An Advanced Systems Pharmacology Strategy Reveals AKR1B1, MMP2, PTGER3 as Key Genes in the Competing Endogenous RNA Network of Compound Kushen Injection Treating Gastric Carcinoma by Integrated Bioinformatics and Experimental Verification.

Wei Zhou,Shan Lu,Xiaotian Fan,Antony Stalin,Xinkui Liu,Chongjun Zhao,Zhishan Wu,Jingyuan Zhang,Rongli You,Yingying Tan,Chao Wu,Zhihong Huang,Jiarui Wu

doi:10.3389/fcell.2021.742421

Abstract

Gastric carcinoma (GC) is a severe tumor of the digestive tract with high morbidity and mortality and poor prognosis, for which novel treatment options are urgently needed. Compound Kushen injection (CKI), a classical injection of Chinese medicine, has been widely used to treat various tumors in clinical practice for decades. In recent years, a growing number of studies have confirmed that CKI has a beneficial therapeutic effect on GC, However, there are few reports on the potential molecular mechanism of action. Here, using systems pharmacology combined with proteomics analysis as a core concept, we identified the ceRNA network, key targets and signaling pathways regulated by CKI in the treatment of GC. To further explore the role of these key targets in the development of GC, we performed a meta-analysis to compare the expression differences between GC and normal gastric mucosa tissues. Functional enrichment analysis was further used to understand the biological pathways significantly regulated by the key genes. In addition, we determined the significance of the key genes in the prognosis of GC by survival analysis and immune infiltration analysis. Finally, molecular docking simulation was performed to verify the combination of CKI components and key targets. The anti-gastric cancer effect of CKI and its key targets was verified by in vivo and in vitro experiments. The analysis of ceRNA network of CKI on GC revealed that the potential molecular mechanism of CKI can regulate PI3K/AKT and Toll-like receptor signaling pathways by interfering with hub genes such as AKR1B1, MMP2 and PTGERR3. In conclusion, this study not only partially highlighted the molecular mechanism of CKI in GC therapy but also provided a novel and advanced systems pharmacology strategy to explore the mechanisms of traditional Chinese medicine formulations.

Highlights

Gastric carcinoma (GC) is a malignant tumor of the digestive system that poses a serious threat to human health (Ajani et al, 2017)
A total of 16 active ingredients in Compound Kushen injection (CKI) were selected for the in-depth study, which included 9α-hydroxymatrine, adenine, baptifoline, isomatrine, lamprolobine, piscidic acid and 10 compounds detected by UPLC-QE-Orbitrap-MS chromatography, and the three-dimensional structures of these active ingredients were derived from PubChem database (Kim et al, 2016)
This study explored the potential molecular mechanism of CKI in the treatment of GC and established a new advanced system pharmacology strategy

Summary

Introduction

Gastric carcinoma (GC) is a malignant tumor of the digestive system that poses a serious threat to human health (Ajani et al, 2017). Among the factors that increase the risk of human GC, Helicobacter pylori gastric infection plays a vital role, and 75% of GC cases worldwide are caused by Helicobacter pylori infection (Plummer et al, 2015). The global 5-year survival rate of patients is still less than 30% (Verdecchia et al, 2007). Because of the internal metastasis and changes of the tumor, the heterogeneity of different patients and the side effects of radiotherapy and chemotherapy, patients’ options in clinical practice are minimal (Ajani et al, 2017)

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Discussion

Conclusion