Six Cell Cycle-related Genes Serve as Potential Prognostic Biomarkers and Correlated with Immune Infiltrates in Hepatocellular Carcinoma.
Six Cell Cycle-related Genes Serve as Potential Prognostic Biomarkers and Correlated with Immune Infiltrates in Hepatocellular Carcinoma.
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六种细胞周期相关基因可作为潜在的预后生物标志物，并与肝细胞癌的免疫浸润相关
DOI：
10.7150/jca.76809
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发表时间：
2023
影响因子：
3.9
通讯作者：
Xu A
中科院分区：
文献类型：
--
作者：
Shi Y;Sang X;Deng J;Wang Y;Chen X;Lin S;Wu F;Xu A
背景资料：细胞周期相关基因（CDK 1、CDK 5、CDC 20、CCNA 2、CCNB 1和CCNB 2）在真核生物有丝分裂细胞周期调控中起重要作用。然而，细胞周期相关基因与肝细胞癌（HCC）浸润和预后的关系还有待进一步研究。方法：利用肿瘤免疫评估资源（TIMER）和Oncomine两个公共网站，评估细胞周期相关基因的表达水平。我们还使用HPA数据库分析了六个细胞周期相关基因的蛋白表达水平。此外，应用Kaplan-Meier法和基因表达谱交互分析（GEPIA）数据库，探讨细胞周期相关基因表达水平对HCC临床预后的影响。通过TIMER网站分析细胞周期相关基因与肿瘤免疫浸润的相关性。随后，使用GEPIA和TIMER数据库分别评估单核细胞和巨噬细胞中6个细胞周期相关基因的表达与多基因标记物之间的相关性。还分别通过Metascape和String数据库的京都基因和基因组百科全书（KEGG）和基因本体论（GO）方法分析了细胞周期相关基因，以寻找变异频率最高的相关基因。结果：与正常组织相比，肿瘤组织中细胞周期相关基因的表达水平上调。随后，高细胞周期相关基因的表达与HCC的总生存期（OS）和无进展生存期（PFS）呈正相关，CDK 1（OS：HR = 2.15，P = 1.1E-05 PFS：HR = 2.03，P = 2.3E-06），CDK5（OS：HR = 1.85，P = 0.0035 PFS：HR = 1.26，P = 0.17），CDC 20（OS：HR = 2.49，P = 5.1E-07 PFS：HR = 1.77，P = 0.00012），CCNA 2（OS：HR = 1.92，P = 0.00018 PFS：HR = 1.96，P = 5.2E-06），CCNB1（OS：HR = 2.34，P = 3.4E-05 PFS：HR = 1.97，P = 5.3E-06）和CCNB2（OS：HR = 1.91，P = 0.0013 PFS：HR = 1.63，P = 0.0011）。此外，细胞周期相关基因的转录水平与HCC中CD 4 + T和CD 8 + T细胞、中性粒细胞、巨噬细胞和树突状细胞（DC）的免疫浸润水平分别显著相关。其中，CDK 1、CDC 20、CCNA 2、CCNB 1和CCNB 2的表达水平与HCC中不同的免疫标志物集密切相关。结论：细胞周期相关基因在肝癌预后中起重要作用。同时，它们分别与HCC中CD 4 + T细胞、CD 8 + T细胞、中性粒细胞、巨噬细胞和DC的免疫浸润水平显著相关。此外，CDK 1、CDC 20、CCNA 2、CCNB 1和CCNB 2的表达可能分别参与了肝癌单核细胞和肿瘤相关巨噬细胞（TAMs）的调节。这些结果表明，细胞周期相关基因可作为新的生物标志物，用于探讨肝癌的预后和免疫细胞浸润。
Background: Cell cycle-related genes (CDK1, CDK5, CDC20, CCNA2, CCNB1, and CCNB2) play important roles in the regulation of mitotic cell cycle in eukaryotes. However, the correlation between cell cycle-related genes and tumor-infiltrating and prognosis of hepatocellular carcinoma (HCC) needs further investigation. Methods: Two public websites, Tumor Immune Estimate Resource (TIMER) and Oncomine, were used to assess the expression levels of cycle-related genes. We also analyzed the protein expression levels of six cell cycle-related genes using the HPA database. In addition, Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) database were used to investigate the impact of cell cycle-related gene expression levels on the clinical prognosis of HCC. The correlation between cell cycle-related genes and cancer immune infiltrates was analyzed through TIMER site. Subsequently, GEPIA and TIMER database were used to assess the correlation between the expression of six cell cycle-related genes and polygenic markers in monocytes and macrophages, respectively. The cell cycle-related genes were also analyzed to find the associated genes with the highest alteration frequency, by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) approaches of Metascape and String database, respectively. Results: The expression levels of cell cycle-related genes were up-regulated in tumor tissues compared with normal tissues. Subsequently, the expression of high cell cycle-related genes was positively correlated with poor overall survival (OS) and progression-free survival (PFS) in HCC, for CDK1 (OS: HR = 2.15, P = 1.1E-05 PFS: HR = 2.03, P = 2.3E-06), CDK5 (OS: HR = 1.85, P = 0.0035 PFS: HR = 1.26, P = 0.17), CDC20 (OS: HR = 2.49, P = 5.1E-07 PFS: HR = 1.77, P = 0.00012), CCNA2 (OS: HR = 1.92, P = 0.00018 PFS: HR = 1.96, P = 5.2E-06), CCNB1 (OS: HR = 2.34, P = 3.4E-05 PFS: HR = 1.97, P = 5.3E-06), and CCNB2 (OS: HR = 1.91, P = 0.0013 PFS: HR = 1.63, P = 0.0011), respectively. Furthermore, the transcription level of cell cycle-related genes was significantly correlated with immune infiltrating levels of CD4+ T and CD8+ T cells, neutrophils, macrophages, and dendritic cells (DCs) in HCC, respectively. Amongst them, the expression levels of CDK1, CDC20, CCNA2, CCNB1 and CCNB2 manifest strongly correlated with diverse immune marker sets in HCC. Conclusions: Our results demonstrated that cell cycle-related genes played key roles in the prognosis of HCC. Meanwhile, they were significantly correlated with immune infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages and DCs in HCC, respectively. In addition, CDK1, CDC20, CCNA2, CCNB1 and CCNB2 expressions may be involved in the regulation of monocytes and tumor-associated macrophages (TAMs) in HCC, respectively. These findings strongly suggested that cell cycle-related genes could be used as novel biomarkers for exploring the prognosis and immune cells infiltration of HCC.
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影响因子：
16.6
作者：
Guan Y;Enejder A;Wang M;Fang Z;Cui L;Chen SY;Wang J;Tan Y;Wu M;Chen X;Johansson PK;Osman I;Kunimoto K;Russo P;Heilshorn SC;Peltz G
通讯作者：
Peltz G
影响因子：
5.4
作者：
DARIAVACH, P;MATTEI, MG;LEFRANC, MP
通讯作者：
LEFRANC, MP
影响因子：
--
作者：
Li, Mengyuan;Liu, Zhixian;Wang, Xiaosheng
通讯作者：
Wang, Xiaosheng
影响因子：
--
作者：
Pu, Ning;Chen, Qiangda;Wu, Wenchuan
通讯作者：
Wu, Wenchuan
影响因子：
12.3
作者：
Li B;Severson E;Pignon JC;Zhao H;Li T;Novak J;Jiang P;Shen H;Aster JC;Rodig S;Signoretti S;Liu JS;Liu XS
通讯作者：
Liu XS