Nei内切核酸酶Ⅷ样蛋白3在肝细胞癌中过表达提示免疫浸润水平增高和预后不良  

Overexpression of Nei endonuclease VIII-like protein 3 in hepatocellular carcinoma indicates increased levels of immune infiltration and an unfavorable prognosis

作　　者：王根年 张亚萍[2] 王满才[1] 韩伟[1] 张有成[1] Wang Gennian;Zhang Yaping;Wang Mancai;Han Wei;Zhang Youcheng(Department of General Surgery,Lanzhou University Second Hospital,Lanzhou 730030,China;Department of Hepatopathy,Lanzhou University Second Hospital,Lanzhou 730030,China)

机构地区：[1]兰州大学第二医院普外科,兰州730030 [2]兰州大学第二医院肝病科,兰州730030

出　　处：《中华肝脏病杂志》2023年第9期986-995,共10页Chinese Journal of Hepatology

基　　金：国家自然科学基金项目(82060800);甘肃省自然科学基金项目(23JRRA0975);甘肃省青年科技基金计划(20JR10RA759、21JR1RA149)。

摘　　要：目的通过癌症基因组图谱数据库评估Nei内切核酸酶Ⅷ样蛋白3(NEIL3)在肝细胞癌(HCC)中的作用及其分子机制。方法先用HCC样本的RNA测序数据分析基因NEIL3在正常组织和肿瘤中的表达水平。再通过基因本体论、京都基因与基因组百科全书、基因富集分析、免疫细胞浸润分析以对NEIL3进行功能和通路富集分析。根据NEIL3在肝癌组织的中位表达水平,将样本分为高表达组和低表达组,通过logistic回归分析、Kaplan-Meier分析、单因素和多因素Cox回归分析以及列线图预后模型探讨NEIL3在HCC中的临床及预后意义。结果与正常样本相比,NEIL3在包括HCC在内的大部分恶性肿瘤中高表达(P<0.05)。NEIL3高表达与细胞周期、DNA复制和细胞受体途径有关。此外,NEIL3高表达与辅助性T细胞2(Th2)的浸润水平呈显著正相关(R=0.670,P<0.001)。和NEIL3低表达组相比,NEIL3高表达患者肿瘤组织Th2细胞浸润水平更高(P<0.001)。Logistic回归分析显示NEIL3过表达与HCC的高T分期、高病理分期、高组织学分级、甲胎蛋白>400μg/L和血管浸润有关。Kaplan-Meier分析结果显示:NEIL3高表达患者的总体生存期[风险比(HR)=2.53,P<0.001]、疾病特异性生存期(HR=2.52,P<0.001)、无进展间隔期(HR=1.82,P<0.001)显著缩短,提示NEIL3高表达HCC患者预后更差。Cox回归分析结果显示:NEIL3高表达是HCC患者不良预后的一个独立危险因素(P=0.002)。列线图及校准图进一步说明NEIL3高表达是HCC患者预后不良危险因素之一。结论NEIL3表达升高与HCC不良预后和免疫细胞比例增加相关,其有望作为评估HCC预后和免疫浸润水平的潜在生物标志物。Objective To evaluate the role and molecular mechanism of Nei endonuclease VIII-like protein 3(NEIL3)in hepatocellular carcinoma(HCC)through The Cancer Genome Atlas database.Methods RNA sequencing of HCC samples was the first step in determining the level of gene NEIL3 expression in normal tissues and tumors.Then,NEIL3 was used for the Gene Ontology,the Kyoto Encyclopedia of Genes and Genomes,gene enrichment analysis,immune cell infiltration analysis.The samples were divided into high and low expression groups according to the median expression level of NEIL3 in liver cancer tissues.Logistic regression analysis,Kaplan-Meier analysis,univariate and multivariate Cox regression analysis,and a nomogram prognostic model were used to explore the clinical and prognostic significance of NEIL3 in HCC.Results Compared with normal samples,NEIL3 was highly expressed in most malignant tumors,including HCC(P<0.05).High expression of NEIL3 was related to cell cycle,DNA replication,and cell receptor pathways.In addition,the high expression of NEIL3 was significantly positively correlated with T-helper 2 lymphocytes and infiltration levels(R=0.670,P<0.001).Compared with the NEIL3 low expression group,the NEIL3 high expression group had a higher level of Th2 cell infiltration in tumor tissues(P<0.001).Logistic regression analysis showed that NEIL3 overexpression was associated with high T stage,high pathological stage,high tissue grade,AFP>400μg/L and vascular invasion of HCC.The Kaplan-Meier analysis results showed that overall survival[hazard ratio(HR)=2.53,P<0.001],disease-specific survival(HR=2.52,P<0.001),and progression-free interval(HR=1.82,P<0.001)in patients with HCC with high NEIL3 expression were unfavorable.Cox regression analysis results showed that high NEIL3 expression was an independent risk factor for an unfavorable prognosis in HCC patients(P=0.002).The nomogram and calibration chart further demonstrated that high NEIL3 expression was one of the risk factors for an unfavorable prognosis in HCC patients.Conclusio

关 键 词：肝细胞癌 免疫浸润 Nei内切核酸酶Ⅷ样蛋白3 不良预后 生物信息学分析 

分 类 号：R735.7[医药卫生—肿瘤]