CENP-A在肝细胞癌中的预后意义和作用机制

Comprehensive analysis of the prognostic significance and mechanism of CENP-A in hepatocellular carcinoma

目的:研究着丝粒蛋白A(CENP-A)在肝癌(HCC)患者中的预后意义和作用机制.方法:从癌症基因组图谱(TCGA)和Oncomine深入挖掘并整合了HCC相关的RNA测序数据集和已发表的研究,评估CENP-A的表达与其在HCC患者中的临床学意义和预后价值之间的关联.使用R语言对TCGA的HCC患者进行总体生存期(OS)和无复发生存期(RFS)的单因素和多因素Cox回归分析,并对CENP-A进行GO功能、KEGG通路的富集分析及蛋白互作网络分析.最后通过c Bio Portal分析CENP-A遗传改变相关的潜在机制及对预后的影响.结果:与正常肝组织相比,肝细胞癌(LIHC)中的CENP-A表达显著上调.在LIHC患者中,高CENP-A表达患者的OS(P=2. 66E-07)和RFS(P=5. 5E-05)显著劣于低表达者.单变量和多变量分析显示高CENP-A表达是LIHC患者OS(HR:2. 266,95%CI:1. 542-3. 330,P=3. 14E-05)和RFS(HR:1. 605,95%CI:1. 118-2. 305,P=0. 010)差的独立预后因素.CENP-A的功能分析提示:通过与BUB1,AURKA,AURKB,KIF2C,CDK1,TOP2A,HJURP等多种基因联合作用,CENP-A在DNA复制、错配修复、同源重组、基础切除修复和细胞周期等通路上影响动粒对染色体的移动及调节,进而干扰有丝分裂的细胞周期.在9%的LIHC病例中观察到CENP-A改变,扩增和mRNA上调是主要的改变类型,CENP-A改变的LIHC患者的OS(P <0. 0001)明显更差.结论:这些发现证实CENP-A可能是HCC中独立的预后生物标志物,并可能促进靶向精确肿瘤学的发展.

Objective: To study the prognostic significance and mechanism of CENP-A in patients with hepatocellular carcinoma( HCC). Methods: HCC-related RNA-sequencing datasets and published studies were deeply mined from The Cancer Genome Atlas( TCGA) and Oncomine and integrated. The relation between CENP-A expression and its clinical significance and prognostic value in HCC patients was assessed. Univariate and multivariate Cox regression analysis of overall survival( overall survival,OS) and recurrence-free survival( recurrence-free survival,RFS) in patients with HCC was processed by R language. The enrichment analysis of GO function,KEGG pathway and the network analysis of protein interaction were performed for CENP-A. Finally,the potential mechanism related to genetic change of CENP-A and its impact on prognosis were analyzed by cBioPortal. Results: CENP-A expression was significantly up-regulated in liver hepatocellular carcinoma( LIHC) compared to normal liver tissue. In LIHC patients,high CENP-A expression was associated with more unfavorable OS( P =2. 66 E-07) and RFS( P = 5. 5 E-05) than low expression. Univariate and multivariate analysis showed that the high CENP-A expression was an independent prognostic factor for poor OS( HR: 2. 266,95% CI: 1. 542-3. 330,P = 3. 14 E-05) and RFS( HR: 1. 605,95% CI: 1. 118-2. 305,P =0. 010) in LIHC patients. In addition,in combination with a variety of genes including BUB1,AURKA,AURKB,KIF2 C,CDK1,TOP2 A,HJURP and so on,CENP-A affects the effect of kinetochore on chromosome movement and regulation from pathways like DNA replication,mismatch repair,homologous recombination,basal excision repair and cell Cycle,thus interfering with mitotic cell cycle. CENP-A alteration were observed in 9% of LIHC cases,and amplification and mRNA up-regulation were major types of change. LIHC patients with CENP-A alteration had significantly worse OS( P < 0. 000 1).Conclusion: These findings confirm that CENP-A may be an independent prognostic biomarker in HCC and may promote the development of targeted precise oncology.