Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2024; 16(2): 493-513
Published online Feb 15, 2024. doi: 10.4251/wjgo.v16.i2.493
Identification of anti-gastric cancer effects and molecular mechanisms of resveratrol: From network pharmacology and bioinformatics to experimental validation
Ying-Qian Ma, Ming Zhang, Zhen-Hua Sun, Hong-Yue Tang, Ying Wang, Jiang-Xue Liu, Zhan-Xue Zhang, Chao Wang
Ying-Qian Ma, Ming Zhang, Zhen-Hua Sun, Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
Ying-Qian Ma, Ying Wang, Jiang-Xue Liu, School of Graduate Studies, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
Hong-Yue Tang, Chao Wang, Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
Zhan-Xue Zhang, Department of Gastrointestinal Surgery, Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Author contributions: Zhang M and Wang C designed the research and supervised the project; Ma YQ and Sun ZH performed network pharmacology analysis and molecular docking; Wang Y and Tang HY performed bioinformatics analysis; Ma YQ and Liu JX performed the experiments, analyzed the data and wrote the paper; Zhang M, Zhang ZX and Wang C revised the paper; all authors approved the final version of the article.
Supported by Natural Science Foundation of Hebei Province, No. H2018307071; Traditional Chinese Medicine Research Plan Project in Hebei Province, No. 2022122; and Hebei Provincial Science and Technology Program, No. 17397763D.
Conflict-of-interest statement: All other authors have nothing to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ming Zhang, MD, Chief Physician, Department of Oncology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, China. zhangming096@163.com
Received: November 9, 2023
Peer-review started: November 9, 2023
First decision: November 23, 2023
Revised: December 5, 2023
Accepted: January 12, 2024
Article in press: January 12, 2024
Published online: February 15, 2024
Abstract
BACKGROUND

Gastric cancer (GC) is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis. Resveratrol, a non-flavonoid polyphenolic compound found in a variety of Chinese medicinal materials, has shown excellent anti-GC effect. However, its exact mechanisms of action in GC have not been clarified.

AIM

To identify the effects of resveratrol on GC progression and explore the related molecular mechanisms.

METHODS

Action targets of resveratrol and GC-related targets were screened from public databases. The overlapping targets between the two were confirmed using a Venn diagram, and a “Resveratrol-Target-GC” network was constructed using Cytoscape software version 3.9.1. The protein-protein interaction (PPI) network was constructed using STRING database and core targets were identified by PPI network analysis. The Database for Annotation, Visualization and Integrated Discovery database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A “Target-Pathway” network was created by using Cytoscape 3.9.1. The RNA and protein expression levels of core target genes were observed using the Cancer Genome Atlas and the Human Protein Atlas databases. DriverDBv3 and Timer2.0 databases were used for survival and immune infiltration analysis. Subsequently, the findings were further verified by molecular docking technology and in vitro experiments.

RESULTS

A total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases, and 181 intersection targets between the two were screened by Venn diagram. The top 20 core targets were identified by PPI network analysis of the overlapping targets. GO function analysis mainly involved protein binding, identical protein binding, cytoplasm, nucleus, negative regulation of apoptotic process and response to xenobiotic stimulus. KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, ErbB signaling pathway, etc. FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9) were selected by differential expression analysis, and they were closely associated with immune infiltration. Molecular docking results showed that resveratrol docked well with these two targets. Resveratrol treatment arrested the cell cycle at the S phase, induced apoptosis, and weakened viability, migration and invasion in a dose-dependent manner. Furthermore, resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression.

CONCLUSION

The anti-GC effects of resveratrol are related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.

Keywords: Resveratrol, Gastric cancer, Network pharmacology, Bioinformatics, Molecular docking

Core Tip: Based on network pharmacology and bioinformatics, the molecular targets and signaling pathways of resveratrol on gastric cancer (GC) were explored, and experiments were used to validate the network analysis. Network analysis results suggested that the action of resveratrol on GC involved multiple targets and pathways. In vitro experiments suggested that the anti-GC effects of resveratrol were related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9). This study confirmed anti-GC effects of resveratrol and highlighted that FOS and MMP9 might be the effective biotargets for GC treatment.