基于网络药理学方法探析汉黄芩素治疗肝细胞癌作用机制和体外实验研究

doi:10.12114/j.issn.1007-9572.2023.0238

中国全科医学 ›› 2024, Vol. 27 ›› Issue (32): 4040-4049.DOI: 10.12114/j.issn.1007-9572.2023.0238

所属专题：消化系统疾病最新文章合辑

• 论著·专病研究·肝癌 • 上一篇下一篇

基于网络药理学方法探析汉黄芩素治疗肝细胞癌作用机制和体外实验研究

杨安银¹, 刘红丽², 陈妙洋¹, 郑玉凤¹, 徐志远³, 杨永峰¹^,^*()

1．210000　江苏省南京市，南京中医药大学附属南京医院　南京市第二医院肝病科
2．210000　江苏省南京市，东南大学医学院
3．210000　江苏省南京市，南京医科大学公共卫生学院

收稿日期:2023-04-04 修回日期:2023-08-19 出版日期:2024-11-15 发布日期:2024-08-08
通讯作者: 杨永峰
作者贡献：
杨永峰提出研究思路，制定总体研究目标；杨安银、刘红丽进行数据分析，实验操作以及文章撰写；陈妙洋、郑玉凤、徐志远进行相关文献和资料收集。
基金资助:
国家自然科学基金面上项目(81970454)

Mechanism and in Vitro Experiment of Wogonin in Treatment of Hepatocellular Carcinoma Based on Network Pharmacology

YANG Anyin¹, LIU Hongli², CHEN Miaoyang¹, ZHENG Yufeng¹, XU Zhiyuan³, YANG Yongfeng¹^,^*()

1. Department of Liver Disease, the Second Hospital of Nanjing/Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, China
2. School of Medicine, Southeast University, Nanjing 210000, China
3. School of Public Health, Nanjing Medical University, Nanjing 210000, China

Received:2023-04-04 Revised:2023-08-19 Published:2024-11-15 Online:2024-08-08
Contact: YANG Yongfeng

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摘要/Abstract

摘要： 背景肝细胞癌是癌症相关死亡的主要原因，目前的防治形势依然严峻，对新的肝细胞癌治疗药物进行探索研究具有科学意义。目的通过网络药理学方法分析汉黄芩素干预肝细胞癌的作用机制，并进行体外实验验证。方法在TCMSP数据库中检索汉黄芩素的药物靶点，从TTD、GenCard、OMIM、DisGent数据库中收集肝细胞癌的疾病靶点。将收集的药物靶点和疾病靶点取交集，作为药物干预疾病的潜在靶点。对交集靶点运用R软件进行富集分析，使用STRING数据库和Cytoscape软件对交集靶点构建蛋白互作网络和筛选核心靶点。在GIEPA数据库对核心靶点行进一步分析。最后通过体外实验对前期分析结果进行验证：采用CCK-8试剂盒测定细胞活性；采用平板克隆形成实验测定细胞增殖；采用划痕实验测定细胞迁移；采用Western-blotting（WB）实验测定蛋白质表达水平。结果分析结果发现汉黄芩素的吸收、分布、代谢、排泄特性符合小分子药物成药规则并且毒性分析结果表明无毒性。收集到汉黄芩素靶点135个，肝细胞癌靶点8 238个，两者交集靶点113个。通过对构建的蛋白互作网络筛选出的前10位的核心基因进行分析，发现细胞周期蛋白依赖性激酶1（CDK1）、原癌基因酪氨酸蛋白激酶Src（SRC）在肝细胞癌组织中mRNA水平较正常肝组织上调（P<0.05），并且在肝细胞癌患者中高表达与不良预后相关（P<0.05）。KEGG富集分析发现交集基因富集在PI3K/AKT信号通路上最多，分子对接结果显示汉黄芩素与CDK1、SRC结合构型活力较强。CCK-8试剂盒检测结果显示，加入汉黄芩素75.0、150.0、300.0 μmol/L组HepG2细胞活性均低于对照组（P<0.05）；平板克隆形成实验结果显示，加入汉黄芩素37.5、75.0、150.0 μmol/L组HepG2细胞克隆形成数均低于对照组（P<0.05）；划痕实验结果表明，加入汉黄芩素37.5、75.0、150.0 μmol/L组HepG2细胞迁移率均低于对照组（P<0.05）；WB实验结果表明，加入汉黄芩素75.0、150.0 μmol/L组PI3K、P-AKT/AKT、CDK1、SRC蛋白表达水平均低于对照组（P<0.05）。结论汉黄芩素通过下调CDK1、SRC蛋白表达，减弱PI3K/AKT通路信号，抑制肝癌细胞增殖和迁移，诱导细胞凋亡，从而达到干预肝细胞癌发生和进展的目的。

关键词: 癌，肝细胞, 汉黄芩素, 网络药理学, 体外实验

Abstract:

Background

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths. The current prevention and treatment situation remains critical. It is of scientific significance to explore new therapeutic agents for HCC.

Objective

To analyze the mechanism of wogonin on HCC by network pharmacology and to verify it in vitro.

Methods

The drug targets of wogonin were searched in TCMSP database, and the disease targets of HCC were collected from TTD, GenCard, OMIM, DisGent databases. The collected drug targets and disease targets were intersected as potential targets for drug intervention in diseases. R software was used for enrichment analysis of intersection targets, STRING database and Cytoscape software were used to construct protein interaction network and screen core targets. The core targets were further analyzed in GIEPA database. Finally, the preliminary analysis results were verified by in vitro experiments, including cell activity determination using CCK-8 kit, cell proliferation determination using plate clone formation experiment, cell migration determination using scoring test, protein expression level determination using Western-blotting (WB) assay.

Results

The AMDE characteristics of wogonin were found to be in accordance with the rules for small molecule drug formation and the toxicity analysis showed no toxicity. A total of 135 wogonin targets and 8 238 HCC targets were collected, and 113 targets were intersected. Through the analysis of the core genes of TOP10 screened by the constructed protein interaction network, it was found that the mRNA levels of CDK1 and SRC in liver cancer tissues were higher than those in normal liver tissues (P<0.05), and the high expression levels in liver cancer patients were related to poor prognosis (P<0.05). KEGG enrichment analysis showed that the intersection genes were enriched in the PI3K/AKT signaling pathway, and the molecular docking results showed that wogonin had strong binding configuration activity with CDK1 and SRC. The results of CCK-8 kit showed that the activity of HepG2 cells in the 75.0, 150.0, and 300.0 μmol/L wogonin groups was lower than that in the control group (P<0.05). The results of plate clone formation experiment showed that the number of colony formation of HepG2 cells in the 37.5, 75.0, 150.0 μmol/L wogonin groups was lower than that in the control group (P<0.05). The results of scoring test showed that the migration rate of HepG2 cells in the 37.5, 75.0 and 150.0 μmol/L wogonin groups was lower than that in the control group (P<0.05). The results of the WB assay showed that the expression levels of PI3K, P-AKT/AKT, CDK1 and SRC proteins in the 75.0 and 150.0 μmol/L wogonin groups were lower than those in the control group (P<0.05) .

Conclusion

Wogonin inhibits the proliferation and migration of HCC cells and induces apoptosis by down-regulating the expression of CDK1 and SRC proteins and attenuating the PI3K/AKT pathway signaling, to achieve the purpose of interfering with the occurrence and progression of HCC.

Key words: Carcinoma, hepatocellular, Wogonin, Network pharmacology, In vitro experiments

中图分类号:

R 730.261

杨安银,刘红丽,陈妙洋,等. 基于网络药理学方法探析汉黄芩素治疗肝细胞癌作用机制和体外实验研究[J]. 中国全科医学, 2024, 27(32): 4040-4049. DOI: 10.12114/j.issn.1007-9572.2023.0238.
YANG Anyin,LIU Hongli,CHEN Miaoyang, et al. Mechanism and in Vitro Experiment of Wogonin in Treatment of Hepatocellular Carcinoma Based on Network Pharmacology[J]. Chinese General Practice, 2024, 27(32): 4040-4049. DOI: 10.12114/j.issn.1007-9572.2023.0238.

图/表 16

图1 交集靶点蛋白互作网络

Figure 1 Intersection target protein interaction network

图2 TOP10核心靶点注：SRC=原癌基因酪氨酸蛋白激酶Src，HSP90AA1=热休克蛋白HSP90-α，TP53=细胞肿瘤抗原p53，CDK1=细胞周期蛋白依赖性激酶1，AKT1=丝氨酸/苏氨酸蛋白激酶，CCND1=G1/S-特异性周期蛋白-D1，JUN=转录因子Jun，RELA=RELA原癌基因，NOS2=一氧化氮合酶，CDKN1A=细胞周期蛋白依赖性激酶抑制剂1。

Figure 2 TOP10 core targets

图3 GEPIA数据库验证核心靶点在肝细胞癌和正常肝组织中mRNA表达水平注：A~J分别代表CDK1、CCND1、AKT1、CDKN1A、HSP90AA1、JUN、NOS2、RELA、SRC、TP53在肝细胞癌组织和正常肝组织中的mRNA表达水平；*P<0.05，**P<0.01；LIHC=肝细胞癌，Normal=正常肝组织。

Figure 3 The GEPIA database verified the mRNA expression levels of core targets in hepatocellular carcinoma and normal liver tissues

图4 GEPIA数据库对前10位核心靶点在肝细胞癌患者中的生存分析注：A为CDK1，B为CCND1，C为AKT1，D为CDKN1A，E为HSP90AA1，F为JUN，G为NOS2，H为RELA，I为SRC，J为TP53。

Figure 4 Survival analysis of TOP10 core targets in hepatocellular carcinoma patients by the GEPIA database

图5 药物-疾病交集基因富集分析注：A为GO富集分析，B为KEGG富集分析。

Figure 5 Drug-disease intersection gene enrichment analysis

图6 药物-靶点分子对接可视化示意图注：A为CDK1-汉黄芩素，结合能：-8.8 kcal/mol；B为SRC-汉黄芩素，结合能：-8.5 kcal/mol。

Figure 6 Visualization diagram of drug-target molecular docking

图7 平板克隆形成实验结果图

Figure 7 Plate clone formation experiment results

表1 汉黄芩素处理后HepG2细胞活性（±s，n=3）

Table 1 Activity of HepG2 cells treated with wogonin

组别	24 h	48 h	72 h
对照组	1.608±0.092	1.473±0.086	1.642±0.087
DMSO溶媒组	1.562±0.071	1.459±0.106	1.641±0.089
18.5 μmol/L	1.344±0.112^a	1.459±0.117	1.655±0.101
37.5 μmol/L	0.922±0.108^a	1.322±0.081^a	1.630±0.161
75.0 μmol/L	0.818±0.022^a	0.976±0.081^a	1.317±0.042^a
150.0 μmol/L	0.737±0.017^a	0.389±0.015^a	0.261±0.043^a
300.0 μmol/L	0.637±0.018^a	0.361±0.029^a	0.223±0.036^a
F值	148.5	178.1	271.2
P值	<0.000 1	<0.000 1	<0.000 1

表2 汉黄芩素处理24 h后，相同浓度下HepG2细胞与LO2细胞活性比较（±s，n=3）

Table 2 Comparison of the activity of HepG2 cells and LO2 cells at the same concentration after 24 h treatment with wogonin

组别	18.5 μmol/L	37.5 μmol/L	75.0 μmol/L	150.0 μmol/L	300.0 μmol/L
HepG2细胞活性	83.45±2.96	57.67±9.28	51.18±4.56	45.97±3.35	39.71±2.90
LO₂细胞活性	113.41±5.68	108.77±4.54	106.06±4.54	82.75±3.92	61.92±3.33
t值	10.06	11.06	17.57	15.96	11.23
P值	<0.000 1	<0.000 1	<0.000 1	<0.000 1	<0.000 1

表3 汉黄芩素处理48 h后，相同浓度下HepG2细胞与LO2细胞活性比较（±s，n=3）

Table 3 Comparison of the activity of HepG2 cells and LO2 cells at the same concentration after 48 h treatment with wogonin

组别	18.5 μmol/L	37.5 μmol/L	75.0 μmol/L	150.0 μmol/L	300.0 μmol/L
HepG2细胞活性	95.23±4.91	91.97±2.40	51.05±2.83	24.11±1.30	13.90±0.80
LO₂细胞活性	99.26±9.30	90.04±8.39	66.62±9.30	26.48±1.75	24.62±2.47
t值	0.857	0.496	3.587	2.428	9.237
P值	0.416	0.633	0.007	0.041	<0.001

表4 汉黄芩素处理72 h后，相同浓度下HepG2细胞与LO2细胞活性比较（±s，n=3）

Table 4 Comparison of the activity of HepG2 cells and LO2 cells at the same concentration after 72 h treatment with wogonin

组别	18.5 μmol/L	37.5 μmol/L	75.0 μmol/L	150.0 μmol/L	300.0 μmol/L
HepG2细胞活性	79.08±5.85	72.73±1.50	65.80±2.43	37.89±2.68	26.71±2.74
LO₂细胞活性	100.79±3.38	99.17±7.47	80.32±3.23	41.55±1.97	34.45±3.76
t值	7.182	7.764	8.029	2.460	3.721
P值	<0.001	<0.001	<0.001	0.039	0.005

表5 HepG2细胞克隆形成集落数和汉黄芩素处理后细胞迁移率比较（±s，n=3）

Table 5 Comparison of clone-forming colonies in HepG2 cells and cell migration rate after wogonin treatment

组别	HepG2细胞克隆形成数	HepG2细胞迁移率
对照组	95.67±4.51	33.83±3.05
37.5 μmol/L	74.00±3.00^a	18.98±0.45^a
75.0 μmol/L	39.67±2.52^a	8.54±2.39^a
150.0 μmol/L	9.67±2.52^a	5.06±1.89^a
F值	410.0	106.7
P值	<0.000 1	<0.000 1

图8 划痕实验结果图

Figure 8 Scoring test results

图9 HepG2细胞凋亡实验结果

Figure 9 The results of HepG2 cell apoptosis experiment

图10 汉黄芩素下调核心靶点SRC、CDK1蛋白表达水平和降低PI3K/AKT通路信号

Figure 10 Wogonin down-regulates the expression of core targets of SRC，CDK1 protein and decreases PI3K/AKT pathway signaling

表6 HepG2细胞PI3K/AKT信号通路和CDK1、SRC蛋白表达（±s，n=3）

Table 6 PI3K/AKT signaling pathway and CDK1，SRC protein expression levels in HepG2 cells

组别	PI3K	P-AKT/AKT	CDK1	SRC
对照组	0.674±0.021	1.141±0.178	0.716±0.121	0.747±0.065
37.5 μmol/L	0.610±0.010	0.992±0.156	0.637±0.104	0.709±0.077
75.0 μmol/L	0.514±0.059^a	0.774±0.105^a	0.454±0.110^a	0.559±0.037^a
150.0 μmol/L	0.488±0.050^a	0.686±0.053^a	0.358±0.037^a	0.462±0.056^a
F值	13.64	7.335	8.324	14.25
P值	0.001 6	0.011 0	0.007 7	0.001 4

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基于网络药理学方法探析汉黄芩素治疗肝细胞癌作用机制和体外实验研究

Mechanism and in Vitro Experiment of Wogonin in Treatment of Hepatocellular Carcinoma Based on Network Pharmacology

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