乳腺癌组织中Survivin与TK1的协同表达现象及临床意义

doi:10.16150/j.1671-2870.2025.05.007

摘要/Abstract

摘要：

目的： 检测分析乳腺癌中生存素（survivin/BIRC5）表达及相关基因，并分析其在临床病理诊断及预测预后的价值。方法： 采用基于基因表达水平值的交互式分析平台（Gene Expression Profiling Interactive Analysis，GEPIA）数据库分析生存素在乳腺癌与正常乳腺组织中间的表达差异，及与其表达相关性最强基因，并分析生存素及相关基因产物与乳腺癌分期之间的关系。通过Kaplan-Meier plotter数据库数据，分析生存素及相关基因表达与乳腺癌患者预后间的关系。2016年1月至2019年3月间收集96例乳腺癌患者的术后组织标本中进行验证。采用免疫组织化学法检测标本中生存素及相关基因产物的表达情况，分析相关性，并评估其对临床病理和预后（5年总体生存率和5年无病生存）的评估价值。结果： GEPIA数据库生物信息分析显示，生存素在乳腺癌组织中表达异常升高；与其表达相关性最强的基因为胸苷激酶1（thymidine kinase 1，TK1），且TK1同时在乳腺癌组织中同样高表达。生存素与TK1在乳腺癌组织中的表达水平具有协同性，均呈现随着乳腺癌分期的升高而上升趋势（P<0.05），两者均与乳腺癌患者无复发生存期呈负相关（P<0.001）。术后组织标本免疫组化检测结果证实，生存素与TK1表达呈较强的正相关。生存素表达与淋巴结转移、TNM分期呈正相关（P<0.01）；TK1表达与组织学分级、淋巴结转移、TNM分期呈正相关（P<0.05）。生存素与TK1共阳性共28例（29.17%），与乳腺癌组织学分级高、淋巴结转移及TNM分期晚相关（P<0.05）。在预后分析中，96例患者的5年总体生存率为61.5%，5年无病生存率为47.9%；生存素与TK1阳性分别是乳腺癌患者5年总体生存率（生存素阳性HR=2.225，95%CI为1.160~4.271，P=0.016；TK1阳性HR=3.176，95%CI为1.658~6.083，P<0.001）和5年无病生存率（生存素阳性HR=3.594，95%CI为2.018~6.401，P<0.001；TK1阳性HR=3.609，95%CI为2.057~6.330，P<0.001）的不良预后因素，且两者共阳性具有更高的风险比（5年总体生存率HR=4.486，95%CI为2.335~8.617，P<0.001；5年无病生存率HR=4.469，95%CI为2.515~7.942，P<0.001）。结论： 生存素与TK1在乳腺癌组织中的表达具有较强协同性，两者共阳性提示着高级别、淋巴结转移、中晚期，预后不佳。联合检测生存素和TK1对评估乳腺癌临床病理与预后具重要意义。

关键词: 乳腺癌, 生存素, 胸苷激酶1, 临床病理, 预后

Abstract:

Objective This study aims to analyze the expression of survivin/BIRC5 and its related genes in breast cancer, as well as their clinicopathological and prognostic roles. Methods The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze survivin expression differences between breast cancer and normal breast tissues, identify the gene most strongly correlated with survivin, and evaluate their association with breast cancer stages. The Kaplan-Meier plotter database was used to assess the relationship between the expression of survivin and related genes and prognosis of breast cancer patients. Immunohistochemistry (IHC) was performed on 96 postoperative breast cancer tissue specimens, collected from January 2016 to March 2019, to validate the expression of survivin and related genes, analyze their correlation, and assess clinicopathological and prognostic significance (5-year overall survival [OS] rate and 5-year disease-free survival [DFS] rate). Results Bioinformatics analysis of the GEPIA database showed that survivin expression was significantly elevated in breast cancer tissues. The gene with the strongest correlation with its expression was thymidine kinase 1 (TK1), which was also over-expressed in breast cancer tissues. Both of them exhibited synergistic expression, increasing with advanced cancer stages (P<0.05) and correlating negatively with recurrence-free survival in breast cancer patients (P<0.001). IHC results from postoperative tissue samples confirmed a significant positive correlation between survivin and TK1 expression levels. Survivin expression correlated with lymph node metastasis and TNM stage (P<0.01), while TK1 correlated with histological grade, lymph node metastasis, and TNM stage (P<0.05). Survivin and TK1 co-expression was observed in 28 cases (29.17%), showing significant associations with higher histological grade, lymph node metastasis, and advanced-stage disease (P<0.05). In prognostic analysis, the five-year OS rate and five-year DFS rate were 61.5% and 47.9%, respectively. Positive survivin (OS HR=2.225, 95%CI: 1.160-4.271, P=0.016; DFS HR=3.594, 95%CI: 2.018-6.401, P<0.001) and TK1 (OS HR=3.176, 95%CI:1.658-6.083, P<0.001; DFS HR=3.609, 95%CI: 2.057-6.330, P<0.001) predicted poorer prognosis, with co-expression showing higher hazard ratios (5-year OS HR=4.486, 95%CI: 2.335-8.617, P<0.001; 5-year DFS HR=4.469, 95%CI: 2.515-7.942, P<0.001). Conclusions Survivin and TK1 exhibit strong synergistic expression in breast cancer tissues. Their co-expression indicates high grade, lymph node metastasis, advanced stage, and poor prognosis. The combined detection of survivin and TK1 is of great significance for evaluating the clinicopathology and prognosis of breast cancer.

Key words: Breast cancer, Survivin, Thymidine kinase1, Clinicopathology, Prognosis

中图分类号:

R737.9
R446

徐图, 史春桃, 韩玮, 姚丽倩, 陈超波, 房灵, 顾婷婷. 乳腺癌组织中Survivin与TK1的协同表达现象及临床意义[J]. 诊断学理论与实践, 2025, 24(05): 518-528.

XU Tu, SHI Chuntao, HAN Wei, YAO Liqian, CHEN Chaobo, FANG Ling, GU Tingting. Synergistic expression of survivin and TK1 in breast cancer tissues and its clinical significance[J]. Journal of Diagnostics Concepts & Practice, 2025, 24(05): 518-528.

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Gene symbol	Genc ID	R
TK1	ENSG00000167900.11	0.82
ALYREF	ENSG00000183684.7	0.70
KIF2C	ENSG00000142945.12	0.64
NCAPH	ENSG00000121152.9	0.64
PLK1	ENSGU000166851.14	0.64
KIF4A	ENSG00000N9088911	0.63
AURKB	ENSG00000178999.12	0.63
TROAP	ENSG00000135451.12	0.63
CCNB2	ENSG00000157456.7	0.63
IPX2	ENSGU0000D88325.15	0.63

Items	Univariate analysis			Multivariate analysis
Items	HR	95%CI	P	HR	95%CI	P
Overall survival
Survivin: Positive vs Negative	2.225	1.160-4.271	0.016	1.130	0.522-2.446	0.756
TK1: Positive vs Negative	3.176	1.658-6.083	<0.001	1.928	0.907-4.100	0.088
Age: ≥56 y vs <56 y	0.992	0.520-1.890	0.980	1.427	0.723-2.817	0.306
Tumor size: >5 cm vs ≤5 cm	1.988	1.037-3.812	0.039	1.327	0.667-2.643	0.421
Histological differentiation: 3 vs 1-2	2.203	1.153-4.208	0.017	1.241	0.623-2.474	0.539
Lymph node metastasis: Yes vs No	4.064	1.439-11.479	0.008	0.929	0.251-3.443	0.913
TNM stage: Ⅲ and Ⅳ vsⅠ and Ⅱ	7.089	3.412-14.728	<0.001	5.705	2.218-14.671	<0.001
Disease-free survival
Survivin: Positive vs Negative	3.594	2.018-6.401	<0.001	2.448	1.201-4.989	0.014
TK1: Positive vs Negative	3.609	2.057-6.330	<0.001	1.997	1.035-3.854	0.039
Age: ≥56 y vs <56 y	0.845	0.484-1.474	0.553	0.829	0.446-1.543	0.555
Tumor size: >5 cm vs ≤5 cm	1.381	0.774-2.461	0.274	1.101	0.578-2.097	0.769
Histological differentiation: 3 vs 1-2	1.344	0.748-2.414	0.322	0.694	0.363-1.325	0.268
Lymph node metastasis: Yes vs No	2.398	1.164-4.940	0.018	0.805	0.316-2.054	0.650
TNM stage: Ⅲ and Ⅳ vs Ⅰ and Ⅱ	5.015	2.802-8.976	<0.001	4.225	1.904-9.376	<0.001

Items	Univariate analysis			Multivariate analysis
Items	HR	95%CI	P	HR	95%CI	P
Overall survival
Survivin+TK1+: Yes vs No	4.486	2.335-8.617	<0.001	2.951	1.455-5.983	0.003
Age: ≥56 y vs <56 y				1.542	0.778-3.055	0.215
Tumor size: >5 cm vs ≤5 cm				1.285	0.646-2.558	0.475
Histological differentiation: 3 vs 1-2				1.064	0.525-2.158	0.863
Lymph node metastasis: Yes vs No				0.887	0.242-3.255	0.857
TNM stage: Ⅲ and Ⅳ vs Ⅰ and Ⅱ				5.806	2.249-14.989	<0.001
Disease-free survival
Survivin+TK1+: Yes vs No	4.469	2.515-7.942	<0.001	3.575	1.875-6.815	<0.001
Age: ≥56 y vs <56 y				0.988	0.547-1.783	0.967
Tumor size: >5 cm vs ≤5 cm				0.945	0.505-1.769	0.860
Histological differentiation: 3 vs 1-2				0.608	0.313-1.181	0.142
Lymph node metastasis: Yes vs No				0.879	0.347-2.225	0.786
TNM stage: Ⅲ and Ⅳ vs Ⅰ and Ⅱ				4.910	2.231-10.805	<0.001