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. 2025 Jun 23;22(12):3053-3069.
doi: 10.7150/ijms.112622. eCollection 2025.

Ginsenoside Rh7 affects β-catenin nuclear translocation by inhibiting SHCBP1 expression, thereby inhibiting epithelial-mesenchymal transition in gastric cancer cells

Xiaohong Zhang  1 , Yanqing Mo  1   2 , Li Feng  1
Affiliations

Ginsenoside Rh7 affects β-catenin nuclear translocation by inhibiting SHCBP1 expression, thereby inhibiting epithelial-mesenchymal transition in gastric cancer cells

Xiaohong Zhang et al. Int J Med Sci. .

Abstract

Background: Ginsenoside Rh7 is a bioactive compound with anticancer properties. This investigation was conducted to analyze the anticancer effects of ginsenoside Rh7 and its underlying molecular mechanisms in gastric cancer (GC) cells. Methods: The key gene module associated with GC was identified through weighted gene co-expression network analysis (WGCNA) of the GSE118897 dataset. Differentially expressed genes (DEGs) were examined in The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD) and the GSE118897 datasets. The central genes of this study were subsequently identified by intersection analysis and protein-protein interaction (PPI) network. Transcriptome sequencing evaluated the changes in SHCBP1 expression in GC cells treated with Rh7. Immunoprecipitation (IP) was employed to analyze the relationship between β-catenin and SHCBP1. Functional assays, including Transwell, cell counting kit-8 (CCK-8), colony assays, and in vivo tumor models, evaluated the effects of Rh7 and SHCBP1 on GC cell behaviors. Results: SHCBP1 was upregulated in tumor samples in GSE118897 and TCGA-STAD. Ginsenoside Rh7 inhibited GC cell invasion, migration, and proliferation dose-dependently by downregulating SHCBP1 expression. Transcriptome analysis confirmed Rh7-mediated SHCBP1 inhibition. Rh7 promoted β-catenin nuclear translocation by reducing SHCBP1 expression. Rescue experiments demonstrated that the overexpression of SHCBP1 partially counterbalanced the impacts of Rh7 on epithelial-mesenchymal transition (EMT) regulation and GC cell growth in vitro and in vivo. Conclusion: Ginsenoside Rh7 suppresses GC progression by regulating SHCBP1-mediated β-catenin nuclear translocation, thereby inhibiting EMT, proliferation, migration, and invasion. This highlights its potential as a GC therapeutic drug and deserves further study of its mechanism of action.

Keywords: SHCBP1; epithelial-mesenchymal transition; gastric cancer; ginsenoside Rh7; β-catenin.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
WGCNA identification of key gene modules associated with GC in the GSE118897 dataset. (A) Determination of the optimal soft-threshold power to ensure a scale-free topology model fit. (B) Dendrogram of 20 samples from the GSE118897 dataset, showing the sample clustering with and without trait heatmaps. (C) Clustering dendrogram showing the division of genes into distinct modules based on their co-expression patterns, with each module represented by a unique color. (D) Heatmap of eigengene adjacency, visualizing the relationships between the 14 identified modules. (E) Correlation heatmap illustrating the relationships between different gene modules and the Normal and Tumor samples from the GSE42955 dataset.
Figure 2
Figure 2
Differential expression and PPI network analysis reveal hub genes in GC. (A) Volcano plot illustrating the differential expression of genes in the GSE118897 dataset, with upregulated genes highlighted in orange and downregulated genes in cyan. (B) Volcano plot depicting DEGs in the TCGA-STAD dataset, with upregulated genes shown in blue and downregulated genes in red. (C) Venn diagram displaying the overlap of genes between the turquoise module and the DEGs from both the GSE118897 and TCGA-STAD datasets. (D) Protein-protein interaction (PPI) network analysis of the intersecting genes, comprising 26 nodes and 239 edges. (E-F) PPI network analysis of the intersecting genes based on the top 10 interacting genes identified by the DMNC (E) and MNC (F) algorithms, with 10 nodes and 41 edges for DMNC and 10 nodes and 45 edges for MNC. (G) Venn diagram illustrating the two overlapping genes identified by both the DMNC and MNC algorithms. (H-I) Expression levels of SHCBP1 and MELK in both the GSE118897 and TCGA-STAD datasets. TCGA-STAD: The Cancer Genome Atlas Stomach Adenocarcinoma; DEGs, differentially expressed genes; PPI, protein-protein interaction; DMNC, density of maximum neighborhood component; MNC, maximum neighborhood component. ***P<0.001.
Figure 3
Figure 3
Inhibitory effects of ginsenosides on GC cell proliferation. (A and B) CCK-8 assay showing the effects of various ginsenosides (RC, Rh7, Rh1, and Rh3) at 100 μM on the proliferation of SGC-7901 and AGS cells. The x-axis represents different ginsenosides, and the y-axis represents the relative proliferation rate. (C) Chemical structure of ginsenoside Rh7. (D and E) IC50 values for ginsenoside Rh7 treatment at various concentrations (0, 1, 5, 10, 50, and 100 μM) in SGC-7901 and AGS cells. The x-axis represents different concentrations, and the y-axis represents the survival rate. GC, gastric cancer; CCK-8, cell counting kit-8; IC50, half-maximal inhibitory concentration; DMSO: Dimethyl sulfoxide. **P<0.01 vs. DMSO group.
Figure 4
Figure 4
Effect of ginsenoside Rh7 on the proliferation, migration, and invasion of GC cells. (A and B) CCK-8 assay results showed the effect of 25 μM and 50 μM ginsenoside Rh7 on the proliferation of SGC-7901 and AGS cells. (C and D) Transwell assay images demonstrating the impact of 25 μM and 50 μM ginsenoside Rh7 on the migration and invasion of SGC-7901 and AGS cells, with corresponding bar graphs for quantification. Scale bar: 50 μm. (E) Clonogenic assay showing the effect of 25 μM and 50 μM ginsenoside Rh7 on colony formation in SGC-7901 and AGS cells. GC, gastric cancer; CCK-8, cell counting kit-8; DMSO: Dimethyl sulfoxide. *P< 0.05 or **P<0.01 vs. DMSO group.
Figure 5
Figure 5
Effect of ginsenoside Rh7 on SHCBP1 expression in GC cell lines. (A) SHCBP1 expression was evaluated in normal human gastric epithelial cells (GES1) and GC cell lines (AGS, SGC-7901, MGC803, and SNU-1) by qRT-PCR. *P< 0.05 or **P<0.01 vs. GES1 group. (B and C) WB analysis of SHCBP1 expression in GES1 and AGS, SGC-7901, MGC803, and SNU-1. The protein levels of SHCBP1 were quantified by bar graphs. *P< 0.05 or **P<0.01 vs. GES1 group. (D) The effect of 50 μM ginsenoside Rh7 treatment on SHCBP1 expression in AGS and SGC-7901 cells was measured by qRT-PCR. (E and F) WB analysis of SHCBP1 expression following 50 μM ginsenoside Rh7 treatment in AGS and SGC-7901 cells. GC, gastric cancer; qRT-PCR, quantitative real-time polymerase chain reaction; WB, Western blot; DMSO: Dimethyl sulfoxide. *P< 0.05 or **P<0.01 vs. DMSO group.
Figure 6
Figure 6
Modulation of SHCBP1-β-catenin interaction and β-catenin nuclear translocation by ginsenoside Rh7 in GC cells. (A-C) WB analysis of β-catenin levels in nuclear (nuc) and cytoplasmic (cyto) fractions of SGC-7901 and AGS cells after treatment with DMSO or 50 μM Rh7. P84 and GAPDH were used as nuclear and cytoplasmic markers, respectively, to confirm fractionation. (D and E) IP assays assessed the interaction between SHCBP1 and β-catenin in GC cells with 50 μM ginsenoside Rh7. (F) IP assays assessed of total SHCBP1 and β-catenin protein levels in SGC-7901 and AGS cells treated with DMSO or Rh7. GC, gastric cancer; WB, Western blot; IP: Immunoprecipitation.
Figure 7
Figure 7
Regulation of EMT in GC cells by ginsenoside Rh7 through SHCBP1-mediated β-catenin translocation. (A-C) Transfection efficiency of SHCBP1 overexpression plasmids in SGC-7901 and AGS cells, evaluated by qRT-PCR (A) and WB (B and C). *P< 0.05 or **P<0.01 vs. vector group. (D and E) Effects of Rh7 treatment and SHCBP1 overexpression on the expression of EMT markers (N-cadherin, E-cadherin, and Vimentin) in GC cells, assessed by qRT-PCR. (F-H) WB analysis of the expression of EMT-related factors (N-cadherin, E-cadherin, and Vimentin) in GC cells following Rh7 treatment and SHCBP1 overexpression, quantified using bar graphs. GC, gastric cancer; qRT-PCR, quantitative real-time polymerase chain reaction; WB, Western blot; EMT, epithelial-mesenchymal transition; DMSO: Dimethyl sulfoxide. *P< 0.05 or **P<0.01 or ***P<0.001 vs. DMSO group. #P< 0.05 or ##P<0.01 or ###P<0.001 vs. Rh7 (50μM) + vector group.
Figure 8
Figure 8
Effects of ginsenoside Rh7 and SHCBP1 overexpression on GC cell migration, invasion, proliferation, and tumor growth. (A and B) Transwell assays assessing the effects of ginsenoside Rh7 treatment and SHCBP1 overexpression on the migration and invasion of GC cells. Scale bar: 50 μm. (C) Clonogenic assays measuring the impact of SHCBP1 overexpression on GC cell proliferation in the presence of Rh7 treatment. The x-axis indicates the treatment conditions, and the y-axis shows the number of colonies formed by GC cells. (D-F) In vivo tumor model studies evaluating the effect of Rh7 treatment and SHCBP1 overexpression on tumor size and weight. GC, gastric cancer; DMSO: Dimethyl sulfoxide. *P< 0.05 or **P<0.01 or ***P<0.001 vs. DMSO group. #P< 0.05 vs. Rh7 (50μM) + vector group.
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