南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (10): 1509-1518.doi: 10.12122/j.issn.1673-4254.2021.10.09

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CDK1、CCNB1和NDC80与乙型肝炎相关肝细胞癌的预后和进展相关：基于生物信息学方法

李玉杰，吴登强，韦常宏，杨雪佳，周素芳   

  1. 广西医科大学基础医学院生物化学与分子生物学教研室，长寿与老年相关疾病教育部重点实验室，广西高校生物分子医学研究重点实验室，区域性高发肿瘤早期防治研究教育部重点实验室，广西 南宁 530021
  • 出版日期:2021-10-20 发布日期:2021-11-11

CDK1, CCNB1 and NDC80 are associated with prognosis and progression of hepatitis B virus-associated hepatocellular carcinoma: a bioinformatic analysis

LI Yujie, WU Dengqiang, WEI Changhong, YANG Xuejia, ZHOU Sufang   

  1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangxi Medical University, The Key Laboratory of Longevity and Geriatric-related Diseases of the Ministry of Education, The Key Laboratory of Biomolecular Medicine Research in Guangxi Universities, The Key Laboratory of the Ministry of Education for Early Prevention and Treatment of Regional High-incidence Tumors, Nanning 530021, China
  • Online:2021-10-20 Published:2021-11-11

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摘要： 目的 探讨 HBV 转化为 HCC 相关的关键基因，并探索相关的分子机制。方法 分析基因表达综合（GEO）数据库中GSE55092、GSE84044和GSE121248的mRNA微阵列数据，其中包括119个HBV相关的HCC组织和252个HBV相关的非肿瘤组织。“sva”R包用于去除批间差。进行整合分析，获取HBV相关肝癌和HBV组织中的差异表达基因（DEGs），通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析对差异表达基因进行功能注释。使用相互作用基因搜索工具（STRING）构建蛋白质-蛋白质相互作用网络，挖掘最重要的模块和关键基因。cBioportal用于分析hub基因的相关性。利用Kaplan-Meier和Oncomine数据库对TCGA数据库中肝癌基因表达数据进行验证，探讨hub基因与肝癌发生、发展和预后的关系。通过逆转录定量PCR（RT-qPCR）实验验证17对临床肝细胞癌样本与邻近非肿瘤组织中hub基因的表达。结果 共获得121个DEGs（P< 0.01），鉴定出3个遗传标记，细胞周期素依赖性激酶1（CDK1）、细胞周期蛋白B1（CCNB1）和核分裂周期蛋白80（NDC80），与细胞周期、嘧啶代谢和DNA复制有关，这3个基因高度相关（P<0.05）。UALCAN数据库证实这些基因在肝癌组织中高表达并获得相关预后信息。Kaplan-Meier表明，它们与HCC患者的低存活率相关。CDK1、CCNB1和NDC80与肝癌分级相关（P< 0.05），RT-qPCR实验证实CDK1、CCNB1和NDC80的mRNA在肝细胞癌中的表达明显高于癌旁组织。结论 CDK1、CCNB1 和NDC80基因可作为HBV相关肝细胞癌的预后标志物，在肝癌的基础研究和临床治疗方面有一定的应用价值。

关键词: 肝细胞癌；慢性乙型肝炎病毒；关键基因；CDK1；CCNB1；NDC80

Abstract: Objective To identify the key genes involved in the transformation of hepatitis B virus (HBV) into hepatocellular carcinoma (HCC) and explore the underlying molecular mechanisms. Methods We analyzed the mRNA microarray data of 119 HBV-related HCC tissues and 252 HBV-related non-tumor tissues in GSE55092, GSE84044 and GSE121248 from the GEO database, and the "sva" R package was used to remove the batch effects. Integration analysis was performed to identify the differentially expressed genes (DEGs) in HBV-related liver cancer and liver tissues with HBV infection. The significant DEGs were functionally annotated using GO and KEGG analyses, and the most important modules and hub genes were explored with STRING analysis. Kaplan-Meier and Oncomine databases were used to verify the HCC gene expression data in the TCGA database to explore the correlations of the hub genes with the occurrence, progression and prognosis of HCC. We also examined the expressions of the hub genes in 17 pairs of surgical specimens of HCC and adjacent tissues using RT-qPCR. Results We identified a total of 121 DEGs and 3 genetic markers in HCC (P<0.01). These DEGs included cyclin1 (CDK1), cyclin B1 (CCNB1), and nuclear division cycle 80 (NDC80), which participated in cell cycle, pyrimidine metabolism and DNA replication and were highly correlated (P<0.05). Analysis of the UALCAN database confirmed high expressions of these 3 genes in HCC tissues, which were correlated with a low survival rate of the patients, as shown by Kaplan-Meier analysis of the prognostic data from the UALCAN database. CDK1, CCNB1 and NDC80 were all correlated with the clinical grading of HCC (P<0.05). The results of RT-qPCR on the surgical specimens verified significantly higher expressions of CDK1, CCNB1 and NDC80 mRNA in HCC tissues than in the adjacent tissues. Conclusion CDK1, CCNB1 and NDC80 genes can be used as prognostic markers of HBV-related HCC and may serve as potential targets in preclinical studies and clinical treatment of HCC.

Key words: hepatocellular carcinoma; hepatitis B virus; hub genes; cyclin1; cyclin B1; nuclear division cycle 80