基于生物信息学分析肝细胞癌嗅质蛋白样蛋白2B表达及临床意义

Expression and clinical significance of OLFML2B in hepatocellular carcinoma based on bioinformatics analysis

目的以生物信息学方法分析嗅质蛋白样蛋白2B(OLFML2B)基因在肝细胞癌中的表达情况及其临床意义。方法通过分析生物医学数据分析盒子(Sangerbox)数据库、癌症基因组图谱(TCGA)数据库获得OLFML2B基因在肝细胞癌组织及正常肝组织中的表达情况和生存情况。分析肿瘤免疫评估资源(TIMER)数据库获得OLFML2B基因与肝细胞癌组织免疫浸润水平的相关性。分析伯明翰阿拉巴马大学癌症数据分析门户网站(UALCAN)数据库、cBio癌症基因组学门户网站(cBioProtal)数据库获得OLFML2B基因启动子区甲基化水平及突变情况。分析TCGA多组学关联分析(LinkedOmics)数据库获得OLFML2B基因导致肝细胞癌发生所涉及的生物学过程和信号通路。结果Sangerbox数据库分析结果显示,OLFML2B基因在多数肿瘤组织的mRNA表达水平高于正常组织,在肝细胞癌中表达量高于正常组织(P<0.001)。TCGA数据库分析结果显示,在配对及非配对的肝细胞癌组织与正常组织中,OLFML2B基因的表达水平显著均高于正常组织(P<0.001)。单因素分析结果表明,OLFML2B基因表达量与年龄、性别、体质量指数(BMI)、病理分期、甲胎蛋白(AFP)、血管浸润等均无相关性(P>0.05)。Kaplan-Meier生存分析结果表明,OLFML2B基因低表达的肝细胞癌患者的总生存率、疾病特异性生存率均高于OLFML2B基因高表达的肝细胞癌患者(P<0.05)。TIMER数据库分析结果显示,肝细胞癌中OLFML2B基因表达与B细胞、CD8^(+)T细胞、CD4^(+)T细胞、巨噬细胞、中性粒细胞、树突状细胞等细胞免疫浸润呈正相关(P<0.05)。UALCAN数据库分析结果显示,OLFML2B基因启动子区甲基化水平高于正常组织(P<0.05)。cBioProtal数据库分析结果显示,OLFML2B基因在肝细胞癌中已被收录4个突变,均为错义突变,突变后蛋白发生改变。LinkedOmics数据库基因富集分析结果发现,OLFML2B基因与免疫系统的正向调节、血管生成、细胞迁移的正向调节、细胞运动的正向调节、胞外分泌调节、免疫应答、细胞凋亡等生物学过程有关。京都基因与基因组百科全书(KEGG)富集分析结果显示,OLFML2B基因与Ras、MAPK、PI3K、pathway in cancer等信号通路有关。结论OLFML2B基因在肝细胞癌组织中高表达。OLFML2B基因低表达的肝细胞癌患者的预后较好。OLFML2B基因与免疫浸润有关。肝细胞癌发生的机制可能与OLFML2B基因启动子区甲基化、错义突变、血管生成、细胞迁移的正向调节、Ras、MAPK、PI3K、pathway in cancer等信号通路有关。

Objective To analyze the expression and clinical significance of olfactomedin like 2B(OLFML2B)gene in hepatocellular carcinoma by bioinformatics method.Methods The expression of OLFML2Bgene in hepatocellular carcinoma tissues and normal liver tissues,and survival were obtained by analyzing the Sangerbox database and the cancer genome atlas(TCGA)database.The tumor immune estimation resource(TIMER)database was analyzed to obtain the correlation between OLFML2Bgene and the level of immune infiltration in hepatocellular carcinoma tissues.university of ALabama at Birmingham cancer data analysis portal(UALCAN)database,cBio cancer genomics portal(cBioProtal)database were analyzed to obtain the methylation level and mutation of OLFML2B gene promoter region.The LinkedOmics database was analyzed to obtain the biological processes,signaling pathways involved in OLFML2Bgene leading to hepatocellular carcinoma development.Results Sangerbox database results showed that the mRNA expression levels of OLFML2B gene were higher in most tumor tissues than in normal tissues and significantly higher in hepatocellular carcinoma(P<0.001).TCGA database analysis showed that the expression levels of OLFML2Bgene were significantly higher in both paired and unpaired hepatocellular carcinoma tissues and normal tissues than in normal tissues.The results of univariate analysis showed that there was no correlation between OLFML2B gene expression and age,gender,body mass index(BMI),pathological stage,alpha-fetoprotein(AFP),and vascular infiltration(P>0.05).Kaplan-Meier survival analysis showed that the overall and disease-specific survival rates of hepatocellular carcinoma patients with low OLFML2Bgene expression were higher than those of hepatocellular carcinoma with high OLFML2Bgene expression.TIMER database analysis showed a significant positive correlation between OLFML2Bgene expression and cellular immune infiltration of B cells,CD8~+T cells,CD4~+T cells,macrophages,neutrophils,and dendritic cells in hepatocellular carcinoma(P<0.05).UALCAN database analysis showed that the methylation level of the promoter region of OLFML2Bgene was significantly higher than that in normal tissues(P<0.05).Analysis of the cBioProtal database showed that the OLFML2Bgene has been included in hepatocellular carcinoma with four mutations,all of which were mis-sense mutations with altered proteins after mutation.Gene enrichment analysis of the LinkedOmics database revealed that the OLFML2Bgene was associated with positive regulation of the immune system,angiogenesis,positive regulation of cell migration,positive regulation of cell movement,extracellular secretion regulation,immune response,and cell apoptosis.The Kyoto Encyclopedia of Genes and Genomes(KEGG)database analysis showed that OLFML2Bgene was associated with Ras,MAPK,PI3K,pathway in cancer and other signaling pathways.Conclusions OLFML2Bgene is highly expressed in hepatocellular carcinoma tissues.Hepatocellular carcinoma patients with lowOLFML2Bgene expression have better prognosis.The OLFML2Bgene is involved in immune infiltration.The pathogenesis of hepatocellular carcinoma may be related to the methylation of the promoter region of the OLFML2B gene,missense mutations,angiogenesis,positive regulation of cell migration,Ras,MAPK,PI3K,pathway in cancer and other signaling pathways.