Research on the Regulatory Mechanism of Ginseng on the Tumor
Microenvironment of Colorectal Cancer based on Network Pharmacology
and Bioinformatics Validation
Authors: Wang Tiancheng , Zhang Weijie , Fang Cancan , Wang Nan , Zhuang Yue , Gao Song 
Published: June 2023

Background:
A network pharmacology study on the biological action of ginseng in the
treatment of colorectal cancer (CRC) by regulating the tumor microenvironment (TME).

Objective:
To investigate the potential mechanism of action of ginseng in the treatment of CRC by regulating
TME.

Methods:
This research employed network pharmacology, molecular docking techniques, and bioinformatics
validation. Firstly, the active ingredients and the corresponding targets of ginseng were retrieved
using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform
(TCMSP), the Traditional Chinese Medicine Integrated Database (TCMID), and the Traditional Chinese
Medicine Database@Taiwan (TCM Database@Taiwan). Secondly, the targets related to CRC
were retrieved using Genecards, Therapeutic Target Database (TTD), and Online Mendelian Inheritance
in Man (OMIM). Tertiary, the targets related to TME were derived from screening the GeneCards and
National Center for Biotechnology Information (NCBI)-Gene. Then the common targets of ginseng,
CRC, and TME were obtained by Venn diagram. Afterward, the Protein-protein interaction (PPI) network
was constructed in the STRING 11.5 database, intersecting targets identified by PPI analysis were
introduced into Cytoscape 3.8.2 software cytoHubba plugin, and the final determination of core targets
was based on degree value. The OmicShare Tools platform was used to analyze the Gene Ontology
(GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis
of the core targets. Autodock and PyMOL were used for molecular docking verification and visual data
analysis of docking results. Finally, we verified the core targets by Gene Expression Profiling Interactive
Analysis (GEPIA) and Human Protein Atlas (HPA) databases in bioinformatics.

Results:
A total of 22 active ingredients and 202 targets were identified to be closely related to the TME of
CRC. PPI network mapping identified SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 as possible core
targets. Go enrichment analysis showed that it was mainly involved in T cell co-stimulation, lymphocyte
co-stimulation, growth hormone response, protein input, and other biological processes; KEGG pathway
analysis found 123 related signal pathways, including EGFR tyrosine kinase inhibitor resistance, chemokine
signaling pathway, VEGF signaling pathway, ErbB signaling pathway, PD-L1 expression and PD-1
checkpoint pathway in cancer, etc. The molecular docking results showed that the main chemical components
of ginseng have a stable binding activity to the core targets. The results of the GEPIA database
showed that the mRNA levels of PIK3R1 were significantly lowly expressed and HSP90AA1 was significantly
highly expressed in CRC tissues. Analysis of the relationship between core target mRNA levels and
the pathological stage of CRC showed that the levels of SRC changed significantly with the pathological
stage. The HPA database results showed that the expression levels of SRC were increased in CRC tissues,
while the expression of STAT3, PIK3R1, HSP90AA1, and AKT1 were decreased in CRC tissues.

Conclusion:
Ginseng may act on SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 to regulate T cell
costimulation, lymphocyte costimulation, growth hormone response, protein input as a molecular
mechanism regulating TME for CRC. It reflects the multi-target and multi-pathway role of ginseng in
modulating TME for CRC, which provides new ideas to further reveal its pharmacological basis, mechanism
of action and new drug design and development.