线粒体相关凋亡因子2在肝细胞癌中的表达及其基因调控网络

Expression and gene regulatory network of apoptosis inducing factor, mitochondrion-associated 2 in hepatocellular carcinoma

背景与目的:铁死亡可作为抗肿瘤作用的新靶点,线粒体相关凋亡因子2(AIFM2)是铁死亡的一个关键调控因子。本研究分析AIFM2在肝细胞癌(HCC)中的表达水平及其与患者临床病理因素、预后的关系,并探讨AIFM2在HCC中的调控网络。方法:利用Oncomine数据库分析AIFM2在HCC和正常肝组织中的表达差异,利用UALCAN数据库分析AIFM2表达与患者临床病理特征的相关性;用Linked Omics数据平台的Link Finder模块进行GO分析和KEGG分析;用Linked Omics数据库分析与AIFM2表达相关的蛋白激酶、miRNA和转录因子;用GeneMANIA数据库分析与AIFM2相关的蛋白质相互作用网络;用c Bio Portal分析HCC中AIFM2突变的频率和类型。结果:HCC组织中AIFM2 mRNA表达和DNA拷贝数均高于正常组织(均P<0.05)。AIMF2与晚期肿瘤、淋巴结转移、较高的病理分级和TP53突变明显有关(均P<0.05)。高表达AIFM2的患者明显比低表达AIFM2患者的预后差(P=0.034)。GO和KEGG分析显示,AIFM2相关基因主要富集与线粒体和核糖体功能有关的途径,与细胞氧化磷酸化和转录后翻译密切相关。GSEA分析表明,多种蛋白激酶(MAPK1/3/7)、miRNA(mi R-30家族)和转录因子(NFAT)与AIFM2的表达密切相关。c Bio Portal分析显示,AIFM2在HCC中的主要变异形式是高mRNA表达,但突变频率低。结论:AIFM2在HCC中高表达,与患者不良预后相关,是HCC诊断和预后的潜在标志物。所揭示的AIFM2在HCC中的调控网络为AIFM2在HCC中的后续研究奠定基础。

Background and Aims: Ferroptosis may serve as a new target for antitumor therapy, and apoptosis inducing factor, mitochondrion-associated 2(AIFM2) is a key regulator of ferroptosis. This study was conducted to analyze the expression level of AIFM2 in hepatocellular carcinoma(HCC), and its relationship with clinicopathologic factors and prognosis of patients, and to investigate the regulatory network of AIFM2 in HCC.Methods: The differential expression of AIFM2 in HCC and normal liver tissue was analyzed using Oncomine database and the correlation between the expression of AIFM2 and the clinicopathologic characteristics of patients was determined using UALCAN database. The Link Finder module of the Linked Omics data platform was used for GO analysis and KEGG analysis, and the Linked Omics database was used to analyze the protein kinases, miRNAs, and transcription factors associated with AIFM2 expression. Analysis of the protein interaction networks associated with AIFM2 was performed by the Gene MANIA database, and the frequency and type of AIFM2 mutations in HCC was defined by c Bio Portal.Results: The AIFM2 mRNA expression and DNA copy number in HCC tissues were higher than that in normal tissues(both P<0.05). AIMF2 was significantly associated with advanced tumors, lymph node metastasis, higher pathological grades, and TP53 mutations(all P<0.05). Patients with high expression of AIFM2 had significantly worse prognosis than those with low expression of AIFM2(P=0.034). GO and KEGG analysis showed that AIFM2-related genes were mainly enriched in pathways related to mitochondrial and ribosomal functions, and were closely related to cellular oxidative phosphorylation and post-transcriptional translation. GSEA analysis showed that various protein kinases(MAPK1/3/7),miRNAs(mi R-30 family) and transcription factors(NFAT) were significantly associated with the expression of AIFM2. C-bioportal analysis showed that the main variant form of AIFM2 in HCC was high mRNA expression but low mutation frequency.Conclusions: AIFM2 is highly expressed in HCC and is associated with poor prognosis of patients.AIFM2 is a potential marker for diagnosis and prognosis of HCC. The revealed regulatory network of AIFM2 in HCC lays a foundation for the follow-up study of AIFM2 in HCC.