KEGG信号通路富集显示,MAGEA4及相关共表达基因主要富集于Notch信号通路、维生素代谢信号通路和DNA复制相关信号通路等。生存分析显示,MAGEA4基因mRNA高表NSCLC患者总生存低于低表达患者(HR=1.3,95%CI:1.04~3.21,P<0.05);而高低表达组无疾病进展生存无统计学差异(HR=0.82,95%CI:0.36~1.94,P>0.05);IHC分析显示,MAGEA4蛋白表达水平与NSCLC患者肿瘤分化程度(P<0.05)和淋巴结转移(P<0.05)存在相关性,MAGEA4蛋白高表达者肿瘤分化程度较低,淋巴结转移率较高。结论 MAGEA4在NSCLC癌组织中表达明显增强,MAGEA4高表达与患者的预后不良有关。抑制MAGEA4基因表达有望成为NSCLC治疗的新靶点。

Objective To investigate the expression of MAGEA4 non-small cell lung cancer(NSCLC), its biological function and its relationship with survival. Methods MAGEA4 expression of NSCLC in paracancerous and cancer tissues were screened in tumor gene expression profile database(TCGA). The protein-protein interaction network relevant to MAGEA4 was constructed by STRING database. Gene ontology(GO) and KEGG signal pathway was enriched for MAGEA4 and relevant genes. The positive and negative correlated genes were identified through searching the linkedom online analysis software. At the same time, 68 NSCLC tissue samples were analyzed retrospectively. The relationship between the expression of MAGEA4 protein and the clinicopathological characteristics of NSCLC was detected by IHC, and the above-mentioned biological information analysis results were verified. Results The expression level of MAGEA4 gene mRNA in NSCLC was significantly higher than that in adjacent tissues(P<0.05). In the MAGEA4 protein interaction network, the region clustering index was 0.90, and the protein interaction network was significantly enriched(P<0.05). The most significant positive correlation gene with MAGEA4 was magea410 gene(r=0.80, P<0.05), while the most significant negative correlation gene was D E4 d(r=-0.37, P<0.05). Functional enrichment analysis showed that the biological process, cell composition and molecular function of MAGEA4 were mainly enriched in phosphatidylinositol 3-kinase binding, cell adhesion protein complex and nucleotide receptor activity. KEGG signal pathway enrichment showed that MAGEA4 and related co-expression genes weremainly enriched in Notch signal pathway,vitamin metabolism signal pathway and DNA replication Relevant signal path,etc. Survival analysis showed that the total survival of NSCLC patients with high expression of MAGEA4 gene mR NA was lower than that of patients with low expression( HR = 1. 3,95% CI: 1. 04 ~ 3. 21,P < 0. 05),but there was no significant difference in disease-free survival between the high and low expression groups( HR = 0. 82,95%CI: 0. 36 ~ 1. 94,P > 0. 05). IHC analysis showed that the expression level of MAGEA4 protein was correlated with tumor differentiation( P < 0. 05) and lymph node metastasis( P < 0. 05). The degree of tumor differentiation was low and the rate of lymph node metastasis was high. Conclusion The expression of MAGEA4 in NSCLC is significantly increased,and the high expression of MAGEA4 is related to the poor prognosis of NSCLC. The inhibition of MAGEA4 gene expression is expected to be a new target of NSCLC therapy.