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

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Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To study the mechanism of Chinese herbal medicine Fuzheng Kang’ai Formula (扶正抗癌方, 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 (P<0.05). Of the targets, CCNA2 as an important target of FZKA (hazard ratio=1.41, 95% confidential interval: 1.01–2.01, P<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.

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Data Availability Statement

All data was availability from public dataset. Discovery data was used from TCGA database (https://xenabrowser.net/). Validation dataset was used Kmplotter database (http://www.kmplot.com/lung).

References

  1. 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.

    PubMed  Google Scholar 

  2. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 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.

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  PubMed  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Google Scholar 

  24. 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.

  25. 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.

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu G, Wang LG, Han Y, He QY. ClusterProfiler: an r package for comparing biological themes among gene clusters. Omics 2012;16:284–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    CAS  Google Scholar 

  34. 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.

    Article  Google Scholar 

  35. 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.

    Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  Google Scholar 

  41. 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.

    Article  Google Scholar 

  42. 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.

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, the First Hospital of Lanzhou University, Lanzhou, 730000, China

    Yun-ling Tian, Song-bo Fu, Bo Li & Ling-yan Yuan

  2. Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou, 730000, China

    Zhi-tong Bing

  3. Department of Computational Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China

    Zhi-tong Bing

  4. School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, 100049, China

    Zhi-tong Bing

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  1. Yun-ling Tian
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Contributions

Conceptualization: Tian YL and Bing ZT; methodology: Yuan LY and Fu SB; software: Li B; validation: Li B Fu SB and Yuan LY; formal analysis: Tian YL; investigation: LI B and Tian YL; resources: Tian YL; data curation: Tian YL; writing-original draft preparation, Tian YL and Fu SB; writing-review and editing: Bing ZT; visualization: Yuan LY; supervision: Tian Y; project administration: Tian YL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yun-ling Tian.

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Conflict of Interest

The authors declare no conflict of interest.

Supported by the Special Funds of Science and Technology Development of the Chinese Central Government to Guide Local in 2020 (No. 21JR1RA066, 20JR10FA667) and Hospital Fund of the First Hospital of Lanzhou University (No. ldyyyn2007-03)

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Tian, Yl., Fu, Sb., Li, B. et al. Mechanism of Fuzheng Kang’ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer. Chin. J. Integr. Med. 28, 425–433 (2022). https://doi.org/10.1007/s11655-021-3451-1

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