血清聚腺苷二磷酸核糖聚合酶2作为潜在的肝细胞癌诊断标志物的研究

doi:10.12114/j.issn.1007-9572.2023.0553

中国全科医学 ›› 2024, Vol. 27 ›› Issue (32): 4060-4065.DOI: 10.12114/j.issn.1007-9572.2023.0553

• 论著·专病研究·肝癌 • 上一篇下一篇

血清聚腺苷二磷酸核糖聚合酶2作为潜在的肝细胞癌诊断标志物的研究

麦尔哈巴·麦麦提艾力¹, 张凯楠², 赵辉², 亚库甫·托合提³, 叶建蔚⁴, 吕国栋¹^,⁵^,^*()

1．830054　新疆乌鲁木齐市，新疆医科大学药学院
2．830054　新疆乌鲁木齐市，新疆医科大学第一附属医院临床检验中心
3．830054　新疆乌鲁木齐市，新疆军区总医院质量管理科
4．830054　新疆乌鲁木齐市，新疆医科大学第一附属医院肿瘤中心
5．830054　新疆乌鲁木齐市，新疆医科大学第一附属医院临床医学研究院

收稿日期:2023-06-15 修回日期:2023-11-26 出版日期:2024-11-15 发布日期:2024-08-08
通讯作者: 吕国栋
作者贡献：
麦尔哈巴·麦麦提艾力负责文章中主体实验的完成及文章撰写；张凯楠负责生信分析及数据统计；赵辉进行数据的收集与整理；亚库甫·托合提和叶建蔚负责收集血清；吕国栋负责研究的构思与设计，文章的质量控制与审查，对文章整体负责、监督管理。
基金资助:
新疆维吾尔自治区自然科学基金资助项目(2022D01C245)

Investigating Serum PARP2 as a Potential Diagnostic Biomarker for Hepatocellular Carcinoma

MAIERHABA· Maimaitiaili¹, ZHANG Kainan², ZHAO Hui², YAKUFU· Tuoheti³, YE Jianwei⁴, LYU Guodong¹^,⁵^,^*()

1. School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China
2. Department of Clinical Laboratory Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
3. Quality Management Section, General Hospital of Xinjiang Military Region, Urumqi 830054, China
4. Cancer Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
5. Institute of Clinical Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China

Received:2023-06-15 Revised:2023-11-26 Published:2024-11-15 Online:2024-08-08
Contact: LYU Guodong

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摘要/Abstract

摘要： 背景肝细胞癌（HCC）是肝脏最常见的恶性肿瘤，近年HCC发病率上升。甲胎蛋白（AFP）是HCC诊断中的经典血清标志物，但其灵敏度低，亟待研发新型分子生物标志物用于HCC的早期诊断。目的检测HCC患者血清聚腺苷二磷酸核糖聚合酶2（PARP2）蛋白表达水平，并探讨其是否可以作为潜在的HCC诊断标志物。方法在TCGA数据库中分析50例健康体检者与371例HCC患者的PARP2 mRNA水平，通过PARP2表达量绘制诊断HCC的受试者工作特征（ROC）曲线，分析诊断效能。在HCC细胞和正常肝细胞中检测PARP2 mRNA表达水平和蛋白水平。收集2021年3月—2022年7月新疆医科大学第一附属医院38例新发HCC患者的血清样本及同期38例体检健康者血清样本，采用ELISA方法，检测血清PARP2蛋白水平，并分析HCC患者血清PARP2蛋白水平与临床特征的相关性，分析血清PARP2表达水平用于HCC诊断与AFP阴性HCC（AFP <20 μg/L）诊断的效能分析，评估血清PARP2与AFP联合诊断HCC患者与体检健康者的效能。结果基于TCGA的大数据分析，癌组织PARP2 mRNA表达量高于癌旁组织（P<0.001）；HCC细胞HepG2中PARP2 mRNA表达水平、PARP2蛋白表达水平高于正常肝细胞WRL68（P<0.05）。HCC患者血清PARP2蛋白表达水平高于体检健康者（P<0.001）。不同淋巴转移、肿瘤数目者血清PARP2表达水平比较，差异均有统计学意义（P<0.05）。血清PARP2表达水平诊断HCC的ROC曲线下面积（AUC）为0.92，灵敏度为76.32%，特异度为97.37%，截断值为19.45 μg/L。经血清AFP检测，38例HCC患者中21例为AFP阴性HCC。血清PARP2蛋白水平诊断AFP阴性HCC的AUC为0.95（95%CI=0.88~1.00），灵敏度为85.71%，特异度为97.37%，截断值为19.59 μg/L。进一步评估PARP2联用AFP的诊断效能，使用"并联"的联合诊断模式，结果显示：联合诊断HCC的灵敏度为92.11%，特异度为94.74%，AUC为0.934 2；针对AFP阴性的HCC患者，联合诊断的灵敏度为85.71%，特异度为94.74%，AUC为0.902 3。结论 PARP2在HCC中高表达，可以作为HCC筛查的生物学标志物，尤其是AFP阴性的HCC。

关键词: 癌，肝细胞, PARP2, 甲胎蛋白, 诊断标志物

Abstract:

Background

Hepatocellular carcinoma (HCC) is the most common malignant liver tumor, with an increasing incidence rate. Since alpha-fetoprotein (AFP), the traditional serum marker for HCC, has a low sensitivity, there is a critical need for novel molecular biomarkers to enable early detection of HCC.

Objective

To detect the protein expression level of serum polyadenosine diphosphate ribose polymerase 2 (PARP2) in HCC patients in the blood of HCC patients and investigate its potential as a diagnostic marker for HCC.

Methods

PARP2 mRNA levels of 50 healthy individuals and 371 HCC patients were analyzed in the TCGA database, and the diagnostic efficacy was analyzed by plotting the receiver operating characteristic (ROC) curve of subjects diagnosed with HCC by PARP2 expression. The levels of PARP2 mRNA and protein expression were assessed in both HCC cells and normal hepatocytes. Serum samples from 38 newly diagnosed HCC patients and 38 healthy individuals undergoing physical examinations at the First Affiliated Hospital of Xinjiang Medical University from March 2021 to July 2022 were collected to measure serum PARP2 protein levels by using the enzyme-linked immunosorbent assay (ELISA) method, and their correlation with HCC clinical characteristics was analyzed. Additionally, the characteristics of serum PARP2 expression levels in diagnosing HCC, particularly in alpha-fetoprotein (AFP) -negative HCC (AFP <20 μg/L) was analyzed, and the efficacy of the combination of serum PARP2 and AFP for the diagnosis of HCC in patients with HCC and healthy individuals was evaluated.

Results

TCGA data showed that PARP2 mRNA expression is higher in malignant tissues compared to paracancerous tissues based on the big data analysis of TCGA (P<0.001). PARP2 mRNA and protein expression levels were higher in HCC cells HepG2 compared to normal hepatocytes WRL68 (P<0.05). HCC patients had higher serum PARP2 protein expression levels compared to healthy individuals (P<0.001). Comparison of serum PARP2 expression levels in those with different lymphatic metastases and tumor counts showed statistically significant differences (P<0.05). The area under the ROC curve (AUC) of serum PARP2 expression level plotted for the diagnosis of HCC was 0.92, with a sensitivity of 76.32%, a specificity of 97.37% and a cut-off value of 19.45 μg/L. Upon serum AFP testing, 21 of the 38 HCC patients were AFP-negative HCC. The AUC of serum PARP2 protein level for diagnosing AFP-negative HCC was 0.95 (95%CI=0.88-1.00), with a sensitivity of 85.71%, a specificity of 97.37%, and a cutoff value of 19.59 μg/L. The diagnostic efficacy of PARP2 in combination with AFP was further evaluated using a "parallel" co-diagnostic approach, the results showed that the diagnostic efficacy of the combined diagnosis of HCC was 92.11%, the specificity was 94.74%, and the AUC was 0.934 2. For AFP-negative HCC patients, the sensitivity of the combined diagnosis was 85.71%, the specificity was 94.74%, and the AUC was 0.902 3.

Conclusion

PARP2 is highly expressed in HCC and can be used as a biological marker for HCC screening, especially in AFP-negative HCC.

Key words: Carcinoma, hepatocellular, PARP2, Alpha-fetoprotein, Diagnostic biomarkers

中图分类号:

R 735.7

麦尔哈巴·麦麦提艾力,张凯楠,赵辉,等. 血清聚腺苷二磷酸核糖聚合酶2作为潜在的肝细胞癌诊断标志物的研究[J]. 中国全科医学, 2024, 27(32): 4060-4065. DOI: 10.12114/j.issn.1007-9572.2023.0553.
MAIERHABA· Maimaitiaili,ZHANG Kainan,ZHAO Hui, et al. Investigating Serum PARP2 as a Potential Diagnostic Biomarker for Hepatocellular Carcinoma[J]. Chinese General Practice, 2024, 27(32): 4060-4065. DOI: 10.12114/j.issn.1007-9572.2023.0553.

图/表 4

图1 PARP2表达量诊断TCGA数据库中HCC患者的ROC曲线

Figure 1 The ROC curve of PARP2 expression for the diagnosis of HCC patients in the TCGA database

图2 HCC细胞和正常肝细胞中PARP2蛋白表达水平注：PARP2=聚腺苷二磷酸核糖聚合酶2。

Figure 2 PARP2 protein expression levels in HCC cells and normal hepatocytes

表1 不同临床病理特征的HCC患者血清PARP2表达水平比较[M（P25，P75），μg/L]

Table 1 Comparison of serum PARP2 expression levels in HCC patients with different clinic opathologic features

临床指标	例数	PARP2	Z值	P值
性别			-0.635	0.525
男	29	27.65（17.32，53.56）
女	9	33.61（23.35，61.85）
年龄（岁）			-1.174	0.240
≤60	17	21.67（15.28，52.52）
>60	21	35.25（24.98，53.96）
TNM分期			-0.597	0.551
Ⅰ~Ⅱ期	26	30.24（18.79，50.73）
Ⅲ~Ⅳ期	12	35.06（19.86，55.56）
淋巴转移			-2.138	0.032
否	35	27.65（18.17，49.78）
是	3	55.66（54.22，75.27）
远处转移			-1.641	0.101
否	32	30.24（17.24，48.54）
是	6	54.22（23.30，87.76）
HBsAg			-1.389	0.165
阴性	23	35.25（19.56，55.66）
阳性	15	25.16（15.84，40.28）
肿瘤大小（cm）			-1.538	0.124
≤5	22	26.13（17.74，44.81）
>5	16	43.25（24.96，55.56）
肿瘤数目（个）			-2.169	0.030
1	25	40.28（23.30，62.23）
≥2	13	19.85（14.28，35.06）
AFP（μg/L）			-0.377	0.706
≤400	31	32.84（18.17，55.26）
>400	7	33.61（19.56，40.28）

图3 血清PARP2联合AFP诊断HCC和AFP阴性HCC患者的ROC曲线注：A为PARP2联用甲胎蛋白（AFP）诊断肝细胞癌（HCC）患者的受试者工作特征（ROC）曲线；B为PARP2联用AFP诊断AFP阴性HCC患者的ROC曲线。

Figure 3 ROC curves of serum PARP2 combined with AFP for diagnosis of HCC and AFP-negative HCC patients

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血清聚腺苷二磷酸核糖聚合酶2作为潜在的肝细胞癌诊断标志物的研究

Investigating Serum PARP2 as a Potential Diagnostic Biomarker for Hepatocellular Carcinoma

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