基于网络药理学探讨扶正化瘀方治疗肝癌的作用机制

齐婧姝; 平大冰; 孙鑫; 薛静波; 陶艳艳; 彭渊; 刘成海

doi:10.3969/j.issn.1001-5256.2021.10.016

基于网络药理学探讨扶正化瘀方治疗肝癌的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.10.016

齐婧姝¹,
平大冰¹,
孙鑫²,
薛静波¹,
陶艳艳¹,
彭渊^1, ,,
刘成海^{1, 2, 3, 4, ,}

1.
上海中医药大学附属曙光医院肝病研究所，上海 201203
2.
上海市中医临床重点实验室，上海 201203
3.
肝肾疾病病证教育部重点实验室，上海 201203
4.
上海中医健康服务协同创新中心，上海 201203

基金项目:

国家自然科学基金 (81730109);

国家自然科学基金 (81874363);

“十三五”国家科技重大专项项目 (2018ZX10302204);

上海市临床重点专科建设项目 (shslczdzk01201)

详细信息

通信作者:
彭渊，pengyuan1026@126.com

刘成海，chenghailiu@hotmail.com

中图分类号: R735.7
计量
- 文章访问数: 471
- HTML全文浏览量: 163
- PDF下载量: 59
- 被引次数: 0
出版历程
- 收稿日期: 2021-02-09
- 录用日期: 2021-03-17
- 出版日期: 2021-10-20

Mechanism of action of Fuzheng Huayu prescription in treatment of liver cancer based on network pharmacology

Jingshu QI¹,
Dabing PING¹,
Xin SUN²,
Jingbo XUE¹,
Yanyan TAO¹,
Yuan PENG^{1
, ,},
Chenghai LIU^{1, 2, 3, 4
, ,}

1.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2.
Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China
3.
Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai 201203, China
4.
Shanghai Innovation Center of TCM Health Service, Shanghai 201203, China

Research funding:

National Natural Science Foundation of China (81730109);

National Natural Science Foundation of China (81874363);

National Science and Technology Major Project during the 13th Five-Year Plan Period (2018ZX10302204);

Shanghai Key Specialty of Traditional Chinese Clinical Medicine (shslczdzk01201)

摘要

摘要: 目的运用网络药理学方法，探讨扶正化瘀(FZHY)方治疗肝癌的作用机制。方法从TCMSP、BATMAN、Drugbank数据库检索该方各味药的主要化学成分及相应靶标信息，采用STRING数据库进行PPI网络分析，Cytoscape软件构建药物-疾病网络模型并进行网络分析，R语言进行靶标功能GO和KEGG富集分析。结果研究筛选得到FZHY与肝癌交集基因192个，潜在化合物95种，其中槲皮素、木犀草素等是起到重要调控作用的活性成分; INS、IL-6、EGFR等是FZHY潜在作用的关键靶点; GO富集分析主要涉及药物反应、氧化反应等多个生物过程，KEGG富集分析主要涉及细胞凋亡、肿瘤坏死因子等信号通路。结论基于网络药理学的方法揭示了FZHY多成分、多靶标治疗肝癌的初步作用机制，为临床和基础科研提供理论依据。
- 肝肿瘤 /
- 扶正化瘀方 /
- 网络药理学
Abstract: Objective To investigate the mechanism of Fuzheng Huayu(FZHY) decoction in the treatment of liver cancer based on network pharmacology. Methods TCMSP, BATMAN, and Drugbank databases were searched for the main chemical components and corresponding targets of FZHY, and STRING database was used to perform a PPI network analysis. Cytoscape software was used to establish a drug-disease network model and perform a network analysis, and R language was used to perform GO and KEGG enrichment analysis of targets. Results A total of 192 intersection genes between FZHY and liver cancer and 95 potential compounds were screened out, among which quercetin and luteolin were the active components with an important regulatory role. INS, IL-6, and EGFR were the key targets for the potential effect of FZHY. The GO enrichment analysis showed the involvement in various biological processes such as response to drug and response to oxygen level, and the KEGG enrichment analysis showed the involvement in the signaling pathways including apoptosis and tumor necrosis factor signaling pathways. Conclusion Based on the method of network pharmacology, this study reveals the mechanism of action of multiple targets and targets of FZHY in the treatment of liver cancer, which provides a theoretical basis for clinical and basic scientific research.
- Liver Neoplasms /
- Fuzheng Huayu Decoction /
- Network Pharmacology

HTML全文

图 1 基于GeneCards和OMIM数据库预测的肝癌与FZHY的靶点基因交集

下载: 全尺寸图片幻灯片

图 2 FZHY治疗肝癌的关键靶标基因

下载: 全尺寸图片幻灯片

表 1 FZHY包含化学成分的对应靶标数

中药	数据库中名称	药材拉丁名	成分数	靶标数
丹参	丹参	Radix Salviae	65	2566
桃仁	桃仁	Persicae Semen	23	139
虫草菌丝	冬虫夏草	Corayceps	7	84
五味子	南五味子/北五味子	Schisandrae Sphenantherae Fructus/Schisandrae Chinensis Fructus	21	37
绞股蓝	绞股蓝	Gynostemmae Pentaphylli Herba	24	189
松花粉	松花粉	Pine Pollen	2	66

下载: 导出CSV

表 2 在线数据库检索关键词及疾病相关基因数

数据库检索关键词	疾病相关基因数
Liver cancer	16 815
Hepatic carcinoma	8971
Hepatoma	3729
Hepatocellular carcinoma	7543

下载: 导出CSV

表 3 FZHY治疗肝癌关键靶标的KEGG富集通路

通路ID	通路名称	靶标基因数	通路基因总数	调整后P值
hsa04210	细胞凋亡	20	174	2.14×10^-9
hsa04668	肿瘤坏死因子信号通路	17	174	1.12×10^-8
hsa05161	乙型肝炎	20	174	1.12×10^-8
hsa04151	PI3K-AKT信号通路	27	174	2.24×10^-7
hsa04215	细胞凋亡-多物种	9	174	4.02×10^-7
hsa05160	丙型肝炎	17	174	7.72×10^-7
hsa04115	53信号通路	12	174	7.72×10^-7
hsa04066	HIF-1信号通路	14	174	1.25×10^-6
hsa04010	MAPK信号通路	22	174	4.04×10^-6
hsa05205	癌症中的蛋白聚糖	18	174	4.63×10^-6
hsa01524	铂耐药	11	174	4.63×10^-6
hsa05225	肝细胞癌	15	174	2.81×10^-5
hsa04926	松弛素信号传导途径	13	174	3.04×10^-5
hsa04657	IL-17信号通路	11	174	3.71×10^-5
hsa01521	EGFR酪氨酸激酶抑制剂抵抗	10	174	4.84×10^-5
hsa05206	癌症中的microRNA	20	174	7.15×10^-5
hsa04064	NF-kappa B信号通路	11	174	8.53×10^-5
hsa04625	C型凝集素受体信号通路	11	174	8.53×10^-5
hsa04920	脂肪细胞因子信号通路	9	174	9.52×10^-5
hsa05230	在癌症中的中枢碳代谢	9	174	1.05×10^-4
hsa04932	非酒精性脂肪性肝病	13	174	1.16×10^-4
hsa04068	FoxO信号通路	12	174	1.32×10^-4

下载: 导出CSV

参考文献(24)

[1]	GE JB, XU YJ. Internal medicine[M]. 9th ed. Beijing: People's Medical Publishing House, 2018. 葛均波, 徐永健. 内科学[M]. 第9版. 北京: 人民卫生出版社, 2018.
[2]	FERLAY J, SOERJOMATARAM I, DIKSHIT R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015, 136(5): e359-e386. DOI: 10.1002/ijc.29210.
[3]	BERTUCCIO P, TURATI F, CARIOLI G, et al. Global trends and predictions in hepatocellular carcinoma mortality[J]. J Hepatol, 2017, 67(2): 302-309. DOI: 10.1016/j.jhep.2017.03.011.
[4]	National Health and Family Planning Commission of the People's Republic of China. Diagnosis, management, and treatment of hepatocellular carcinoma (V2017)[J]. J Clin Hepatol, 2017, 33(8): 1419-1431. DOI: 10.3969/j.issn.1001-5256.2017.08.003. 中华人民共和国国家卫生和计划生育委员会. 原发性肝癌诊疗规范(2017年版)[J]. 临床肝胆病杂志, 2017, 33(8): 1419-1431. DOI: 10.3969/j.issn.1001-5256.2017.08.003.
[5]	LIU C, HU Y, XU L, et al. Effect of Fuzheng Huayu formula and its actions against liver fibrosis[J]. Chin Med, 2009, 4: 12. DOI: 10.1186/1749-8546-4-12.
[6]	LIU L, ZHANG HX, CHEN L, et al. Effect of Fuzheng Huayu decoction on the expression of MMP-3 and ESM-1 in patients with hepatocellular carcinoma[J]. China J Chin Med, 2019, 34(5): 1065-1069. DOI: 10.16368/j.issn.1674-8999.2019.05.252. 刘莲, 张红霞, 陈蕾, 等. 扶正化瘀方对肝癌患者MMP-3和ESM-1表达的影响[J]. 中医学报, 2019, 34(5): 1065-1069. DOI: 10.16368/j.issn.1674-8999.2019.05.252.
[7]	JI G, CAO CL, LIU P, et al. Pathology and immunohistochemistry research on effects of Fuzheng-Huayu prescription on hepatocyte proliferation of cirrhosis rats[J]. Chin J Basic Med Tradit Chin Med, 2001, 7(2): 29-32. DOI: 10.3969/j.issn.1006-3250.2001.02.015. 季光, 曹承楼, 刘平, 等. 扶正化瘀方影响肝硬化大鼠肝细胞增殖的病理及免疫组化研究[J]. 中国中医基础医学杂志, 2001, 7(2): 29-32. DOI: 10.3969/j.issn.1006-3250.2001.02.015.
[8]	JI G, CAO CL, LIU P, et al. The study on inhibiting effect of Fuzhenghuayufang on hepatocarcinoma induced by DMN in rat[J]. Chin J Integr Trad West Med Digestion, 2001, 9(1): 20-22. DOI: 10.3969/j.issn.1671-038X.2001.01.007. 季光, 曹承楼, 刘平, 等. 扶正化瘀方预防大鼠肝癌形成机制的研究[J]. 中国中西医结合消化杂志, 2001, 9(1): 20-22. DOI: 10.3969/j.issn.1671-038X.2001.01.007.
[9]	LIU P, LIU C, WANG XS, et al. Fuzheng Hua yu Recipe and Yangyin Rou gan Recipe in preven ting hepatocarcinoma of rats[J]. Chin J Exp Tradit Med Form, 1996, 2(3): 35-40. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX603.010.htm 刘平, 刘成, 王晓素, 等. 扶正化瘀方与养阴柔肝方预防大鼠实验性肝癌的研究[J]. 中国实验方剂学杂志, 1996, 2(3): 35-40. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX603.010.htm
[10]	ZHOU J, SUN HC, WANG Z, et al. Guidelines for diagnosis and treatment of primary liver cancer in China (2017 edition)[J]. Liver Cancer, 2018, 7(3): 235-260. DOI: 10.1159/000488035.
[11]	GAO YR, CHEN SJ, HOU YW, et al. Clinical effect of Huaier Granule sequential with radiofrequency ablation and TACE in treating primary hepatic carcinoma[J]. J Changchun Univ Chin Med, 2020, 36(4): 684-687. DOI: 10.13463/j.cnki.cczyy.2020.04.021. 高远韧, 陈思佳, 侯英文, 等. TACE联合射频消融术序贯槐耳颗粒治疗原发性肝癌[J]. 长春中医药大学学报, 2020, 36(4): 684-687. DOI: 10.13463/j.cnki.cczyy.2020.04.021.
[12]	WANG H, SHAN L, WU XX, et al. Clinical efficacy of Qinggan Quai recipe combined with hepatic artery chemoembolization in the treatment of advanced heat stasis liver cancer[J]. Clin J Med Offic, 2021, 49(3): 306-308. DOI: 10.16680/j.1671-3826.2021.03.23. 王昊, 单良, 吴孝雄, 等. 清肝祛癌方联合肝动脉化疗栓塞术治疗晚期热瘀型肝癌临床疗效[J]. 临床军医杂志, 2021, 49(3): 306-308. DOI: 10.16680/j.1671-3826.2021.03.23.
[13]	LIU CH. Change of understanding of liver cirrhosis and some key points of research[J]. Chin J Integr Tradit West Med Liver Dis, 2014, 24(1): 1-6. DOI: 10.3969/j.issn.1005-0264.2014.01.001. 刘成海. 对肝硬化认识的改变与部分研究重点[J]. 中西医结合肝病杂志, 2014, 24(1): 1-6. DOI: 10.3969/j.issn.1005-0264.2014.01.001.
[14]	REN KW, LI YH, WU G, et al. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells[J]. Int J Oncol, 2017, 50(4): 1299-1311. DOI: 10.3892/ijo.2017.3886.
[15]	BRITO AF, RIBEIRO M, ABRANTES AM, et al. New approach for treatment of primary liver tumors: The role of quercetin[J]. Nutr Cancer, 2016, 68(2): 250-266. DOI: 10.1080/01635581.2016.1145245.
[16]	YEE SB, CHOI HJ, CHUNG SW, et al. Growth inhibition of luteolin on HepG2 cells is induced via p53 and Fas/Fas-ligand besides the TGF-β pathway[J]. Int J Oncol, 2015, 47(2): 747-754. DOI: 10.3892/ijo.2015.3053.
[17]	LI Y, WANG WM, CAO M, et al. Effects of insulin on proliferation, invasion and apoptosis of hepatocellular carcinoma cells[J]. Chin J Integr Tradit West Med Liver Dis, 2018, 28(5): 297-299, 306. DOI: 10.3969/j.issn.1005-0264.2018.05.012. 李燕, 王卫民, 曹萌, 等. 胰岛素对肝癌细胞增殖、侵袭、凋亡的影响及机制[J]. 中西医结合肝病杂志, 2018, 28(5): 297-299, 306. DOI: 10.3969/j.issn.1005-0264.2018.05.012.
[18]	HE G, DHAR D, NAKAGAWA H, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling[J]. Cell, 2013, 155(2): 384-396. DOI: 10.1016/j.cell.2013.09.031.
[19]	WANG HM. Reciprocal control of miR-197 and IL-6/STAT3 pathway in hepatocellular carcinoma[D]. Hangzhou: Zhejiang University, 2015. 王华敏. miR-197与IL6/STAT3信号通路相互调控在肝癌生长的作用及机制研究[D]. 杭州: 浙江大学, 2015.
[20]	PANVICHIAN R, TANTIWETRUEANGDET A, SORNMAYURA P, et al. Missense mutations in exons 18-24 of EGFR in hepatocellular carcinoma tissues[J]. Biomed Res Int, 2015, 2015: 171845. DOI: 10.1155/2015/171845.
[21]	ALTIMARI A, FIORENTINO M, GABUSI E, et al. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours[J]. Dig Liver Dis, 2003, 35(5): 332-338. DOI: 10.1016/s1590-8658(03)00077-x.
[22]	NIU J. Mechanism of P300-dependent acetylation of H3 contributes to EGF-mediated DKK1 transcription and hepatocellular carcinoma metastasis[D]. Kaifeng: Henan University, 2020. 牛杰. P300乙酰化H3促进EGF介导的DKK1转录及肝癌转移的机制研究[D]. 开封: 河南大学, 2020.
[23]	SCHUMANN DM, MAEDLER K, FRANKLIN I, et al. The Fas pathway is involved in pancreatic beta cell secretory function[J]. Proc Natl Acad Sci U S A, 2007, 104(8): 2861-2866. DOI: 10.1073/pnas.0611487104.
[24]	CHOI D, RADZISZEWSKA A, SCHROER SA, et al. Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion[J]. Am J Physiol Endocrinol Metab, 2009, 297(6): e1304-e1312. DOI: 10.1152/ajpendo.00217.2009.