Mechanism of Loulu <italic style="font-style: italic">（Radix Rhapontici）</italic> Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model

Bowen WANG; Congcong WANG; Cun LIU; Changgang SUN

doi:10.13288/j.11-2166/r.2022.14.014

您当前的位置：

首页 >

文章列表页 >

Mechanism of Loulu （Radix Rhapontici） Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model

更新时间：2022-07-11

- Mechanism of Loulu （Radix Rhapontici） Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model
- Journal of Traditional Chinese Medicine Vol. 63, Issue 14, Pages: 1381-1387(2022)
- 作者机构：
  
  1.山东大学齐鲁医学院，山东省济南市历下区文化西路107号， 250012
  2.山东中医药大学
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2022.14.014
  CLC：
- Received：21 January 2022，
  
  Revised：2022-03-01，
  
  Published：17 July 2022
- 稿件说明：
移动端阅览
王博文,汪丛丛,刘存等.基于整合药理学模型的漏芦干预三阴性乳腺癌转移药理机制研究[J].中医杂志,2022,63(14):1381-1387.

WANG Bowen,WANG Congcong,LIU Cun,et al.Mechanism of Loulu （Radix Rhapontici） Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model[J].Journal of Traditional Chinese Medicine,2022,63(14):1381-1387.
王博文,汪丛丛,刘存等.基于整合药理学模型的漏芦干预三阴性乳腺癌转移药理机制研究[J].中医杂志,2022,63(14):1381-1387. DOI： 10.13288/j.11-2166/r.2022.14.014.

WANG Bowen,WANG Congcong,LIU Cun,et al.Mechanism of Loulu （Radix Rhapontici） Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model[J].Journal of Traditional Chinese Medicine,2022,63(14):1381-1387. DOI： 10.13288/j.11-2166/r.2022.14.014.

摘要

目的

通过整合药理学研究方法探索漏芦干预三阴性乳腺癌转移的潜在机制。

方法

首先通过网络药理学方法筛选漏芦关键成分及关键靶点，再筛选三阴性乳腺癌转移的特定靶标及关键靶标。其次对筛选出漏芦的关键成分和三阴性乳腺癌转移的关键靶标进行分子对接，以评估化合物与靶标之间的亲和力，并获得准确的组合模型。最后通过体外实验验证关键成分与靶标，MTT法评估细胞活性、细胞划痕实验评估运动能力，并使用定量RT-PCR评估关键靶标mRNA表达。

结果

网络药理学研究共获得了漏芦的4个关键成分（β-谷甾醇、甘草素、黄毒乙素、谷甾醇）和84个关键靶点。得到13个与三阴性乳腺癌转移相关的特定靶标，其中层粘连蛋白α2（LAMA2）以及血管性血友病因子（VWF）是两个关键靶标，靶标有效地富集在“细胞外基质相互作用”以及“局灶性粘连”两条信号通路。将筛选出的漏芦关键成分β-谷甾醇、甘草素、黄毒乙素、谷甾醇与关键靶标LAMA2以及VWF进行分子对接研究，结果显示β-谷甾醇与LAMA2形成了最优构象。体外实验结果显示，25、50、100 μmol/L浓度β-谷甾醇干预24 h、36 h时均能不同程度降低人三阴性乳腺癌细胞系MDA-MB-468和MDA-MB-231细胞增殖率（

＜0.05或

＜0.01）。50 μmol/L浓度β-谷甾醇干预24 h时可明显降低MDA-MB-468和MDA-MB-231细胞运动能力。将50 μmol/L β-谷甾醇干预MDA-MB-231细胞系24 h和36 h，采用qRT-PCR检测LAMA2和涉及上皮间质转化的关键靶点［E-钙黏蛋白（CDH1）、N-钙黏蛋白（CDH2）、波形蛋白（VIM）］mRNA表达，结果显示与24 h比较，LAMA2以及CDH1 mRNA表达在36 h均显著增加（

＜0.05或

＜0.01）。

结论

β-谷甾醇是漏芦干预三阴性乳腺癌转移的关键成分，其能够有效地抑制细胞系的增殖，可能是通过增强LAMA2和CDH1的表达实现的。

Abstract

Objective

To explore the potential mechanism of Loulu （

Radix Rhapontici

） intervention on the metastasis of triple-negative breast cancer （TNBC） through the construction of integrative pharmacological model.

Methods

Firstly， the key components and targets of Loulu were selected by network pharmacology， and then the specific targets and key targets of TNBC metastasis were selected. Secondly， molecular docking was used to evaluate the affinity between key components of Loulu and key targets of TNBC metastasis and to obtain an accurate combinatorial model. Finally， the key components and targets were verified in vitro， while the cell viability and motor ability were evaluated by MTT assay and cell scratch assay， and the mRNA expression of key targets was evaluated by quantitative RT-PCR.

Results

A total of four key components （β-sitosterol， liquiritigenin， xanthotoxin B， sitosterol） and 84 key targets were obtained in this network pharmacology study. Finally， Thirteen specific targets were found to be associated with TNBC metastasis， of which laminin α2 （LAMA2） and von Willebrand factor （VWF） were the two key targets， with efficient enrichment in the “extracellular matrix interaction” and “focal adhesion” signaling pathways， respectively. Molecular docking was performed between identified key components of Loulu （β-sitosterol， liquiritigenin， xanthotoxin B， sitosterol） and the key targets including LAMA2 and VWF， showing best docking conformation of β-sitosterol with LAMA2. The in vitro results showed that β-sitosterol at the concentration of 25， 50， and 100 μmol/L for 24 h and 36 h could effectively reduce the proliferation rate of TNBC MDA-MB-468 and MDA-MB-231 cells with varying degrees （

＜0.05 or

＜0.01）. The motility of MDA-MB-468 and MDA-MB-231 cells was significantly reduced by 50 μmol/L β-sitosterol intervention for 24 h. qRT-PCR was used to detect mRNA expression of LAMA2 and key targets involved in epithelial-mesenchymal transition including E-cadherin （CDH1）， N -Cadherin （CDH2）， and Vimentin （VIM）， and the results showed that compared with 24 h of 50 μmol/L β-sitosterol intervention on MDA-MB-231 cell line， the 36 h intervention significantly increased the mRNA expressions of LAMA2 and CDH1 （

＜0.05 or

＜0.01）.

Conclusion

β-Sitosterol is a key component of Loulu in the intervention of TNBC metastasis， which can effectively inhibit the proliferation of cell lines possibly by enhancing the expression of LAMA2 and CDH1.

关键词

Keywords

references

SIEGEL MB ， HE X ， HOADLEY KA ， et al . Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer ［J］. J Clin Invest ， 2018 ， 128 （ 4 ）： 1371 - 1383 .

DAVIES C ， GODWIN J ， GRAY R ， et al . Early Breast Cancer Trialists' Collaborative Group （EBCTCG） relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen： patient-level meta-analysis of randomised trials ［J］. Lancet ， 2011 ， 378 （ 9793 ）： 771 - 784 .

TOBIN NP ， HARRELL JC ， LÖVROT J ， et al . Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival ［J］. Ann Oncol ， 2015 ， 26 （ 1 ）： 81 - 88 .

MILLER KD ， NOGUEIRA L ， MARIOTTO AB ， et al . Cancer treatment and survivorship statistics， 2019 ［J］. CA Cancer J Clin ， 2019 ， 69 （ 5 ）： 363 - 385 .

李晓彤 . 基于数据挖掘探究李秀荣教授治疗乳腺癌临床用药规律及临证思辨特点［D］. 济南：山东中医药大学， 2019 .

FONTANA RJ ， CIRULLI ET ， GU J ， et al . The role of HLA-A *33：01 in patients with cholestatic hepatitis attributed to terbinafine ［J］. J Hepatol ， 2018 ， 69 （ 6 ）： 13171325 .

NIETO MA ， HUANG RY ， JACKSON RA ， et al . EMT： 2016 ［J］. Cell ， 2016 ， 166 （ 1 ）： 21 - 45 .

李梢 . 网络靶标：中药方剂网络药理学研究的一个切入点［J］. 中国中药杂志， 2011 ， 36 （ 15 ）： 2017 - 2020 .

张晓雨，杨欣宇，张琴，等 . 方证相应理论的系统生物学研究进展［J］. 辽宁中医杂志， 2018 ， 45 （ 6 ）： 1335 - 1337 .

杨美珍，王晓琴，刘勇，等 . 祁州漏芦化学成分与药理活性研究［J］. 中成药， 2015 ， 37 （ 3 ）： 611 - 618 .

缪成贵，徐健，高虎，等 . 禹州漏芦总黄酮抑制佐剂性关节炎大鼠Wnt信号［J］. 中国中药杂志， 2015 ， 40 （ 1 ）： 129 - 133 .

CAO ZQ ， WANG XX ， LU L ， et al . β-sitosterol and gemcitabine exhibit synergistic anti-pancreatic cancer activity by modulating apoptosis and inhibiting epithelial-mesenchymal transition by deactivating Akt/GSK-3β signaling ［J］. Front Pharmacol ， 2019 ， 9 ： 1525 . doi： 10.3389/fphar.2018.01525 http://dx.doi.org/10.3389/fphar.2018.01525 .

BABU S ， JAYARAMAN S . An update on β-sitosterol： a potential herbal nutraceutical for diabetic management ［J］. Biomed Pharmacother ， 2020 ， 131 ： 110702 . doi： 10.1016/j.biopha.2020.110702 http://dx.doi.org/10.1016/j.biopha.2020.110702 .

MSBINSAYEED ， KARIM SMR ， SHARMIN T ， et al . Critical analysis on characterization， systemic effect， and therapeutic potential of beta-sitosterol： a plant-derived orphan phytosterol ［J］. Medicines （Basel）， 2016 ， 3 （ 4 ）： 29 .

AIELLO NM ， KANG Y . Context-dependent EMT programs in cancer metastasis ［J］. J Exp Med ， 2019 ， 216 （ 5 ）： 1016 - 1026 .

CHO ES ， KANG HE ， KIM NH ， et al . Therapeutic implications of cancer epithelial-mesenchymal transition （EMT）［J］. Arch Pharm Res ， 2019 ， 42 （ 1 ）： 14 - 24 .

THIERY JP . Epithelial-mesenchymal transitions in tumour progression ［J］. Nat Rev Cancer ， 2002 ， 2 （ 6 ）： 442 - 454 .

FEARON ER . Cancer： context is key for E-cadherin in invasion and metastasis ［J］. Curr Biol ， 2019 ， 29 （ 21 ）： R1140 - R1142 .

LOH CY ， CHAI JY ， TANG TF ， et al . The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition： signaling， therapeutic implications， and cha-llenges ［J］. Cells ， 2019 ， 8 （ 10 ）： 1118 .

MENDONSA AM ， NA TY ， GUMBINER BM . E-cadherin in contact inhibition and cancer ［J］. Oncogene ， 2018 ， 37 （ 35 ）： 4769 - 4780 .

ZHANG Z ， LIANG Z ， LI D ， et al . Development of a CAFs-related gene signature to predict survival and drug response in bladder cancer ［J］. Hum Cell ， 2022 ， 35 （ 2 ）： 649 - 664 .

DIAO B ， YANG P . Comprehensive analysis of the expression and prognosis for laminin genes in ovarian cancer ［J］. Pathol Oncol Res ， 2021 ， 27 ： 1609855 . doi： 10. 3389/pore.2021.1609855 http://dx.doi.org/10.3389/pore.2021.1609855 .

ZHANG M ， ZENG L ， PENG Y ， et al . Immune-related genes LAMA2 and IL1R1 correlate with tumor sites and predict poor survival in pancreatic adenocarcinoma ［J］. Future Oncol ， 2021 ， 17 （ 23 ）： 3061 - 3076 .

LIANG J ， LI H ， HAN J ， et al . Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway ［J］. Cell Death Dis ， 2020 ， 11 （ 8 ）： 614 .

查看原文

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effects of Modified Ruai Shuhou Formula（乳癌术后方） on Three-year Disease-free Survival Rate in Patients with Triple-Negative Breast Cancer Based on Single-Group Target Value Method

Influence of Serum Containing Stiff Silkworm [Bombyx Batryticatus] on Invasion Ability of Hepatocarcinoma

Effect of Jianpi Xiao’ ai Fang（Spleen-fortifying Cancer-dissolving Decoction,健脾消癌方） on Epithelial-mesenchymal Transition and Transforming Growth Factor-β in Tumor Tissue of Human Colorectal Cancer Xenograft Model in Nude Mice

Effect of Aqueous Extract of Jiedu Sanjie Fang（解毒散结方） on Proliferation,Apoptosis,Migration,Adhesion of A549 Cell

Exploring the Comorbidity Mechanism，Prevention and Treatment Strategies of Rheumatoid Arthritis with Coronary Atherosclerotic Heart Disease Based on Collateral Disease Theory

Related Author

LIU Sheng

QIN Yuenong

CHEN Juan

ZHANG Shuai

XIE Juan

DU Yongping

ZHAO Xingcheng

YAN Yiquan

Related Institution

Longhua Hospital,Shanghai University of Traditional Chinese Medicine

First Affiliated Hospital of the Fourth Military Medical University

Department of Aerospace Medicine,the Fourth Military Medical University

Affiliated Hospital of Hunan Academy of Chinese Medicine

Tumor Institute in Chinese Medicine,Shanghai Institute of Chinese Medicine

Address：No.16, Nanxiao street, Dongzhimen, Dongcheng District, Beijing Postal code：100700
Tel：010-64035632 Email：jtcmcn@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19 京公网安备11010102007558号
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰

Mechanism of Loulu （Radix Rhapontici） Intervention on the Metastasis of Triple-negative Breast Cancer： based on the Integrative Pharmacological Model

DOI：10.13288/j.11-2166/r.2022.14.014

摘要

Abstract

关键词

Keywords

references