基因DCAF8在多发性骨髓瘤中的临床意义  

Expression and clinical significance of DCAF8 gene in multiple myeloma

作　　者：孙浩 王可飞 方腾 郝牧 SUN Hao;WANG Kefei;FANG Teng;HAO Mu(Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Tianjin 300020,China)

机构地区：[1]北京协和医学院暨中国医学科学院血液病医院/中国医学科学院血液学研究所实验血液学国家重点实验室国家血液系统疾病临床医学研究中心,天津300020

出　　处：《中国肿瘤生物治疗杂志》2021年第10期990-997,共8页Chinese Journal of Cancer Biotherapy

基　　金：国家自然科学基金资助项目(82170194,81570181,81920108006);中国医学科学院中央级公益性科研院所科研项目(2018PT31006,2018RC320012)。

摘　　要：目的:寻找多发性骨髓瘤(MM)基因芯片数据集中的潜在致病基因、疾病诊断和预后相关因子并阐明其作用机制。方法:获取基因芯片数据集GSE13591和Zhan Myeloma,使用R语言进行基因差异表达分析。对共同高表达基因进行Meta分析,得到P值中位秩次TOP10基因。CCLE数据库分析TOP10基因在各肿瘤细胞系中的mRNA表达情况,筛选出蛋白酶体通路相关基因8(DCAF8)。cBioPortal数据库中分析DCAF8基因在各肿瘤细胞系的突变率。WB检测DCAF8蛋白在骨髓瘤细胞系中的表达情况。SPSS和Graph Pad软件分析DCAF8表达量和MM患者临床特征之间的相关性,进行受试者工作特征曲线(ROC曲线)绘制和生存分析。R语言Custer Profiler Package和Metascape数据库对DCAF8互作蛋白基因和共表达基因进行GO和KEGG功能富集分析。结果:数据集GSE13591和Zhan Myeloma的上调基因取交集得到477个共同高表达基因。在合并数据集中对上述基因进行Meta分析,得到P值中位秩次TOP10基因,DCAF8在MM细胞系中的平均表达水平最高。DCAF8基因在浆细胞骨髓瘤中的突变率位于各肿瘤细胞系的第一位。DCAF8蛋白在多种MM细胞系中的表达量显著升高(P<0.01)。DCAF8表达量与MM患者的肿瘤负荷显著正相关,1q21扩增阳性组的DCAF8的表达量显著高于1q21阴性组。ROC曲线显示DCAF8的表达水平可以很好地区分MM患者和正常人(P<0.01)。DCAF8高表达组比DCAF8低表达组中位生存时间显著缩短。蛋白互作网络显示DCAF8可与XPO1蛋白直接相互作用。GO和KEGG功能富集分析结果表明,DCAF8与蛋白酶体功能、剪切体活性、组蛋白乙酰化酶活性、RNA转运等功能相关。结论:DCAF8在MM中显著高表达,其表达水平可以很好地区分MM患者和正常人;其高表达与MM患者的生存预后显著负相关,且与1q21扩增和XPO1蛋白相关。Objective:To search for potential pathogenic genes,disease diagnosis and prognosis related factors in multiple myeloma(MM)microarray datasets and clarify their mechanism.Methods:GSE13591 and Zhan Myeloma datasets were obtained,and the gene differential expression was analyzed by R language.Meta-analysis was performed based on merged datasets,and the TOP10 genes in median rank of P-value were screened.The mRNA expression of TOP10 genes in tumor cell lines were analyzed using CCLE database,and proteasome pathway related gene 8(DCAF8)was screened.The mutation frequency of DCAF8 gene in each tumor cell lines was analyzed in cBioPortal database.Furthermore,the expression of DCAF8 protein in MM cell lines were detected by using WB.SPSS and Graph Pad software were employed to analyze the correlation between DCAF8 expression and clinical characteristics of MM patients.In addition,the receiver operating characteristic curve(ROC curve)and survival analysis were conducted according to the expression level of DCAF8.Finally,R clusterProfiler package and Metascape database were used to perform GO and KEGG functional enrichment analyses of DCAF8 interacting protein gene and co-expressed genes.Results:A total of 477 high expression genes were obtained from the intersection of the up-regulated genes of GSE13591 and Zhan Myeloma datasets.Meta-analysis of the above genes in the merged dataset was performed,the TOP10 genes in median P-value rank were HGF,AKAP1,TCTA,NEB,DCAF8,COPS6,MAP3 K5,PON2,BAG1 and CD59.The analysis of CCLE database showed that the average expression level of DCAF8 was the highest in MM cell lines.The mutation frequency of DCAF8 gene in plasma cell myeloma ranked first among all tumor cell lines in cBioPortal database.The result of WB showed that the level of DCAF8 protein was increased significantly in a variety of MM cell lines compared with 293 T control.The results showed that the expression of DCAF8 was positively correlated with the tumor load of MM patients,and the expression of DCAF8 in positive group of

关 键 词：多发性骨髓瘤 蛋白酶体通路相关基因8 泛素-蛋白酶体通路 XPO1蛋白 

分 类 号：R730.54[医药卫生—肿瘤] R733.3[医药卫生—临床医学]