Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer

Yun-ling TIAN; Song-bo FU; Bo LI; Ling-yan YUAN; Zhi-tong BING

doi:10.1007/s11655-021-3451-1

Your Location：

Home >

Browse articles >

Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer

Original Article | Updated：2022-06-27

- Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer
- Chinese Journal of Integrative Medicine Vol. 28, Issue 5, Pages: 425-433(2022)
- Affiliations：
  
  1.Department of Endocrinology and Metabolism, the First Hospital of Lanzhou University, Lanzhou (730000), China
  2.Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou (730000), China
  3.Department of Computational Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou (730000), China
  4.School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing (100049), China
- Author bio：
  
  Dr. TIAN Yun-ling, E-mail: yunlingtian7318@126.com
- Funds：
- DOI：10.1007/s11655-021-3451-1
  CLC：
- Published：01 May 2022，
  
  Published Online：21 September 2021，
  
  Accepted：09 April 2021
Scan for full text
Yun-ling TIAN, Song-bo FU, Bo LI, et al. Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer. [J]. Chinese Journal of Integrative Medicine 28(5):425-433(2022)
DOI：

Yun-ling TIAN, Song-bo FU, Bo LI, et al. Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer. [J]. Chinese Journal of Integrative Medicine 28(5):425-433(2022) DOI： 10.1007/s11655-021-3451-1.

摘要

目的:

研究中医药方剂扶正抗癌在肿瘤微环境中的调节机制.

方法:

本研究使用CIBERSORTx软件工具通过转录组数据分析肿瘤微环境. 中医药系统药学和分析平台 (TCMSP) 用于得到中医药成分和目标靶点的相互作用网络. 并使用癌症基因组图谱工具 (TCGA) 分析非小细胞肺癌与癌旁组织之间的差异基因. 此外

具有预后指示功能的差异基因通过单变量和多变量的Cox回归进行分析

与预后具有显著相关性的基因作为核心靶点. 使用扶正抗癌方的核心靶点结合肺腺癌肿瘤微环境进行相关性分析. 蛋白质相互作用数据库用于预测核心靶点下游基因

这些靶点是药物发挥作用的直接反应. 定量聚合酶链式反应的生物实验用于A549

H1299和PC9细胞系验证表达量

对于药物直接作用靶点以及靶点下游基因进行表达量的验证.

结果:

肿瘤微环境结果显示

活化的肥大细胞与非小细胞肺癌患者的预后具有显著性的关联(

0.05)

活化的肥大细胞分数高的显示预后越差. 在扶正抗癌方的靶点中

CCNA2是一个重要的的靶点 (风险率 (HR) =1.41

0.05) . CCNA2不仅是一个非小细胞肺癌的具有差异表达的预后基因

同时也与活化的肥大细胞具有显著的正相关性. CCNA2的下游基因包括BCL1L2、ACTL6A和ITGAV三个下游靶点

并通过A549验证这三个下游基因在扶正抗癌方的影响下表达变化情况.

结论:

扶正抗癌能够直接结合在CCNA2上并且通过调节下游基因来抑制肿瘤生长. 并且和肿瘤生长的相关肿瘤微环境紧密的与CCNA2相关.

Abstract

Objective:

To study the mechanism of Chinese herbal medicine Fuzheng Kang'ai Formula (FZKA) on tumor microenvironment (TME).

Methods:

CIBERSORTx was used for analysis of TME. Traditional Chinese Medicine Systems Pharmacology and Analysis Platform was applied to identify compounds-targets network and the Cancer Genome Atlas (TCGA) was employed to identify the differential expression genes (DEGs) between tumor and paracancerous tissues in lung adenocarcinoma (LUAD) from TCGA-LUAD. Additionally

DEGs with prognosis in LUAD was calculated by univariable and multivariate Cox regression. The core targets of FZKA were analyzed in lung adenocarcinoma TME. Protein-protein interaction database was employed to predict down-stream of target. Quantitative reverse transcription polymerase chain reaction was employed for biological experiment in A549

H1299 and PC9 cell lines.

Results:

The active and resting mast cells were significantly associated with prognosis of LUAD (

0.05). Of the targets

CCNA2 as an important target of FZKA (hazard ratio=1.41

95% confidential interval: 1.01–2.01

0.05) was a prognostic target and significantly associated with mast cells. CCNA2 was positively correlated with mast cell activation and negatively correlated with mast cell resting state. BCL1L2

ACTL6A and ITGAV were down-stream of CCNA2

which were validated by qRT-PCR in A549 cell.

Conclusion:

FZKA could directly bind to CCNA2 and inhibit tumor growth by regulating CCNA2 downstream genes and TME of NSCLC closely related to CCNA2.

关键词

Keywords

network pharmacologyprognosistumor microenvironmentFuzheng Kang'ai FormulaChinese medicinelung adenocarcinoma

references

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA,Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 2018;68:394-424.

Meza R, Meernik C, Jeon J, Cote ML. Lung cancer incidence trends by gender, race and histology in the United States, 1973–2010. PLoS One 2015;10:e0121323.

Sechler M, Cizmic AD, Avasarala S, Van Scoyk M,Brzezinski C, Kelley N, et al. Non-small-cell lung cancer: molecular targeted therapy and personalized medicine—drug resistance, mechanisms, and strategies.Pharmacogenomics Pers Med 2013;6:25-36.

Coussens LM, Laurence Z, P A Karolina. Neutralizing tumor-promoting chronic inflammation: a magic bullet?Science 2013;339:286-291.

Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol 2013;33:S79-S84.

Liu XS, Mardis ER. Applications of immunogenomics to cancer. Cell 2017;168:600-612.

Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nature Methods 2015;12:453-457.

Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nature Rev Cancer 2011;11:805-812.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev Cancer 2012;12:252-264.

Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US,White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma.Clin Cancer Res 2012;18:2039-2047.

Li L, Tian J, Tian H, Moher D, Liang F, Jiang T, et al.Network meta-analyses could be improved by searching more sources and by involving a librarian. J Clin Epidemiol 2014;67:1001-1007.

Norris SL, Meerpohl JJ, Akl EA, Schünemann HJ,Gartlehner G, Chen Y, et al. The skills and experience of GRADE methodologists can be assessed with a simple tool. J Clin Epidemiol 2016;79:150-158.

Tian J, Zhang J, Ge L, Yang K, Song F. The methodological and reporting quality of systematic reviews from China and the USA are similar. J Clin Epidemiol 2017;85:S0895435616308162.

Liu TG, Xiong SQ, Yan Y, Zhu H, Yi C. Use of Chinese herb medicine in cancer patients: a survey in southwestern China. Evid Based Complement Alternat Med 2012;2012:769042.

Keerthana K, Steptoe AL, Martin HC, Wani S, Nones K,Waddell N, et al. MicroRNA-182-5p targets a network of genes involved in DNA repair. RNA 2013;19:230-242.

Han Y, Wang H, Xu W, Cao B, Han L, Jia L, et al. Chinese herbal medicine as maintenance therapy for improving the quality of life for advanced non-small cell lung cancer patients. Complement Ther Med 2016;24:81-89.

Wu WY, Yang XB, Deng H, Long SQ, Sun LS, He WF, et al. Treatment of advanced non-small cell lung cancer with extracorporeal high frequency thermotherapy combined with Chinese medicine. Chin J Integr Med 2010;16:406-410.

Yang XB, Wu WY, Long SQ, Deng H, Pan ZQ, He WF,et al. Fuzheng Kang'ai Decoction combined with gefitinib in advanced non-small cell lung cancer patients with epidermal growth factor receptor mutations: study protocol for a randomized controlled trial. Trials 2015;16:146.

Yang XB, Chai XS, Wu WY, Long SQ, Deng H, Pan ZQ, et al. Gefitinib plus Fuzheng Kang'ai Formula in patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutation: a randomized controlled trial. Chin J Integr Med 2018;24:734-740.

Bing ZT, Cheng ZY, Shi DF, Liu XK, Tian JH, Yao XJ,et al. Investigate the mechanisms of Chinese medicine Fuzhengkangai towards EGFR mutation-positive lung adenocarcinomas by network pharmacology. BMC Complement Alternat Med 2018;18:293.

Yang XB, Wu WY, Long SQ, Deng H, Pan ZQ. Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: a retrospective case-control study. Complement Ther Med 2014;22:1010-1018.

Ru J, Peng L, Wang J, Zhou W, Li B, Huang C, et al.TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminf 2014;6:13.

Xia W, Xue X, Yan L, Li X, Tao W, Li B, et al. Systems pharmacology uncovers Janus functions of botanical drugs:activation of host defense system and inhibition of influenza virus replication. Integr Biol 2013:2:351-371.

Zheng C, Pei T, Huang C, Chen X, Bai Y, Xue J, et al. A novel systems pharmacology platform to dissect action mechanisms of traditional Chinese medicines for bovine viral diarrhea disease. Eur J Pharm Sci 2016:33-45.

Liu JL, Pei TL, Mu JX, Zheng CL, Chen XT, Huang C, et al.Systems pharmacology uncovers the multiple mechanisms of Xijiao Dihuang Decoction for the treatment of viral hemorrhagic fever. Evid Based Complement Alternat Med 2016;2016:1-17.

Shannon P. Cytoscape: a software environment for integrated models of biomolecular interaction networks.Genome Res 2003;13:2498.

Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics 2012;16:284-287.

Love MI, Wolfgang H, Simon A. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genom Biol 2014;15:550.

Rohr-Udilova N, Klinglmuller F, Schulte-Hermann R, Stift J, Herac M, Salzmann M, et al. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep 2018;8:6220.

Győrffy B, Surowiak P, Budczies J, Lánczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 2013;8:e82241.

Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010;38:W214-W220.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S,Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.Nucleic Acids Res 2019;47:D607-D613.

Chan A, Tan HL, Ching TH, Tan HC. Clinical outcomes for cancer patients using complementary and alternative medicine. Alternat Ther Health Med 2012;18:12-17.

Chen Z, Gu K, Zheng Y, Zheng W, Lu W, Shu XO. The use of complementary and alternative medicine among Chinese women with breast cancer. J Alternat Complement Med 2008;14:1049.

Teng L, Jin K, He K, Bian C, Chen W, Fu K, et al. Use of complementary and alternative medicine by cancer patients at Zhejiang University Teaching Hospital Zhuji Hospital,China. Afr J Tradit Complement Alternat Med 2010;7:322.

Li L, Liu YD, Zhan YT, Zhu YH, Li Y, Xie D, et al. High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma.Thoracic Cancer 2018;9:775-784.

Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis. Cytokine 2017;89:127-135.

Wang RF. Regulatory T cells and innate immune regulation in tumor immunity. Springer Semin Immunopathol 2006;28:77.

Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z,et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 2001;108:1151.

Theoharides TC, Kempuraj D, Tagen M, Conti P,Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 2010;217:65-78.

Imada A, Shijubo N, Kojima H, Abe S. Mast cells correlate with angiogenesis and poor outcome in stage Ⅰ lung adenocarcinoma. Eur Resp J 2010;15:1087-1093.

Xiao H, Lässer C, Shelke GV, Wang J, Rådinger M,Lunavat TR, et al. Mast cell exosomes promote lung adenocarcinoma cell proliferation—role of KIT-stem cell factor signaling. Cell Commun Signal 2014;12:1-10.

Hanahan D, Coussens LM. Accessories to the crime:functions of cells recruited to the tumor microenvironment.Cancer Cell 2012;21:309-322.

Visciano C, Liotti F, Prevete N, Cali' G, Franco R, Collina F,et al. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway. Oncogene 2015;34:5175-5186.

Showe MK, Kossenkov AV, Showe LC. The peripheral immune response and lung cancer prognosis.Oncoimmunology 2012;1:1414-1416.

Ni M, Liu X, Wu J, Zhang D, Tian J, Wang T, et al.Identification of candidate biomarkers correlated with the pathogenesis and prognosis of non-small cell lung cancer via integrated bioinformatics analysis. Front Genet 2018;9:469.

Giannou AD, Marazioti A, Spella M, Kanellakis NI,Apostolopoulou H, Psallidas I, et al. Mast cells mediate malignant pleural effusion formation. J Clin Invest 2015;125:2317-2334.

Marazioti A, Lilis I, Vreka M, Apostolopoulou H,Kalogeropoulou A, Giopanou I, et al. Myeloid-derived interleukin-1β drives oncogenic KRAS -NF-κΒ addiction in malignant pleural effusion. Nature Commun 2018;9:672.

More>

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Safflower Yellow Inhibits Progression of Hepatocellular Carcinoma by Modulating Immunological Tolerance via FAK Pathway

Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice

Monotropein Induced Apoptosis and Suppressed Cell Cycle Progression in Colorectal Cancer Cells

Therapeutic Mechanism of Kai Xin San on Alzheimer's Disease Based on Network Pharmacology and Experimental Validation

Chinese Medicine as Supporting Therapy for Psoriasis:Past, Present, and Future

Related Author

No data

Related Institution

Department of General Surgery, First People's Hospital of Hangzhou Lin'an District

Institute of Chinese Medicine, The Chinese University of Hong Kong

State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong

Department of Chemical Pathology, The Chinese University of Hong Kong

Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University

Address：1 Caochang, xiyuan, Beijing, People's Republic of China Postal code：100091
Tel：010-62886827, 62877592 Fax：010-62874291
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备05067934号-1 京公网安备11010802024621
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