凋亡抑制基因天然自身抗体在肝细胞癌患者血浆中的表达及其临床意义

doi:10.13481/j.1671-587X.20260124

摘要/Abstract

摘要：

目的探讨凋亡抑制基因BIRC5天然自身抗体在肝细胞癌（HCC）患者血浆中的表达特征及其临床意义，评估其作为HCC预后生物标志物的潜在价值。方法纳入119例HCC患者作为病例组，根据巴塞罗那临床肝癌（BCLC）分期将患者分为0+A期、B期和C+D期；132名健康对照（健康对照组）研究对象来源于本院体验中心。采集所有研究对象血液样本，通过表位预测软件设计合成2条高效检测的线性抗原肽（BIRC5a和BIRC5b），采用优化酶联免疫吸附测定（ELISA）法检测2组研究对象血浆中BIRC5天然自身抗体水平，并绘制受试者工作特征（ROC）曲线以评估诊断效能，采用Pearson/Spearman相关分析检验抗体水平与临床指标［甲胎蛋白（AFP）、肝功能、癌胚抗原（CEA）、糖类抗原199（CA199）、总胆红素（TBil）、白蛋白（Alb）和凝血酶原时间（PT）］的关联性。结果与健康对照组比较，病例组男性HCC患者血浆中BIRC5a和BIRC5b天然自身抗体水平升高（P<0.05），女性HCC患者抗体水平差异无统计学意义（P>0.05）；与健康对照组比较，病例组BCLC C+D期患者血浆中BIRC5a天然自身抗体水平升高（P<0.05）。相关性分析，BIRC5a天然自身抗体水平随着BCLC分期升高而升高（r=0.132，P<0.05），与碱性磷酸酶（ALP）升高和PT延长呈正相关关系（r=0.328，P<0.05；r=0.247，P<0.05），与Alb降低呈负相关关系（r=-0.423，P<0.01）。ROC曲线分析BIRC5a曲线下面积（AUC）为0.559；BIRC5b的AUC为0.543；联合分析AUC为0.561，最佳诊断临界值（Cut-off）下表现出最佳诊断效能值（AUC=0.569），诊断HCC的灵敏度为45.1%，特异度为74.6%。结论 BIRC5a天然自身抗体是HCC预后的一种潜在生物标志物，尤其在男性HCC患者中，其血浆水平升高与疾病进展及肝功能恶化显著相关，提示其可能作为影响HCC预后的独立危险因素。

关键词: 凋亡抑制蛋白, 天然自身抗体, 肝细胞癌, 预后生物标志物

Abstract:

Objective To discuss the expression characteristics of natural autoantibodies against the apoptosis inhibitor gene BIRC5 in plasma of the patients with hepatocellular carcinoma （HCC） and their clinical significances， and to evaluate the potential value as the prognostic biomarker for HCC. Methods A total of 119 HCC patients were enrolled as case group. According to the Barcelona Clinic Liver Cancer （BCLC） staging system， the patients were divided into stages 0+A stage， B stage， and C+D stage. A total of 132 healthy control subjects （healthy control group） were recruited from the physical examination center of our hospital. The blood samples were collected from all the subjects. Two highly efficient linear antigenic peptides （BIRC5a and BIRC5b） for detection were designed and synthesized using epitope prediction software； optimized enzyme-linked immunosorbent assay （ELISA） method was used to detect the levels of BIRC5 natural autoantibodies in plasma of the subjects in two groups； receiver operating characteristic （ROC） curve was plotted to evaluate diagnostic performance； Pearson/Spearman correlation analysis was used to examine the association between antibody levels and clinical indicators ［alpha-fetoprotein （AFP）， liver function， carcinoembryonic antigen （CEA）， carbohydrate antigen 199 （CA199）， total bilirubin （TBil）， albumin （Alb）， and prothrombin time （PT）］. Results Compared with healthy control group， the levels of BIRC5a and BIRC5b natural autoantibodies in plasma of male HCC patients in case group were increased （P<0.05）， while no statistically significant difference was observed in female HCC patients （P>0.05）. Compared with healthy control group， the level of BIRC5a natural autoantibodies in plasma of the patients with BCLC stage C+D in case group was increased （P<0.05）. The correlation analysis results showed that the level of BIRC5a natural autoantibodies increased with higher BCLC stage （r=0.132， P<0.05）， was positively correlated with increased alkaline phosphatase （ALP） and prolonged PT （r=0.328， P<0.05； r=0.247， P<0.05）， and was negatively correlated with decreased Alb （r=-0.423， P<0.01）. The ROC curve analysis results showed that the area under the curve （AUC） for BIRC5a was 0.559； the AUC for BIRC5b was 0.543； the combined analysis AUC was 0.561， and it demonstrated the best diagnostic performance （AUC=0.569） under the optimal diagnostic cut-off value， with a sensitivity of 45.1% and a specificity of 74.6% for diagnosing HCC. Conclusion BIRC5a natural autoantibody is a potential biomarker for HCC prognosis， particularly in male HCC patients. Its elevated plasma level is significantly associated with disease progression and deterioration of liver function， suggesting it may serve as an independent risk factor affecting the prognosis of HCC.

Key words: Apoptosis inhibitor proteins, Natural autoantibodies, Hepatocellular carcinoma, Prognostic biomarkers

中图分类号:

R735.7

王嘉欣,毛俊文,张萱. 凋亡抑制基因天然自身抗体在肝细胞癌患者血浆中的表达及其临床意义[J]. 吉林大学学报(医学版), 2026, 52(1): 228-235.

Jiaxin WANG,Junwen MAO,Xuan ZHANG. Expression of natural autoantibodies against apoptosis inhibitory genes in plasma of patients with hepatocellular carcinoma and its clinical significance[J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 228-235.

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Characteristic	Healthy control group (n=132)	Case group (n=119)
AFP [M（P25,P75）, μg·L?1]	-	46.13(6.50,611.31)
ALT [M（P25,P75）, U·L?1]	-	43.10(25.00,108.00)
AST [M（P25,P75）, U·L?1]	-	37.95(28.67,86.45)
ALP [M（P25,P75）, U·L?1]	-	83.10(69.62,105.92)
CEA （x±s, μg·L?1）	-	2.10±1.19
CA199[M（P25,P75）, U·mL?1]	-	22.63(13.64,42.46)
TBil [M（P25,P75）, μmol·L?1]	-	16.75(13.02,23.80)
Alb （x±s, g·L?1)	-	39.68±6.10
PT [M（P25,P75）, s]	-	11.40(10.90,12.60)
BCLC
0+A [n(%)]	-	25(21.0)
B [n(%)]	-	45(36.1)
C+D [n(%)]	-	51(42.9)

Group	BIRC5a			BIRC5b
Group	Male	Female	Both	Male	Female	Both
Healthy control	0.83±0.31 (107)	0.86±0.29 (25)	0.84±0.31 (132)	1.44±0.59 (107)	1.63±0.58 (25)	1.48±0.59 (132)
Case	0.93±0.37^* (102)	0.82±0.2 (17)	0.91±0.36 (119)	1.63±0.70^* (102)	1.38±0.68 (17)	1.60±0.70 (119)

Group	BIRC5a			BIRC5b
Group	0+A	B	C+D	0+A	B	C+D
Healthy control	0.84±0.31 (132)	0.84±0.31 (132)	0.84±0.31 (132)	1.48±0.59 (132)	1.48±0.59 (132)	1.48±0.59 (132)
Case	0.86±0.25 (25)	0.90±0.32 (43)	0.96±0.43^* (51)	1.52±0.76 (25)	1.55±0.64 (43)	1.68±0.74 (51)

Clinical indicator	BIRC5a		BIRC5b
Clinical indicator	r	P	r	P
BCLC stage	0.132	0.036	0.079	0.210
AFP	0.297	0.062	-0.142	0.381
ALT	0.134	0.411	0.037	0.822
AST	0.084	0.604	0.043	0.791
ALP	0.328	0.039	0.126	0.439
CEA	0.035	0.841	0.005	0.977
CA199	0.308	0.060	0.031	0.852
TBil	0.065	0.518	0.129	0.202
Alb	-0.423	<0.001	-0.150	0.136
PT	0.247	0.015	0.065	0.524

Group	AUC （95%CI）	SE	Cut-off value	Youden index	Sensitivity (η/%)	Specificity (η/%)
BIRC5a
0+A	0.538 (0.429,0.660)	0.059	0.971	0.066	32.0	74.6
B	0.559 (0.466,0.666)	0.051	0.968	0.165	41.9	74.6
C+D	0.569 (0.473,0.678)	0.052	0.971	0.197	45.1	74.6
Overall	0.559 (0.494,0.637)	0.037	0.969	0.158	41.2	74.6
BIRC5b
0+A	0.496 (0.335,0.594)	0.066	2.165	0.014	16.0	85.4
B	0.526 (0.376,0.586)	0.053	2.151	0.063	20.9	85.4
C+D	0.580 (0.461,0.662)	0.051	2.129	0.187	33.3	85.4
Overall	0.543 (0.439,0.585)	0.037	2.128	0.106	25.2	85.4