基于网络药理学探讨抵当汤治疗膀胱癌的作用机制

沈炀; 芦倩; 张东健; 汤井源; 朱辰; 朱清毅; 卢子杰; 袁琳

doi:10.13422/j.cnki.syfjx.20201423

您当前的位置：

首页 >

文章列表页 >

基于网络药理学探讨抵当汤治疗膀胱癌的作用机制

数据挖掘 | 更新时间：2020-09-09

- 基于网络药理学探讨抵当汤治疗膀胱癌的作用机制
- Mechanism of Didangtang in Treatment of Bladder Cancer Based on Network Pharmacology
- 中国实验方剂学杂志 2020年26卷第14期页码：200-207
- 作者机构：
  
  南京中医药大学附属医院，江苏省中医院，南京 210000
- 作者简介：
  
  沈炀，在读硕士，从事中西医结合泌尿系肿瘤研究，E-mail：dryang9483@126.com
  袁琳，博士，副教授，博士生导师，从事中西医结合泌尿系肿瘤研究，Tel：025-86617141，E-mail：yuanlin47@163.com
- 基金信息：
  
  江苏省中医药科技发展计划项目(YB201920);南京市科技计划项目(201605009);江苏省中医院创新发展基金项目(Y2019CX11)
- DOI：10.13422/j.cnki.syfjx.20201423
  中图分类号： R22;R242;R2-031;R285.5
- 网络出版日期：2020-05-06，
  
  纸质出版日期：2020-07-20
- 稿件说明：
移动端阅览
沈炀,芦倩,张东健等.基于网络药理学探讨抵当汤治疗膀胱癌的作用机制[J].中国实验方剂学杂志,2020,26(14):200-207.

SHEN Yang,LU Qian,ZHANG Dong-jian,et al.Mechanism of Didangtang in Treatment of Bladder Cancer Based on Network Pharmacology[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(14):200-207.
沈炀,芦倩,张东健等.基于网络药理学探讨抵当汤治疗膀胱癌的作用机制[J].中国实验方剂学杂志,2020,26(14):200-207. DOI： 10.13422/j.cnki.syfjx.20201423.

SHEN Yang,LU Qian,ZHANG Dong-jian,et al.Mechanism of Didangtang in Treatment of Bladder Cancer Based on Network Pharmacology[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(14):200-207. DOI： 10.13422/j.cnki.syfjx.20201423.

摘要

目的

探讨抵当汤治疗膀胱癌的作用靶点及可能作用机制。

方法

基于多个中药与疾病数据库，运用网络药理学筛选潜在作用靶点，分析潜在靶点的生物学功能，构建“中药-靶点-通路-疾病”关系网络。并运用生物信息学方法在人群、基因数据库，探讨核心靶点的在组织中差异表达，人群中的分布以及与预后的相关性。采用体外实验验证抵当汤的作用功能，并检测抵当汤对候选靶点的作用机制。

结果

本研究共筛选出21个核心靶点，16条通路，构建了抵当汤治疗膀胱癌的作用网络。检测出6个靶点：钙黏蛋白1（CDH1），环磷腺苷结合蛋白1（CREB1），菌落刺激因子2（CSF2），AP-1转录因子（JUN），基质金属肽酶2（MMP2）和前列腺素-内过氧化物合成酶（PTGS2）在膀胱癌组织中均存在差异表达（

0.05），其中JUN与MMP2在人群中也存在差异分布（

0.05）。同时，JUN的表达水平与膀胱癌患者的预后相关（

0.05）。细胞实验发现抵当汤可抑制膀胱癌细胞的增殖，同时可降低候选靶点JUN的表达（

0.01）。

结论

抵当汤治疗膀胱癌存在多靶点、多通路的特点。其中已初步证实抵当汤可影响靶点JUN的表达并抑制膀胱癌的增殖，为进一步机制研究奠定良好基础。

Abstract

Objective

To investigate the targets and possible mechanism of Didangtang in the treatment of bladder cancer.

Method

Based on multiple traditional Chinese medicine and disease databases

the network pharmacology was used to screen potential targets

analyze the biological functions of potential targets

and construct a network of "Chinese medicine-target-path-disease". Bioinformatics analysis was applied in population and gene databases

in order to explore the differential expressions of core targets in tissues

distribution in the population and the correlation with prognosis. The

in vitro

experiment was used to verify the biological function of Didangtang. The underlying mechanism of Didangtang on the candidate target was detected.

Result

A total of 21 core target genes and 16 highly enriched pathways were screened out. A functional network of Didangtang was constructed systematically. At the same time

six targets

namely cadherin 1 (CDH1)

CAMP responsive element binding protein 1 (CREB1)

colony stimulating factor 2 (CSF2)

AP-1 transcription factor (JUN)

matrix metalloproteinase 2 (MMP2)

and prostaglandin-endoperoxide synthase (PTGS2)

were differentially expressed in bladder cancer tissues (

0.05). Furthermore

JUN and MMP2 were also differentially distributed in population (

0.05). At the same time

the expression level of JUN was correlated with the prognosis of patients with bladder cancer (

0.05). The

in vitro

experiment revealed that Didangtang inhibited the proliferation of bladder cancer cells and decreased the expression of candidate target JUN (

0.01).

Conclusion

Didangtang has the characteristics of multiple targets and multiple pathways in treatment of bladder cancer. It is initially confirmed that Didangtang can affect the expression of target JUN and inhibit the proliferation of bladder cancer

which lays a good foundation for further studies on mechanism.

关键词

Keywords

references

SIEGEL R L , MILLER K D , JEMAL A . Cancer statistics,2018 [J]. CA Cancer J Clin , 2018 , 68 ( 1 ): 7 - 30 .

CHEN W , ZHENG R , BAADE P D , et al . Cancer statistics in China,2015 [J]. CA Cancer J Clin , 2016 , 66 ( 2 ): 115 - 132 .

PANG C , GUAN Y , LI H , et al . Urologic cancer in China [J]. Jpn J Clin Oncol , 2016 , 46 ( 6 ): 497 - 501 .

KAMAT A M , HAHN N M , EFSTATHIOU J A , et al . Bladder cancer [J]. Lancet , 2016 , 388 ( 10061 ): 2796 - 2810 .

王学良 , 杨运高 , 王程 . 抵当汤抑制肿瘤转移的实验研究 [J]. 湖南中医杂志 , 2004 , 20 ( 3 ): 69 - 70 .

曹科 , 潘艳芳 , 陈佩禅 , 等 . 抵当汤对小鼠肿瘤转移及酪氨酸激酶受体信号传导系统EGFR的影响 [J]. 中医药学刊 , 2004 , 22 ( 11 ): 2026 - 2027 .

姜波 , 艾华 . 抵当汤化裁方对荷瘤小鼠抑瘤作用及对T淋巴细胞亚群的影响 [J]. 吉林中医药 , 2008 , 28 ( 2 ): 147 - 148 .

杨运高 , 华何与 , 陈先明 , 等 . 中药抵当汤对小鼠结肠癌脾移植肝转移模型肿瘤增殖细胞核抗原的影响 [J]. 中国老年学杂志 , 2013 , 33 ( 3 ): 579 - 581 .

王庆才 . 仲景方药与肿瘤临床 [J]. 辽宁中医杂志 , 2000 , 27 ( 8 ): 344 - 346 .

赵怡 , 陈美琪 , 郝书婷 , 等 . 基于网络药理学的小柴胡汤抗肺癌作用机制 [J]. 中国实验方剂学杂志， 2020 ， doi： org/10.13422/j.cnki.syfjx.20200323 http://dx.doi.org/org/10.13422/j.cnki.syfjx.20200323 .

官扬 , 曾文雪 , 胡慧明 , 等 . 基于网络药理学探讨甘草-枳壳活性成分抗乳腺癌作用机制 [J]. 中国实验方剂学杂志， 2020 ， doi： org/10.13422/j.cnki.syfjx.20200125 http://dx.doi.org/org/10.13422/j.cnki.syfjx.20200125 .

DAVIS A P , GRONDIN C J , JOHNSON R J , et al . The comparative toxicogenomics database:update 2019 [J]. Nucleic Acids Res , 2019 , 47 ( D1 ): D948 - D954 .

LIU Y , LIANG Y , WISHART D . PolySearch2:a significantly improved text-mining system for discovering associations between human diseases,genes,drugs,metabolites,toxins and more [J]. Nucleic Acids Res , 2015 , 43 ( W1 ): W535 -W542.

LI Y H , YU C Y , LI X X , et al . Therapeutic target database update 2018:enriched resource for facilitating bench-to-clinic research of targeted therapeutics [J]. Nucleic Acids Res , 2018 , 46 ( D1 ): D1121-D1127 .

BRAY F , FERLAY J , SOERJOMATARAM I , et al . Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin , 2018 , 68 ( 6 ): 394 - 424 .

MIYAMOTO H , YAO J L , CHAUX A , et al . Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder [J]. BJU Int , 2012 , 109 ( 11 ): 1716 - 1726 .

MIZUSHIMA T , TIRADOR K A , MIYAMOTO H . Androgen receptor activation:a prospective therapeutic target for bladder cancer? [J]. Expert Opin Ther Targets , 2017 , 21 ( 3 ): 249 - 257 .

MASSARI F , SANTONI M , CICCARESE C , et al . Emerging concepts on drug resistance in bladder cancer:Implications for future strategies [J]. Crit Rev Oncol Hematol , 2015 , 96 ( 1 ): 81 - 90 .

SHU T , LI Y , WU X , et al . Down-regulation of HECTD3 by HER2 inhibition makes serous ovarian cancer cells sensitive to platinum treatment [J]. Cancer Lett , 2017 , 411 ( 2 ): 65 - 73 .

LEE Y , MA J , LYU H , et al . Role of erbB3 receptors in cancer therapeutic resistance [J]. Acta Biochim Biophys Sin (Shanghai) , 2014 , 46 ( 3 ): 190 - 198 .

MOOSO B A , VINALL R L , MUDRYJ M , et al . The role of EGFR family inhibitors in muscle invasive bladder cancer:a review of clinical data and molecular evidence [J]. J Urol , 2015 , 193 ( 1 ): 19 - 29 .

LIU J , ZHANG C , HU W , et al . Tumor suppressor p53 and its mutants in cancer metabolism [J]. Cancer Lett , 2015 , 356 ( 2 Pt A): 197 - 203 .

LI X , YANG Z , SONG W , et al . Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)2,MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway [J]. Int J Oncol , 2013 , 43 ( 3 ): 793 - 802 .

CHEN J S , HUANG X H , WANG Q , et al . Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/Akt signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer [J]. Carcinogenesis , 2013 , 34 ( 1 ): 10 - 19 .

ROOMI M W , MONTERREY J C , KALINOVSKY T , et al . Patterns of MMP-2 and MMP-9 expression in human cancer cell lines [J]. Oncol Rep , 2009 , 21 ( 5 ): 1323 - 1333 .

MENDES O , KIM H T , LUNGU G , et al . MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2 [J]. Clin Exp Metastasis , 2007 , 24 ( 5 ): 341 - 351 .

JIN H , YU Y , HU Y , et al . Divergent behaviors and underlying mechanisms of cell migration and invasion in non-metastatic T24 and its metastatic derivative T24T bladder cancer cell lines [J]. Oncotarget , 2015 , 6 ( 1 ): 522 - 536 .

PENG M , WANG J , ZHANG D , et al . PHLPP2 stabilization by p27 mediates its inhibition of bladder cancer invasion by promoting autophagic degradation of MMP2 protein [J]. Oncogene , 2018 , 37 ( 43 ): 5735 - 5748 .

LU H F , LAI K C , HSU S C , et al . Involvement of matrix metalloproteinases on the inhibition of cells invasion and migration by emodin in human neuroblastoma SH-SY5Y cells [J]. Neurochem Res , 2009 , 34 ( 9 ): 1575 - 1583 .

YU C , WANG W , JIN X . Hirudin Protects Ang II-induced myocardial fibroblasts fibrosis by inhibiting the extracellular signal-regulated kinase1/2 (ERK1/2) pathway [J]. Med Sci Monit , 2018 , 24 ( 9 ): 6264 - 6272 .

田晋帆 , 葛长江 , 吕树铮 , 等 . 重组水蛭素对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块的影响及机制 [J]. 中国中西医结合杂志 , 2015 , 35 ( 2 ): 198 - 203 .

HU H M , LIU S , ZHANG Y , et al . Expression levels of transcription factors c-Fos and c-Jun and transmembrane protein HAb18G/CD147 in urothelial carcinoma of the bladder [J]. Mol Med Rep , 2017 , 15 ( 5 ): 2991 - 3000 .

VOGT P K . Jun,the oncoprotein [J]. Oncogene , 2001 , 20 ( 19 ): 2365 - 2377 .

SHAULIAN E , KARIN M . AP-1 as a regulator of cell life and death [J]. Nat Cell Biol , 2002 , 4 ( 5 ): 131 - 136 .

LI L , LI M , SUN C , et al . Altered hematopoietic cell gene expression precedes development of therapy-related myelodysplasia/acute myeloid leukemia and identifies patients at risk [J]. Cancer Cell , 2011 , 20 ( 5 ): 591 - 605 .

VLEUGEL M M , GREIJER A E , BOS R , et al . c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer [J]. Hum Pathol , 2006 , 37 ( 6 ): 668 - 674 .

MAHNER S , BAASCH C , SCHWARZ J , et al . C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma [J]. Br J Cancer , 2008 , 99 ( 8 ): 1269 - 1275 .

TANG Q , ZHAO S , WU J , et al . Inhibition of integrin-linked kinase expression by emodin through crosstalk of AMPKalpha and ERK1/2 signaling and reciprocal interplay of Sp1 and c-Jun [J]. Cell Signal , 2015 , 27 ( 7 ): 1469 - 1477 .

LI L , RUI X , LIU T , et al . Effect of heparin-derived oligosaccharide on vascular smooth muscle cell proliferation and the signal transduction mechanisms involved [J]. Cardiovasc Drugs Ther , 2012 , 26 ( 6 ): 479 - 488 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

计算机辅助药物设计和实验验证探讨柴胡皂苷D诱导膀胱癌细胞凋亡的分子机制

抵当汤联合吉西他滨治疗非肌层浸润性膀胱癌术后患者的疗效评价

复方狼毒酊干预湿毒蕴结型多发性掌跖疣的临床疗效及机制探讨

治疗慢性萎缩性胃炎新方的挖掘及其对胃阴亏虚证型的验证