Abstract
BackgroundCompound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated.MethodsHere, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis.ResultsThe WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92 and SFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111B and MMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found that CDK1, JAK1, EGFR, MAPK1 and MAPK3 served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis.ConclusionsOverall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.
Highlights
Pancreatic cancer (PC) is a common malignant tumour of the digestive tract characterized by concealed onset, high malignancy, and rapid development, and the majority of pancreatic can‐ cer (PC) cases have locally advanced or metastatic at the time of diagnosis [1,2,3]
This study aimed to reveal the complex mechanism of multi-component, multi-target, and multi-pathway of Compound kushen injection (CKI) in the treatment of PC at a system level, and provide a better basis for the diagnosis, treatment and prognosis of PC
weighted gene co-expression network analysis (WGCNA) module construction In this study, a total of 177 samples and 5000 genes were screened for WGCNA analysis
Summary
Pancreatic cancer (PC) is a common malignant tumour of the digestive tract characterized by concealed onset, high malignancy, and rapid development, and the majority of PC cases have locally advanced or metastatic at the time of diagnosis [1,2,3]. In countries with a high human development index, such as Europe and North America, the incidence of PC is three to four times higher, and the number of deaths from PC in the United States is expected to increase significantly by 2030, which PC will become the second leading cause of cancer death [4, 5]. The underlying mechanism of CKI in pancreatic can‐ cer (PC) treatment has not been totally elucidated
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