目的 通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分析弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中铁死亡相关基因的表达及其与程序性死亡受体配体-1(programmed death ligand-1,PD-L1)和免疫细胞的关系,为DLBCL的治疗提供新的靶标.方法 通过TCGA数据库查找获得22个铁死亡相关基因.从TCGA数据库获取48例DLBCL(DLBCL组)及54例反应性淋巴结增生患者(对照组)淋巴结标本的铁死亡相关基因以及PD-L1的表达数据.使用Wilcoxon秩和检验进行组间差异性表达分析.基因表达相关性分析采用Spearman相关性分析.采用R软件包pheatmap分析DLBCL中铁死亡相关基因表达与免疫细胞的相关性.采用R软件GSVA包分析铁死亡相关基因表达与磷脂酰肌醇-3-激酶-蛋白激酶 B-哺乳动物雷帕霉素靶蛋白(phosphatidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin,PI3K-Akt-mTOR)信号通路的相关性.结果 DLBCL中周期素依赖性激酶抑制因子1A(cyclin dependent kinase inhibitor 1A,CDKN1A)、70 kDa 热休克蛋白 5(heat shock 70 kDa protein 5,HSPA5)、内质膜蛋 白复合体亚基 2(endoplasmic membrane protein complex subunit 2,EMC2)、溶质载体家族 7 成员 11(solute carrier family 7,member 11,SLC7A11)、金属硫蛋白 1G(metallothionein 1G,MT1G)、热休克蛋白 B1(heat shock protein B1,HSPB1)、谷胱甘肽过氧化酶 4(glutathione peroxidase 4,GPX4)、范可尼贫血互补群 D2(Fanconi anemia complementary group D2,FANCD2)、柠檬酸合成酶(citrate synthase,CS)、CDGSH 铁硫结构域 1(CDGSH iron sulfur domain 1,CISD1)、法尼基二磷酸法尼基转移酶 1(farnesyl diphosphate farnesyltransferase 1,FDFT1)、SLC1A5、转铁蛋白受体(transferrin receptor,TFRC)、核糖体蛋白 L8(ribosomal protein L8,RPL8)、核受体共激活因子 4(nuclear receptor coativator 4,NCOA4)、二肽基肽酶Ⅳ(dipeptidyl peptidase Ⅳ,DPP4)和花生四烯酸15脂氧合酶(arachidonate-15-lipoxygenase,ALOX15)基因表达均上调(均P＜0.05).免疫细胞相关分析显示,铁死亡相关基因可激活体内巨噬细胞M1(P＜0.05).DLBCL中长链脂酰辅酶A合成酶4(acyl-CoA synthetase long chain family member 4,ACSL4)、CDKN1A、DPP4、EMC2、谷氨酰胺酶 2(glutaminase 2,GLS2)、HSPA5、溶血卵磷脂酰基转移酶 3(lysophosphatidylcholine acyltransferase 3,LPCAT3)、MT1G、NCOA4、红细胞衍生核因子 2 样蛋白 2(nuclear factor erythroid 2-like-2,NFE2L2)、精脒/精胺 N1-乙酰基转移酶 1(spermidine/spermine N1-acetyltransferase 1,SAT1)、SLC7A11 和 TFRC 这些铁死亡相关基因的表达均与PD-L1表达呈正相关(均r＞0.4,均P＜0.05).铁死亡相关基因LPCAT3、NCOA4和TFRC的表达均与PI3K-Akt-mTOR通路呈正相关(均r＞0.4,均P＜0.05).结论 多数铁死亡相关基因在DLBCL组织中高表达,且与PD-L1、免疫浸润及PI3K-Akt-mTOR 通路有关.
Expressions of ferroptosis-related genes in diffuse large B-cell lymphoma and their correlation with immune cells and signaling pathways
Objective To analyze the expressions of ferroptosis-related genes in diffuse large B-cell lymphoma(DLBCL)and their rela-tionship with programmed death ligand-1(PD-L1)and immune cells using The Cancer Genome Atlas(TCGA)database,providing a new target for the treatment of DLBCL.Methods A total of 22 ferroptosis-related genes were identified in TCGA database.The expression data of the ferroptosis-related genes and PD-L1 in the lymph node samples of 48 DLBCL patients(DLBCL group)and 54 patients with reactive lymph node hyperplasia(control group)were obtained from TCGA database.The differential expressions of the ferroptosis-related genes in the two groups were analyzed by Wilcoxon test,and the correlation of gene expressions was analyzed by Spearman correlation analysis.The pheatmap R package was used to analyze the correlation between the expressions of the ferroptosis-related genes and immune cells in DLBCL.The GSVA R package was used to analyze the correlation between the expressions of the ferroptosis-related genes and phospha-tidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin(PI3K-Akt-mTOR)signaling pathway.Results In DLBCL,the upregulation of expression was observed in the ferroptosis-related genes including cyclin dependent kinase inhibitor 1A(CDKN1A),heat shock 70 kDa protein 5(HSPA5),endoplasmic membrane protein complex subunit 2(EMC2),solute carrier family 7,member 11(SLC7A11),metallothionein 1G(MT1G),heat shock protein B1(HSPB1),glutathione peroxidase 4(GPX4)、Fanconi anemia complementary group D2(FANCD2)、citrate synthase(CS),CDGSH iron sulfur domain 1(CISD1),farnesyl diphosphate farnesyltransferase 1(FDFT1),SLC1A5,transferrin receptor(TFRC),ribosomal protein L8(RPL8),nuclear receptor coativator 4(NCOA4),dipeptidyl peptidase Ⅳ(DPP4),arachi-donate-15-lipoxygenase(ALOX15)(all P＜0.05).Immune-cell correlation analysis showed that ferroptosis-related genes activated mac-rophage M1 in vivo(P＜0.05).In DLBCL,PD-L1 expression was positively correlated with the expressions of the ferroptosis-related genes including acyl-CoA synthetase long chain family member 4(ACSL4),CDKN1A,DPP4,EMC2,glutaminase 2(GLS2),HSPA5,lysophos-phatidylcholine acyltransferase 3(LPCAT3),MT1G,NCOA4,nuclear factor erythroid 2-like-2(NFE2L2),spermidine/spermine N1-acet-yltransferase 1(SAT1),SLC7A11 and TFRC(all r＞0.4,all P＜0.05).The expressions of the ferroptosis-related genes LPCAT3,NCOA4 and TFRC were all positively correlated with the PI3K-Akt-mTOR pathway(all r＞0.4,all P＜0.05).Conclusions Most ferroptosis-related genes are highly expressed in DLBCL tissues,and are related to PD-L1,immune infiltration and the PI3K-Akt-mTOR pathway.
diffuse large B-cell lymphomaferroptosisprogrammed death receptor-ligand 1immune cellphosphatidylinositol 3 ki-nase-protein kinase B-mammalian target of rapamycin signaling pathway
万方数据
维普
