耐药基因蛋白和Ki67在原发性肝癌中的表达及其在预后中的价值

doi:10.3877/cma.j.issn.2095-3232.2018.01.019

目的

探讨P-糖蛋白（Pgp）、胎盘型谷胱甘肽-S-转移酶（GST-π）、拓扑异构酶Ⅱ（TopoⅡ）和胸苷酸合酶（TS）4种耐药基因蛋白及Ki67在原发性肝癌（肝癌）中的表达及其在预后中的价值。

方法

标本来源于2008年3月至2016年12月在南通大学第三附属医院接受诊治的41例肝癌患者。患者均签署知情同意书，符合医学伦理学规定。其中男26例，女15例；平均年龄（56±10）岁。采用免疫组化法检测肝癌组织中Pgp、GST-π、TopoⅡ、TS和Ki67的表达水平。相关性分析采用Spearman相关分析，生存率分析采用Kaplan-Meier法和Log-rank检验，患者的预后影响因素采用Cox比例风险回归模型分析。

结果

Pgp、GST-π、TopoⅡ、TS和Ki67在肝癌组织中存在阳性表达，阳性率分别为73%（30/41）、7%（3/41）、61%（25/41）、39%（16/41）和51%（21/41）。TS表达与Pgp、TopoⅡ表达呈正相关（r_s=0.484，0.333；P<0.05）。生存分析结果显示TS和Ki67阳性患者和阴性患者生存情况差异有统计学意义（χ²=4.695，5.784；P<0.05）。Cox多因素回归分析显示TS和Ki67为影响患者总体预后的独立危险因素（HR=3.007，17.108；P<0.05）。

结论

Pgp、GST-π、TopoⅡ、TS在肝癌中均有表达，且TS和Pgp、TopoⅡ的表达呈正相关，TS和Ki67是影响患者预后的独立危险因素。

关键词: 多药耐药相关蛋白质类, P-糖蛋白, 谷胱甘肽S-转移酶pi, DNA拓扑异构酶类, 胸苷酸合酶, 肝肿瘤, 预后, 危险因素

Objective

To investigate the expressions of 4 drug resistance gene proteins P-glycoprotein (Pgp), Glutathionine-S-Transferase π (GST-π), topoisomerase Ⅱ (TopoⅡ) and thymidylate synthase (TS) and Ki67 in primary liver cancer (PLC) and their value in the prognosis of patients.

Methods

Samples were collected from 41 patients with PLC in the Third Affiliated Hospital of Nantong University between March 2008 and December 2016. The informed consents of all patients were obtained and the local ethical committee approval was received. There were 26 males and 15 females, with an average age of (56±10) years old. The expressions of Pgp, GST-π, Topo Ⅱ, TS and Ki67 in PLC tissues were detected by immunohistochemistry. Correlation analysis was conducted using Spearman correlation analysis. Survival rate was analyzed using Kaplan-Meier method and Log-rank test. Prognostic factors of these patients were analyzed by Cox proportional hazard regression model.

Results

Positive expressions of Pgp, GST-π, Topo Ⅱ, TS and Ki67 were detected in PLC tissues, and the positive expression rate was 73% (30/41), 7% (3/41), 61% (25/41), 39% (16/41) and 51% (21/41), respectively. The expression of TS was positively correlated with those of Pgp and Topo Ⅱ (r_s=0.484, 0.333; P<0.05). Survival analysis showed that there were significant differences in the survival between TS, Ki67 positive and negative patients (χ²=4.695, 5.784; P<0.05). Cox multivariate regression analysis showed that TS and Ki67 were the independent risk factors for the overall prognosis (HR=3.007, 17.108; P<0.05).

Conclusions

Expressions of Pgp, GST-π, Topo Ⅱ and TS can be detected in PLC. The expression of TS is positively correlated with those of Pgp and Topo Ⅱ. TS and Ki67 are the independent risk factors for the prognosis of patients.

Key words: Multidrug resistance-associated proteins, P-Glycoprotein, Glutathione S-transferase pi, DNA topoisomerases, Thymidylate synthase, Liver neoplasms, Prognosis, Risk factors

图1 肝癌组织中Pgp、GST-π、TopoⅡ、TS和Ki67的表达（Envision法　×400）

表1 肝癌组织中Pgp、GST-π、TopoⅡ、TS和Ki67相关性分析结果

统计值	TS和Pgp	TS和GST-π	TS和TopoⅡ	TS和Ki67
r_s值	0.484	0.159	0.333	-0.054
P值	0.001	0.32	0.034	-0.737

表1 肝癌组织中Pgp、GST-π、TopoⅡ、TS和Ki67相关性分析结果

统计值	TS和Pgp	TS和GST-π	TS和TopoⅡ	TS和Ki67
r_s值	0.484	0.159	0.333	-0.054
P值	0.001	0.32	0.034	-0.737

图2 TS和Ki67对原发性肝癌患者生存情况影响的Kaplan-Meier生存曲线

表2 Pgp、GST-π、TopoⅡ、TS和Ki67对影响原发性肝癌患者总体预后的单因素和多因素分析

参数	单因素分析			多因素分析
参数	HR	95％CI	P值	HR	95％CI	P值
PgP	1.639	0.941～2.853	0.081	?	?	?
GST-π	1.325	0.723～2.427	0.362	?	?	?
TopoⅡ	1.943	1.026～3.678	0.041	1.143	0.428～3.054	0.789
TS	1.883	-1.056～-3.358	0.032	3.007	1.501～6.022	0.002
Ki67	5.890	-1.177～29.482	0.031	17.108	０2.576～113.608	0.003

表2 Pgp、GST-π、TopoⅡ、TS和Ki67对影响原发性肝癌患者总体预后的单因素和多因素分析

参数	单因素分析			多因素分析
参数	HR	95％CI	P值	HR	95％CI	P值
PgP	1.639	0.941～2.853	0.081	?	?	?
GST-π	1.325	0.723～2.427	0.362	?	?	?
TopoⅡ	1.943	1.026～3.678	0.041	1.143	0.428～3.054	0.789
TS	1.883	-1.056～-3.358	0.032	3.007	1.501～6.022	0.002
Ki67	5.890	-1.177～29.482	0.031	17.108	０2.576～113.608	0.003

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Expressions of drug resistance gene proteins and Ki67 in primary liver cancer and their value in prognosis

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Expressions of drug resistance gene proteins and Ki67 in primary liver cancer and their value in prognosis