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Co-Expression Network Analysis and Molecular Docking Demonstrate That Diosgenin Inhibits Gastric Cancer Progression
1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
Background:
Tumor-Node-Metastasis (TNM) stage of gastric cancer (GC) is one of the main factors affecting clinical outcome. The aim of this study was to explore the targets related to TNM stage of GC, and screening natural bioactive drug.
Methods:
RNA sequencing data of the TCGA-STAD cohort were downloaded from UCSC database. Genes associated with TNM staging were identified by weighted gene co-expression network analysis (WGCNA). Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (Xgboost), random forest (RF) and cytohubba plug-in of cytoscope were applied to screen hub genes. Natural bioactive ingredients were available from the HERB database. Molecular docking was used to evaluate the binding activity of active ingredients to the hub protein. CCK-8, flow cytometry, transwell and Western blot assays were used to analyze the effects of diosgenin on GC cells.
Results:
898 TNM-related genes were screened out through WGCNA. Three genes associated with GC progression/prognosis were identified, including nuclear receptor subfamily 3 group C member 2 (NR3C2), solute carrier family 1 member 5 (SLC1A5) and FAT atypical cadherin 1 (FAT1) based on the machine learning algorithms and hub co-expression network analysis. Diosgenin had good binding activity with SLC1A5. SLC1A5 was highly expressed in GC and was closely associated with tumor stage, overall survival and immune infiltration of GC patients. Diosgenin could inhibit cell viability and invasive ability, promote apoptosis and induce cell cycle arrest in G0/G1 phase. In addition, diosgenin promoted cleaved caspase 3 expression and inhibited Ki67, cyclin D1, p-S6K1, and SLC1A5 expression levels, while the mTORC1 activator (MHY1485) reversed this phenomenon.
Conclusion:
For the first time, this work reports diosgenin may inhibit the activation of mTORC1 signaling through targeting SLC1A5, thereby inhibiting the malignant behaviors of GC cells.
Insights
This study identifies solute carrier family 1 member 5 (SLC1A5) as a target for gastric cancer (GC) treatment. The natural compound diosgenin inhibits GC cell growth by targeting SLC1A5 and the mTORC1 signaling pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastric cancer (GC) staging, particularly Tumor-Node-Metastasis (TNM) stage, significantly impacts clinical outcomes.
- Identifying novel therapeutic targets and natural compounds is crucial for improving GC treatment strategies.
Purpose of the Study:
- To explore genes associated with GC TNM staging.
- To screen for natural bioactive compounds that target these genes for potential GC therapy.
Main Methods:
- Weighted gene co-expression network analysis (WGCNA) identified TNM-related genes.
- Machine learning algorithms and network analysis screened for hub genes.
- Molecular docking evaluated the binding of natural compounds to hub proteins, followed by in vitro assays for diosgenin's effects on GC cells.
Main Results:
- Three key genes (NR3C2, SLC1A5, FAT1) were identified as associated with GC progression and prognosis.
- Diosgenin demonstrated strong binding to solute carrier family 1 member 5 (SLC1A5), which is highly expressed in GC and linked to poor outcomes.
- Diosgenin inhibited GC cell viability and invasion, induced apoptosis, and arrested the cell cycle, partly via the mTORC1 pathway.
Conclusions:
- Diosgenin may act as an anti-gastric cancer agent by targeting SLC1A5 and inhibiting the mTORC1 signaling pathway.
- This study provides a novel therapeutic strategy for gastric cancer using a natural compound targeting a specific molecular pathway.
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