Skip to content
2000
Volume 31, Issue 25
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Background

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, is a significant global health issue. Despite advancements in surgery and systemic therapies, drug resistance remains a challenge, and more effective treatments are needed. Scutellarin, a natural flavonoid with anticancer properties, is a promising therapeutic option for ccRCC.

Methods

This present study identified the potential target genes of scutellarin by searching four databases and utilized the TCGA-KIRC and GSE53757 datasets to identify ccRCC features genes. Protein-protein interaction networks and molecular complex detection analyses determined the hub genes through which scutellarin acts on ccRCC. Differential expression, receiver operating characteristic analysis, survival, and immune cell infiltration analyses were conducted successively on these hub genes in tumor and normal tissues to verify their clinical significance. The intracellular mechanism of the hub genes was explored using a single-cell dataset (GSE222703) to elucidate the intracellular pathway through which scutellarin exerts its anti-ccRCC effects. At last, molecular docking and molecular dynamics simulations were performed to confirm the stability of the receptor protein of the hub gene binding to scutellarin.

Results

158 scutellarin targets were collected and identified through database searches. Analyzing the TCGA-KIRC and GSE53757 datasets separately identified finally 132 ccRCC feature genes through differential expression analysis and WGCNA. Protein-protein interaction network and molecular complex detection analyses revealed 26 hub genes potentially involved in key pathways of scutellarin in ccRCC. Differential expression analysis revealed significant differences in the expression of these hub genes between tumor and normal tissues. Receiver operating characteristic analysis demonstrated the fine diagnostic efficacy of these hub genes. Survival analysis indicated that the hub genes TYMS and CDCA2 were associated with a better prognosis, whereas the remaining hub genes had a poorer prognosis. Enrichment analysis revealed that hub genes mainly involved oxidative stress and cell cycle regulation. Single-cell RNA sequencing analysis suggested that most hub genes exert their effects on T helper cells. Molecular docking results showed stable docking of hub genes with scutellarin, except for SPAG5 and ASPM. Molecular dynamics simulations of the most stable docking sites, KIF20A, TYMS, and KIF18B, indicated stable complex formation compared with that of the internal reference protein GAPDH.

Conclusion

This integrated study provides a comprehensive analysis of the molecular targets and pathways affected by scutellarin in ccRCC. The identified hub genes and their related pathways present exciting prospects for therapeutic intervention and highlight the potential of scutellarin as a novel treatment for ccRCC. Additional research is necessary to investigate the precise molecular mechanisms and therapeutic advantages of scutellarin in preclinical and clinical contexts.

Loading

Article metrics loading...

/content/journals/cpd/10.2174/0113816128340451241224055536
2025-04-22
2025-10-23
Loading full text...

Full text loading...

References

  1. SiegelR.L. GiaquintoA.N. JemalA. Cancer statistics, 2024.CA Cancer J. Clin.2024741124910.3322/caac.21820 38230766
    [Google Scholar]
  2. EscudierB. PortaC. SchmidingerM. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann. Oncol.201930570672010.1093/annonc/mdz056 30788497
    [Google Scholar]
  3. MakhovP. JoshiS. GhataliaP. KutikovA. UzzoR.G. KolenkoV.M. Resistance to systemic therapies in clear cell renal cell carcinoma: Mechanisms and management strategies.Mol. Cancer Ther.20181771355136410.1158/1535‑7163.MCT‑17‑1299 29967214
    [Google Scholar]
  4. MoJ. YangR. LiF. Scutellarin protects against vascular endothelial dysfunction and prevents atherosclerosis via antioxidation.Phytomedicine201842667410.1016/j.phymed.2018.03.021
    [Google Scholar]
  5. WangL. MaQ. Clinical benefits and pharmacology of scutellarin: A comprehensive review.Pharmacol. Ther.201819010512710.1016/j.pharmthera.2018.05.006
    [Google Scholar]
  6. PengL. WenL. ShiQ.F. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation.Cell Death Dis.2020111197810.1038/s41419‑020‑03178‑2 33188176
    [Google Scholar]
  7. LvW.L. LiuQ. AnJ.H. SongX.Y. Scutellarin inhibits hypoxia-induced epithelial-mesenchymal transition in bladder cancer cells.J. Cell. Physiol.201923412231692317510.1002/jcp.28883 31127618
    [Google Scholar]
  8. DengW. HanW. FanT. Scutellarin inhibits human renal cancer cell proliferation and migration via upregulation of pten.Biomed. Pharmacother.20181071505151310.1016/j.biopha.2018.08.127
    [Google Scholar]
  9. LiH. HuangD. GaoZ. Scutellarin inhibits cell migration by regulating production of αvβ6 integrin and E-cadherin in human tongue cancer cells.Oncol. Rep.201024511531160 20878105
    [Google Scholar]
  10. HuX. ZhouM. HuX. ZengF. Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion.Acta Pharmacol. Sin.200526121454145910.1111/j.1745‑7254.2005.00239.x 16297343
    [Google Scholar]
  11. CuiZ. LiC. LiuW. Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression.Cell Death Dis.202415426710.1038/s41419‑024‑06625‑6 38622131
    [Google Scholar]
  12. BaiY. ChenR. SunJ. GuoY. Evaluation of therapeutic mechanism of hedyotis diffusa willd (hdw)- Scutellaria barbata (sb) in clear cell renal cell carcinoma via single-cell RNA sequencing and network pharmacology.Comb. Chem. High Throughput Screen.202427691092110.2174/1386207326666230731155309 37526191
    [Google Scholar]
  13. ZhangY. WangD. PengM. Single-cell RNA sequencing in cancer research.J. Exp. Clin. Cancer Res.20214018110.1186/s13046‑021‑01874‑1 33648534
    [Google Scholar]
  14. HopkinsA.L. Network pharmacology: The next paradigm in drug discovery.Nat. Chem. Biol.200841168269010.1038/nchembio.118 18936753
    [Google Scholar]
  15. MorrisG.M. Lim-WilbyM. Molecular docking.Methods Mol. Biol.200844336538210.1007/978‑1‑59745‑177‑2_19
    [Google Scholar]
  16. DavisA.P. GrondinC.J. JohnsonR.J. Comparative toxicogenomics database (CTD): Update 2021.Nucleic Acids Res.202149D1D1138D114310.1093/nar/gkaa891 33068428
    [Google Scholar]
  17. DainaA. MichielinO. ZoeteV. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules.Nucleic Acids Res.201947W1W357-6410.1093/nar/gkz382 31106366
    [Google Scholar]
  18. LiuT LinY WenX JorissenRN GilsonMK BindingDB: A web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res200735DatabaseD19820110.1093/nar/gkl99917145705
    [Google Scholar]
  19. YaoZ.J. DongJ. CheY.J. TargetNet: A web service for predicting potential drug-target interaction profiling via multi-target SAR models.J. Comput. Aided Mol. Des.201630541342410.1007/s10822‑016‑9915‑2 27167132
    [Google Scholar]
  20. BlumA. WangP. ZenklusenJ.C. SnapShot: TCGA-analyzed tumors.Cell2018173253010.1016/j.cell.2018.03.059 29625059
    [Google Scholar]
  21. von RoemelingC.A. RadiskyD.C. MarlowL.A. Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4.Cancer Res.201474174796481010.1158/0008‑5472.CAN‑14‑0210 24962026
    [Google Scholar]
  22. Massenet-RegadL. PoirotJ. JacksonM. Large-scale analysis of cell-cell communication reveals angiogenin-dependent tumor progression in clear cell renal cell carcinoma.iScience2023261210836710.1016/j.isci.2023.108367 38025776
    [Google Scholar]
  23. GuT. ZhongY. LuY.T. Synthesis and bioactivity characterization of scutellarein sulfonated derivative.Molecules2017226102810.3390/molecules22061028 28635646
    [Google Scholar]
  24. ZengS. ChenL. SunQ. Scutellarin ameliorates colitis-associated colorectal cancer by suppressing wnt/β-catenin signaling cascade.Eur. J. Pharmacol.2021906174253
    [Google Scholar]
  25. LiuF. ZuX. XieX. Scutellarin suppresses patient-derived xenograft tumor growth by directly targeting akt in esophageal squamous cell carcinoma.Cancer Prev. Res. (Phila.)2019121284986010.1158/1940‑6207.CAPR‑19‑0244 31554627
    [Google Scholar]
  26. SunC.Y. ZhuY. LiX.F. Scutellarin increases cisplatin-induced apoptosis and autophagy to overcome cisplatin resistance in non-small cell lung cancer via erk/p53 and c-met/akt signaling pathways.Front. Pharmacol.2018993
    [Google Scholar]
  27. ZhangL. MengX. JuX. One-carbon metabolism pathway gene variants and risk of clear cell renal cell carcinoma in a Chinese population.PLoS One2013811e8112910.1371/journal.pone.0081129 24278388
    [Google Scholar]
  28. ColavitoD. CarteiG. Dal BiancoM. Thymidylate synthetase allelic imbalance in clear cell renal carcinoma.Cancer Chemother. Pharmacol.20096461195120010.1007/s00280‑009‑0986‑9 19306093
    [Google Scholar]
  29. ZhouJ. YangZ. WuX. ZhangJ. ZhaiW. ChenY. Identification of genes that correlate clear cell renal cell carcinoma and obesity and exhibit potential prognostic value.Transl. Androl. Urol.202110268069110.21037/tau‑20‑891 33718070
    [Google Scholar]
  30. LinY.C. ChangY.T. CampbellM. Maoa-a novel decision maker of apoptosis and autophagy in hormone refractory neuroendocrine prostate cancer cells.Sci. Rep.201774633810.1038/srep46338
    [Google Scholar]
  31. GaoX. BuH. GaoX. WangY. WangL. ZhangZ. Pan-cancer analysis: SPAG5 is an immunological and prognostic biomarker for multiple cancers.FASEB J.20233710e2315910.1096/fj.202300626R 37650687
    [Google Scholar]
  32. RenX. ChenX. JiY. Upregulation of KIF20A promotes tumor proliferation and invasion in renal clear cell carcinoma and is associated with adverse clinical outcome.Aging (Albany NY)20201224258782589410.18632/aging.202153 33232285
    [Google Scholar]
  33. SzarkowskaJ. CwiekP. SzymanskiM. RRM2 gene expression depends on BAF180 subunit of SWISNF chromatin remodeling complex and correlates with abundance of tumor infiltrating lymphocytes in ccRCC.Am. J. Cancer Res.2021111259655978 35018236
    [Google Scholar]
  34. LinehanW.M. RickettsC.J. The cancer genome atlas of renal cell carcinoma: Findings and clinical implications.Nat. Rev. Urol.201916953955210.1038/s41585‑019‑0211‑5 31278395
    [Google Scholar]
  35. LeeM.H. JärvinenP. NísenH. T and NK cell abundance defines two distinct subgroups of renal cell carcinoma.OncoImmunology2022111199304210.1080/2162402X.2021.1993042 35003893
    [Google Scholar]
  36. ZiblatA. IraolagoitiaX.L.R. NuñezS.Y. Circulating and tumor-infiltrating nk cells from clear cell renal cell carcinoma patients exhibit a predominantly inhibitory phenotype characterized by overexpression of CD85j, CD45, CD48 and PD-1.OncoImmunology2021111199304210.3389/fimmu.2021.681615
    [Google Scholar]
  37. XingQ. ZengT. LiuS. ChengH. MaL. WangY. A novel 10 glycolysis-related genes signature could predict overall survival for clear cell renal cell carcinoma.BMC Cancer202121138110.1186/s12885‑021‑08111‑0 33836688
    [Google Scholar]
  38. YiS. LiaoR. ZhaoW. LiuZ. Scutellarin-loaded pH/H2O2 dual-responsive polymer cyclodextrin mesoporous silicon framework nanocarriers for enhanced cancer therapy.Int. J. Biol. Macromol.2024269Pt 113213410.1016/j.ijbiomac.2024.132134 38719013
    [Google Scholar]
  39. LiL. ZouY. WangL. Nanodelivery of scutellarin induces immunogenic cell death for treating hepatocellular carcinoma.Int. J. Pharm.202364212311410.1016/j.ijpharm.2023.123114
    [Google Scholar]
/content/journals/cpd/10.2174/0113816128340451241224055536
Loading
/content/journals/cpd/10.2174/0113816128340451241224055536
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test