富含亮氨酸重复序列和免疫球蛋白样结构域1(LRIG1)基因在非小细胞肺癌中的表达、信号通路及其与预后的关系

LRIG1 Gene Expression and Signaling Pathway and Prognosis in Non-Small Cell Lung Cancer

目的:探讨富含亮氨酸重复序列和免疫球蛋白样结构域1(LRIG1)基因在非小细胞肺癌(NSCLC)患者中的表达、相关信号通路及其与患者预后的关系。方法:依靠癌症基因组图谱(TCGA)数据库分析LRIG1基因mRNA在NSCLC患者癌组织和癌旁组织中的表达水平;依靠蛋白相互作用(STRING)数据库构建LRIG1蛋白-蛋白相互作用网络,并对相关蛋白功能和京都基因与基因组百科全书(KEGG)信号通路进行富集。同时分析比较LRIG1基因表达与NSCLC患者总生存期和无疾病进展生存期的关系。选取手术治疗的96例NSCLC患者,采用免疫组织化学法检测LRIG1蛋白在癌组织和癌旁组织中的表达,对数据库分析结果进行验证。结果:LRIG1基因在癌旁正常组织中表达水平较高,而在癌组织中表达较低;与LRIG1蛋白相互作用较为紧密的10蛋白相互作用网络富集显著(P<0.001);共表达分析显示,L-型电压依赖性钙离子通道α1D亚基(CACNA1D)基因与LRIG1基因正向共表达最为明显(r=0.51,P<0.05),而G蛋白信号转导调节因子20(RGS20)基因与LRIG1基因负向共表达最为明显(r=–0.49,P<0.05);LRIG1基因生物学过程、细胞成分和分子功能主要分别富集于表皮生长因子受体信号通路的负调控、胞质囊泡部和磷脂酰肌醇-4,5-二磷酸3-激酶活性等;LRIG1基因主要富集于癌症中的蛋白多糖、内吞作用、丝裂原活化蛋白激酶(MAPK)信号通路、磷脂酰肌醇-3激酶/蛋白激酶B(PI3K-AKT)信号通路、Ras相关蛋白1(RAP1)信号通路、癌症的途径和ras等肿瘤相关信号通路;LRIG1基因mRNA高表组患者的总生存期高于低表达组[(风险比(HR)=0.74,P<0.05)],而两组的无疾病进展生存期差异无统计学意义(HR=1.0,P=0.97);LRIG1蛋白在NSCLC癌旁组织的阳性表达率显著高于癌组织(P<0.05)。LRIG1蛋白高表达与NSCLC患者临床分期、肿瘤大小及纵膈淋巴结转移有关(P<0.05)。结论:LRIG1基因在NSCLC癌组织中低表达,并与患者肿瘤大小、淋巴结转移及总生存期有关。

Objective To investigate the expression of LRIG1 gene in patients with non-small cell lung cancer(NSCLC),its signal pathway and its relationship with prognosis.Methods The expression level of LRIG1 gene mRNA in NSCLC patients was analyzed in TCGA database.The LRIG1 protein-protein interaction network was constructed in string database and the related protein function and KEGG signal pathway were enriched.The relationship between LRIG1 gene expression and total survival(OS)and disease free survival(DFS)of NSCLC patients was analyzed.We selected 96 patients with NSCLC who were operated in our hospitaland detected the LRIG1 protein in cancer tissue and adjacent tissue by immunohistochemistry,then verified the results of database analysis.Results In NSCLC,the expression level of LRIG1 gene was higher in normal tissues but lower in cancer tissues.The 10 protein interaction network with LRIG1 protein was enriched significantly(P<0.001).The co-expression analysis showed that the positive co-expression of CACNAID gene and LRIG1 gene was the most significant(r=0.51,P<0.05),while the negative co-expression of RGS20 gene and LRIG1 gene was the most significant(r=–0.49).The biological process,cell composition and molecular function of LRIG1 gene are mainly enriched in negative regulation of epidermal growth factor receptor signal pathway,cytoplasmic vesicle and phosphatidylinositol-4,5-diphosphate 3-kinase activity,etc.The LRIG1 gene is mainly enriched in proteoglycan,endocytosis,MAPK signal pathway,PI3K Akt signal pathway and Rap1 in cancer.The OS rate of patients with high expression of LRIG1 gene mRNA(HR=0.74,P<0.05)was higher than that of patients with low expression of LRIG1 gene mRNA,but there was no statistical difference in patients with high or low expression of DFS(HR=1.0,P=0.97).The positive expression rate of LRIG1 protein in NSCLC adjacent tissues was significantly higher than that in cancer tissues(P<0.05).The high expression of LRIG1 was related to clinical stage,tumor size and mediastinal lymph node metastasis(P<0.05).Conclusion The expression of LRIG1 gene is low in NSCLC,which is related to tumor size,lymph node metastasis and overall survival.