Evaluation of Therapeutic Mechanism of Hedyotis Diffusa Willd (HDW)‒ Scutellaria Barbata (SB) in Clear Cell Renal Cell Carcinoma via Singlecell RNA Sequencing and Network Pharmacology


Cite item

Full Text

Abstract

Objective:The present study aimed to investigate the therapeutic mechanism of Hedyotis diffusa Willd (HDW) and Scutellaria barbata (SB) in ccRCC using a combination of single-cell RNA sequencing (scRNA-seq) and network pharmacology.

Methods:The active ingredients and potential molecular targets of HDW-SB were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Gene expression data (GSE53757) were obtained from the Gene Expression Omnibus database. The hub genes of HDW-SB against ccRCC were identified via the protein–protein interaction network, and further analyzed by molecular complex detection. The roles of these genes in the diagnosis and immune infiltration of ccRCC were analyzed. The clinical significance of hub genes was verified using scRNA-seq data (GSE121638) and molecular docking.

Results:Following the PPI network analysis, 29 hub genes of HDW-SB against ccRCC were identified. All hub genes, except for CENPE, had significantly different expressions in tumor tissue and a more accurate diagnosis of ccRCC. Fifteen cell clusters were defined based on the scRNA-seq dataset, and the clusters were annotated as six cell types using marker genes. TYMS and KIAA0101 from hub genes were highly expressed in NK cells. Three active compounds, quercetin, luteolin, and baicalein, were found to target TYMS and KIAA0101 from the compound-target interaction network.

Conclusion:29 hub genes of HDW-SB against ccRCC were identified and showed good performance in terms of diagnosis and prognosis. Moreover, among these hub genes docking with the main ingredients of HDW-SB, TYMS and KIAA0101 exerted anti-ccRCC effects through NK cells.

About the authors

Yangyang Bai

Department of Urology, Henan Province Hospital of TCM, The Second Affiliated Hospital of Henan University of Chinese Medicine

Email: info@benthamscience.net

Ruiting Chen

Department of Urology, Henan Province Hospital of TCM, The Second Affiliated Hospital of Henan University of Chinese Medicine

Email: info@benthamscience.net

Jijian Sun

Department of Urology, Henan Province Hospital of TCM, The Second Affiliated Hospital of Henan University of Chinese Medicine

Email: info@benthamscience.net

Yilin Guo

Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Zhengzhou University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Escudier, B.; Porta, C.; Schmidinger, M.; Rioux-Leclercq, N.; Bex, A.; Khoo, V.; Grünwald, V.; Gillessen, S.; Horwich, A. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2019, 30(5), 706-720. doi: 10.1093/annonc/mdz056 PMID: 30788497
  3. Makhov, P.; Joshi, S.; Ghatalia, P.; Kutikov, A.; Uzzo, R.G.; Kolenko, V.M. Resistance to systemic therapies in clear cell renal cell carcinoma: Mechanisms and management strategies. Mol. Cancer Ther., 2018, 17(7), 1355-1364. doi: 10.1158/1535-7163.MCT-17-1299 PMID: 29967214
  4. Tao, W.; Luo, X.; Cui, B.; Liang, D.; Wang, C.; Duan, Y.; Li, X.; Zhou, S.; Zhao, M.; Li, Y.; He, Y.; Wang, S.; Kelley, K.W.; Jiang, P.; Liu, Q. Practice of traditional Chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: A systematic review and meta-analysis. Oncotarget, 2015, 6(37), 39725-39739. doi: 10.18632/oncotarget.5388 PMID: 26498685
  5. Lin, L.; Cheng, K.; Xie, Z.; Chen, C.; Chen, L.; Huang, Y.; Liang, Z. Purification and characterization a polysaccharide from Hedyotis diffusa and its apoptosis inducing activity toward human lung cancer cell line A549. Int. J. Biol. Macromol., 2019, 122, 64-71. doi: 10.1016/j.ijbiomac.2018.10.077 PMID: 30342944
  6. Kuo, Y.J.; Yang, J.S.; Lu, C.C.; Chiang, S.; Lin, J.G.; Chung, J.G. Ethanol extract of Hedyotis diffusa willd upregulates G0/G1 phase arrest and induces apoptosis in human leukemia cells by modulating caspase cascade signaling and altering associated genes expression was assayed by cDNA microarray. Environ. Toxicol., 2015, 30(10), 1162-1177. doi: 10.1002/tox.21989 PMID: 24677778
  7. Zhang, P.; Zhang, B.; Gu, J.; Hao, L.; Hu, F.; Han, C. The study of the effect of hedyotis diffusa on the proliferation and the apoptosis of the cervical tumor in nude mouse model. Cell Biochem. Biophys., 2015, 72(3), 783-789. doi: 10.1007/s12013-015-0532-9 PMID: 25677988
  8. Su, X.; Li, Y.; Jiang, M.; Zhu, J.; Zheng, C.; Chen, X.; Zhou, J.; Li, Y.; Xiao, W.; Wang, Y. Systems pharmacology uncover the mechanism of anti-non-small cell lung cancer for Hedyotis diffusa Willd. Biomed. Pharmacother., 2019, 109, 969-984. doi: 10.1016/j.biopha.2018.10.162 PMID: 30551551
  9. Sun, P.; Sun, D.; Wang, X. Effects of Scutellaria barbata polysaccharide on the proliferation, apoptosis and EMT of human colon cancer HT29 Cells. Carbohydr. Polym., 2017, 167, 90-96. doi: 10.1016/j.carbpol.2017.03.022 PMID: 28433181
  10. Lin, J.; Feng, J.; Yang, H.; Yan, Z.; Li, Q.; Wei, L.; Lai, Z.; Jin, Y.; Peng, J. Scutellaria barbata D. Don inhibits 5-fluorouracil resistance in colorectal cancer by regulating PI3K/AKT pathway. Oncol. Rep., 2017, 38(4), 2293-2300. doi: 10.3892/or.2017.5892 PMID: 28849113
  11. Kan, X.; Zhang, W.; You, R.; Niu, Y.; Guo, J.; Xue, J. Scutellaria barbata D. Don extract inhibits the tumor growth through down-regulating of Treg cells and manipulating Th1/Th17 immune response in hepatoma H22-bearing mice. BMC Complement. Altern. Med., 2017, 17(1), 41. doi: 10.1186/s12906-016-1551-9 PMID: 28086772
  12. Xu, Y.; Chen, X.X.; Jiang, Y.X.; Zhang, D.D. Ethyl acetate fraction from hedyotis diffusa plus scutellaria barbata exerts anti-inflammatory effects by regulating miR-155 expression and JNK signaling pathway. Evid. Based Complement. Altern. Med., 2018, 2018, 3593408. doi: 10.1155/2018/3593408 PMID: 29725352
  13. Xu, X.; Chen, F.; Zhang, L.; Liu, L.; Zhang, C.; Zhang, Z.; Li, W. Exploring the mechanisms of anti-ovarian cancer of Hedyotis diffusa Willd and Scutellaria barbata D. Don through focal adhesion pathway. J. Ethnopharmacol., 2021, 279, 114343. doi: 10.1016/j.jep.2021.114343 PMID: 34147618
  14. Wang, X.; Shen, Y.; Wang, S.; Li, S.; Zhang, W.; Liu, X.; Lai, L.; Pei, J.; Li, H. PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res., 2017, 45(W1), W356-W360. doi: 10.1093/nar/gkx374 PMID: 28472422
  15. Liu, W.; Xu, W.; Li, C.; Xu, J.; Huang, K.; Hu, R.; Huang, H.; Liu, X. Network pharmacological systems study of Huang-Lian-Tang in the treatment of glioblastoma multiforme. Oncol. Lett., 2021, 21(1), 18. PMID: 33240424
  16. Wesołowski, W.; Szklarczyk, M.; Szalonek, M.; Słowińska, J. Analysis of the mitochondrial proteome in cytoplasmic male-sterile and male-fertile beets. J. Proteomics, 2015, 119, 61-74. doi: 10.1016/j.jprot.2014.12.013 PMID: 25573812
  17. Bader, G.D.; Hogue, C.W.V. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics, 2003, 4(1), 2. doi: 10.1186/1471-2105-4-2 PMID: 12525261
  18. Liu, Y.; Lv, H.; Li, X.; Liu, J.; Chen, S.; Chen, Y.; Jin, Y.; An, R.; Yu, S.; Wang, Z. Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway. Int. J. Biol. Sci., 2021, 17(13), 3522-3537. doi: 10.7150/ijbs.62114 PMID: 34512163
  19. Teekaraman, D.; Elayapillai, S.P.; Viswanathan, M.P.; Jagadeesan, A. Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line. Chem. Biol. Interact., 2019, 300, 91-100. doi: 10.1016/j.cbi.2019.01.008 PMID: 30639267
  20. Liu, H.; Zeng, Z.; Wang, S.; Li, T.; Mastriani, E.; Li, Q.H.; Bao, H.X.; Zhou, Y.J.; Wang, X.; Liu, Y.; Liu, W.; Hu, S.; Gao, S.; Yu, M.; Qi, Y.; Shen, Z.; Wang, H.; Gao, T.; Dong, L.; Johnston, R.N.; Liu, S.L. Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol. Ther., 2017, 18(12), 990-999. doi: 10.1080/15384047.2017.1394542 PMID: 29173024
  21. Lv, Y.X.; Pan, H.R.; Song, X.Y.; Chang, Q.Q.; Zhang, D.D. Hedyotis diffusa plus scutellaria barbata suppress the growth of non-small-cell lung cancer via NLRP3/NF- κ B/MAPK signaling pathways. Evid. Based Complement. Alternat. Med., 2021, 2021, 1-8. doi: 10.1155/2021/6666499 PMID: 34239588
  22. Ma, T.T.; Zhang, G.L.; Dai, C.F.; Zhang, B.R.; Cao, K.X.; Wang, C.G.; Yang, G.W.; Wang, X.M. Scutellaria barbata and Hedyotis diffusa herb pair for breast cancer treatment: Potential mechanism based on network pharmacology. J. Ethnopharmacol., 2020, 259, 112929. doi: 10.1016/j.jep.2020.112929 PMID: 32416245
  23. Xiao, G.F.; Yan, X.; Chen, Z.; Zhang, R.J.; Liu, T.Z.; Hu, W.L. Identification of a novel immune-related prognostic biomarker and small-molecule drugs in Clear Cell Renal Cell Carcinoma (ccRCC) by a merged microarray-acquired dataset and TCGA database. Front. Genet., 2020, 11, 810. doi: 10.3389/fgene.2020.00810 PMID: 33014010
  24. Chen, J.; Li, Z.; Chen, A.; Ye, X.; Luo, H.; Rankin, G.; Chen, Y. Inhibitory effect of baicalin and baicalein on ovarian cancer cells. Int. J. Mol. Sci., 2013, 14(3), 6012-6025. doi: 10.3390/ijms14036012 PMID: 23502466
  25. Liu, Z.; Sun, T.; Piao, C.; Zhang, Z.; Kong, C. METTL13 inhibits progression of clear cell renal cell carcinoma with repression on PI3K/AKT/mTOR/HIF-1α pathway and c-Myc expression. J. Transl. Med., 2021, 19(1), 209. doi: 10.1186/s12967-021-02879-2 PMID: 33985542
  26. Mizumoto, A.; Yamamoto, K.; Nakayama, Y.; Takara, K.; Nakagawa, T.; Hirano, T.; Hirai, M. Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to sunitinib resistance in human renal cell carcinoma cell lines. J. Pharmacol. Exp. Ther., 2015, 355(2), 152-158. doi: 10.1124/jpet.115.226639 PMID: 26306766
  27. Reyes-Farias, M.; Carrasco-Pozo, C. The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int. J. Mol. Sci., 2019, 20(13), 3177. doi: 10.3390/ijms20133177 PMID: 31261749
  28. Han, S.; Lin, F.; Qi, Y.; Liu, C.; Zhou, L.; Xia, Y.; Chen, K.; Xing, J.; Liu, Z.; Yu, W.; Zhang, Y.; Zhou, X.; Rao, T.; Cheng, F. HO-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation. Oxid. Med. Cell. Longev., 2022, 2022, 3846217. doi: 10.1155/2022/3846217 PMID: 35656025
  29. Rahmani, A.H.; Almatroudi, A.; Khan, A.A.; Babiker, A.Y.; Alanezi, M.; Allemailem, K.S. The multifaceted role of baicalein in cancer management through modulation of cell signalling pathways. Molecules, 2022, 27(22), 8023. doi: 10.3390/molecules27228023 PMID: 36432119
  30. Varghese, V.; Magnani, L.; Harada-Shoji, N.; Mauri, F.; Szydlo, R.M.; Yao, S.; Lam, E.W.F.; Kenny, L.M. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Sci. Rep., 2019, 9(1), 1505. doi: 10.1038/s41598-018-38017-0 PMID: 30728402
  31. Shichijo, S.; Azuma, K.; Komatsu, N.; Ito, M.; Maeda, Y.; Ishihara, Y.; Itoh, K. Two proliferation-related proteins, TYMS and PGK1, could be new cytotoxic T lymphocyte-directed tumor-associated antigens of HLA-A2+ colon cancer. Clin. Cancer Res., 2004, 10(17), 5828-5836. doi: 10.1158/1078-0432.CCR-04-0350 PMID: 15355913
  32. Yuan, R.H.; Jeng, Y.M.; Pan, H.W.; Hu, F.C.; Lai, P.L.; Lee, P.H.; Hsu, H.C. Overexpression of KIAA0101 predicts high stage, early tumor recurrence, and poor prognosis of hepatocellular carcinoma. Clin. Cancer Res., 2007, 13(18), 5368-5376. doi: 10.1158/1078-0432.CCR-07-1113 PMID: 17875765
  33. Sun, T.; An, Q.; Yan, R.; Li, K.; Zhu, K.; Dang, C.; Yuan, D. MicroRNA 216a 5p suppresses esophageal squamous cell carcinoma progression by targeting KIAA0101. Oncol. Rep., 2020, 44(5), 1971-1984. doi: 10.3892/or.2020.7751 PMID: 32901882

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers