TOP2A基因对预测肝细胞癌预后的作用

doi:10.24920/004006

Chinese Medical Sciences Journal ›› 2022, Vol. 37 ›› Issue (4): 331-339.doi: 10.24920/004006

TOP2A基因对预测肝细胞癌预后的作用

陆进^1,²,安韶光³,马俊杰³,杨月⁴,张磊⁵,俞鹏¹,陶恒¹,陈云帆¹,张浩轩^1,^2,^*()

¹蚌埠医学院基础医学院, 安徽, 蚌埠 233030
²蚌埠医学院数字医学与智慧健康安徽省重点实验室, 安徽, 蚌埠 233030
³蚌埠医学院临床医学院, 安徽, 蚌埠 233030
⁴蚌埠医学院第一附属医院耳鼻喉科, 安徽, 蚌埠 233030
⁵蚌埠医学院第二附属医院肿瘤外科, 安徽, 蚌埠 233030

收稿日期:2021-09-22 接受日期:2021-12-10 出版日期:2022-12-31 发布日期:2022-10-04
通讯作者: 张浩轩 E-mail:0100197@bbmc.edu.cn

Topoisomerase Ⅱα Gene as a Marker for Prognostic Prediction of Hepatocellular Carcinoma: A Bioinformatics Analysis

Jin Lu^1,²,Shaoguang An³,Junjie Ma³,Yue Yang⁴,Lei Zhang⁵,Peng Yu¹,Heng Tao¹,Yunfan Chen¹,Haoxuan Zhang^1,^2,^*()

¹School of Basic Medicine, Bengbu Medical College, Bengbu, Anhui 233030, China
²Anhui Key Laboratory of Computational Medicine and Intelligent Health, Bengbu Medical College, Bengbu, Anhui 233030, China
³Clinical Medical College, Bengbu Medical College, Bengbu, Anhui 233030, China
⁴Department of Otolaryngology, First Affiliated Hospital, Bengbu Medical College, Bengbu, Anhui 233030, China
⁵Department of Surgical Oncology, Second Affiliated Hospital, Bengbu Medical College, Bengbu, Anhui 233030, China

Received:2021-09-22 Accepted:2021-12-10 Published:2022-12-31 Online:2022-10-04
Contact: Haoxuan Zhang E-mail:0100197@bbmc.edu.cn

摘要/Abstract

摘要：

目的研究拓扑异构酶Ⅱα(topoisomerase II α，TOP2α)基因在肝细胞癌（hepatocellular carcinoma，HCC）中的表达及其在预测HCC患者预后中的作用。
方法我们利用UALCAN、HCCDB、cBioPortal和Enrichr数据库中的HCC相关数据集，分析TOP2α及其共表达基因在HCC组织中的表达和突变情况,以及TOP2α及其共表达基因的GO功能和KEGG通路富集情况。利用TIMER数据库分析HCC组织中浸润的免疫细胞水平。采过Kaplan-Meier分析TOP2α及其共同表达基因与浸润的免疫细胞对HCC患者生存的影响。
结果 TOP2α及其共同表达基因在HCC组织中高表达（P < 0.001），并与HCC患者的总生存期缩短有关（P < 0.0001）。TOP2α及其共表达基因主要参与细胞有丝分裂和增殖以及细胞周期通路过程（ID：hsa04110，P = 0.001945）。TOP2α及其共同表达基因的突变与HCC患者的总生存期（P = 0.0247）和无病生存期（P = 0.0265）的缩短有关。TOP2α与HCC肿瘤组织中B细胞（r = 0.459, P < 0.01）、CD8⁺T细胞（r = 0.312, P < 0.01）、CD4⁺T细胞（r = 0.370, P < 0.01）、巨噬细胞（r = 0.459, P < 0.01）、中性粒细胞（r = 0.405, P < 0.01）和树突状细胞（r = 0.473, P < 0.01）的浸润量呈正相关。CD8⁺T细胞的浸润能显著延长HCC患者3年和5年生存期（P均 < 0.05），而CD4⁺T细胞的浸润能显著缩短HCC患者的3、5和10年生存期（P均 < 0.05）。
结论 TOP2α可能是一种癌基因，与HCC患者预后不良有关，其可能成为预测肝细胞癌患者预后的生物标志物。

关键词: 拓扑异构酶Ⅱ α, 无病生存, 总体生存, 肝细胞癌, 生物信息学分析

Abstract:

Objective To investigate the expression of topoisomeraseⅡα (TOP2α) in hepatocellular carcinoma (HCC) and its role in predicting prognosis of HCC patients.
Methods We used HCC-related datasets in UALCAN, HCCDB, and cBioPortal databases to analyze the expression and mutation of TOP2α and its co-expressed genes in HCC tissues. GO function and KEGG pathway enrichment of TOP2α and its co-expressed genes were identified. The TIMER database was used to analyze infiltration levels of immune cells in HCC. The impacts of TOP2α and its co-expression genes and the infiltrated immune cells on the survival of HCC patients were assayed by Kaplan-Meier plotter analysis.
Results TOP2α and its co-expression genes were highly expressed in HCC (P< 0.001) and detrimental to overall survival of HCC patients (P< 0.001). TOP2α and its co-expression genes were mainly involved in cell mitosis and proliferation, and cell cycle pathway (ID: hsa04110, P = 0.001945). TOP2α and its co-expression genes were mutated in HCC and the mutations were significantly detrimental to overall survival (P = 0.0247) and disease-free survival (P = 0.0265) of HCC patients. High TOP2α expression was positively correlated with the infiltration of B cell (r = 0.459, P< 0.01), CD8⁺ T cell (r = 0.312, P< 0.01), CD4⁺ T cell (r = 0.370, P< 0.01), macrophage (r = 0.459, P< 0.01), neutrophil (r = 0.405, P< 0.01), and dendritic cell (r = 0.473, P< 0.01) in HCC. The CD8⁺ T cell infiltration significantly prolonged the 3- and 5-year survival of HCC patients (all P< 0.05), and CD4⁺ T cell infiltration significantly shortened the 3-, 5-, and 10-year survival of HCC patients (all P< 0.05).
Conclusion TOP2α may be an oncogene, which was associated with poor prognosis of HCC patients and could be used as a biomarker for the prognostic prediction of HCC.

Key words: topoisomeraseⅡα, disease-free survival, overall survival, hepatocellular carcinoma, bioinformatics analysis

Jin Lu, Shaoguang An, Junjie Ma, Yue Yang, Lei Zhang, Peng Yu, Heng Tao, Yunfan Chen, Haoxuan Zhang. Topoisomerase Ⅱα Gene as a Marker for Prognostic Prediction of Hepatocellular Carcinoma: A Bioinformatics Analysis[J].Chinese Medical Sciences Journal, 2022, 37(4): 331-339.

图/表 10

参考文献 21

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Co-expression genes	TOP2α coeffcient
Co-expression genes	Log₂OR	P value	Spearman correlation
KIF18B	>3	<0.001	0.95
BUB1B	>3	<0.001	0.94
CKAP2L	>3	<0.001	0.93
ANLN	>3	<0.001	0.93
TPX2	>3	<0.001	0.93
BUB1	>3	<0.001	0.92
PRC1	>3	<0.001	0.92
NUSAP1	>3	<0.001	0.92
KIF11	>3	<0.001	0.92
GINS1	>3	<0.001	0.91
HJURP	>3	<0.001	0.91
MELK	>3	<0.001	0.90
TTK	>3	<0.001	0.90
DLGAP5	>3	<0.001	0.90
KIFC1	>3	<0.001	0.90
KIF4A	>3	<0.001	0.90
NCAPG	>3	<0.001	0.90
KIF20A	>3	<0.001	0.90
CCNB2	>3	<0.001	0.87

Category	Biological function	GO term ID	Adjusted P value
Biological process	Mitotic spindle organization	GO:0007052	4.30E-07
	Mitotic sister chromatid segregation	GO:0000070	4.01E-07
	Mitotic nuclear division	GO:0140014	1.63E-05
	Sister chromatid segregation	GO:0000819	3.72E-05
	Microtubule cytoskeleton organization involved in mitosis	GO:1902850	1.08E-04
	Mitotic spindle assembly	GO:0090307	1.07E-04
	Mitotic cytokinesis	GO:0000281	2.49E-04
	Mitotic spindle assembly checkpoint	GO:0007094	3.68E-04
	Mitotic spindle checkpoint	GO:0071174	3.27E-04
	Spindle assembly checkpoint	GO:0071173	2.94E-04
	Cytoskeleton-dependent cytokinesis	GO:0061640	3.14E-04
	Chromosome condensation	GO:0030261	6.36E-04
	Centromeric sister chromatid cohesion	GO:0070601	0.005580
Cellular component	Spindle	GO:0005819	3.04E-13
	Microtubule cytoskeleton	GO:0015630	2.39E-10
	Mitotic spindle	GO:0072686	2.71E-08
	Microtubule	GO:0005874	1.01E-07
	Kinesin complex	GO:0005871	1.18E-07
	Spindle microtubule	GO:0005876	1.21E-05
	Condensed chromosome kinetochore	GO:0000777	5.23E-05
	Polymeric cytoskeletal fiber	GO:0099513	1.22E-04
	Condensed chromosome, centromeric region	GO:0000779	1.22E-04
	Condensed nuclear chromosome kinetochore	GO:0000778	0.002317
	Condensed nuclear chromosome, centromeric region	GO:0000780	0.002527
	Microtubule-organizing center	GO:0005815	0.004354
	Spindle pole	GO:0000922	0.005601
Molecular function	Microtubule motor activity	GO:0003777	3.85E-06
	Motor activity	GO:0003774	1.11E-05
	Microtubule-binding	GO:0008017	1.09E-05
	Tubulin-binding	GO:0015631	3.98E-05
	ATPase activity	GO:0016887	3.31E-04
	ATP-dependent microtubule motor activity, plus-end-directed	GO:0008574	7.99E-04
	ATP-dependent microtubule motor activity	GO:1990939	0.00251
	Nucleoside-triphosphatase activity	GO:0017111	0.00725
KEGG	Cell cycle pathway	hsa04110	0.001945

Genes	Expression level			OS
Genes	Normal liver	HCC	P value	HR	95%CI	P value
ANLN	Low	High	<0.001	2.38	1.68-3.38	5.90E-07
BUB1	Low	High	<0.001	2.11	1.49-2.99	1.60E-05
BUB1B	Low	High	<0.001	2.10	1.46-3.03	4.30E-05
CCNB2	Low	High	< 0.001	1.89	1.31-2.71	0.00048
CKAP2L	Low	High	<0.001	2.03	1.43-2.88	4.70E-05
DLGAP5	Low	High	<0.001	2.28	1.61-3.22	1.50E-06
GINS1	Low	High	<0.001	2.36	1.64-2.37	1.50E-06
HJURP	Low	High	<0.001	2.09	1.48-2.95	2.00E-05
KIF11	Low	High	<0.001	2.35	1.64-3.36	1.70E-06
KIF18B	Low	High	<0.001	2.20	1.54-3.16	1.10E-05
KIF20A	Low	High	<0.001	2.46	1.72-3.51	3.30E-07
KIF4A	Low	High	<0.001	2.17	1.52-3.10	1.30E-05
KIFC1	Low	High	<0.001	2.53	1.78-3.58	7.10E-08
MELK	Low	High	<0.001	2.38	1.68-3.37	4.90E-07
NCAPG	Low	High	<0.001	2.20	1.53-3.17	1.20E-05
NUSAP1	Low	High	<0.001	1.77	1.25-2.50	0.0012
PRC1	Low	High	<0.001	1.91	1.35-2.70	0.00021
TPX2	Low	High	<0.001	2.32	1.64-3.27	9.30E-07
TTK	Low	High	<0.001	2.82	1.96-4.07	6.50E-09

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TOP2A基因对预测肝细胞癌预后的作用

Topoisomerase Ⅱα Gene as a Marker for Prognostic Prediction of Hepatocellular Carcinoma: A Bioinformatics Analysis

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