Quercetin targets Serpine1 to inhibit angiogenesis and suppress gastric cancer progression

Gastric cancer (GC) is one of the most common malignancies, characterized by high mortality and recurrence rates. Quercetin, a natural flavonoid found in various herbs and foods, exhibits potential therapeutic effects against GC. This study aims to explore the potential molecular mechanisms of quercetin in the treatment of GC.

Bioinformatic analyses were performed using the TCGA-STAD dataset to evaluate SERPINE1 expression, prognosis, angiogenesis-related pathway enrichment, and correlations with angiogenic factors. Molecular docking was employed to predict the binding affinity between quercetin and Serpine1, followed by validation using cellular thermal shift assay (CETSA). Cell proliferation and cytotoxicity were assessed by CCK-8 assays in GC cells and normal gastric epithelial GES-1 cells, and IC50 values were calculated. Serpine1 overexpression and siRNA-mediated knockdown were performed to investigate its functional role. Colony formation assays were used to evaluate clonogenic ability, apoptosis was analyzed by flow cytometry, and Transwell and wound healing assays were used to assess invasion and migration. Tube formation assays were conducted to examine angiogenic potential in HUVECs. Western blotting and qPCR were used to detect Serpine1, angiogenesis-related genes (VEGFA, FGF-2, FGF-7), and HUVEC angiogenesis markers (VEGFR-2, CD31, VE-cadherin). VEGFA secretion in cell supernatants was quantified by ELISA.

Bioinformatic analysis showed that Serpine1 was highly expressed in GC tissues, associated with poor prognosis, and positively correlated with angiogenesis-related signatures and factors, including VEGFA, FGF-2, and FGF-7. Quercetin suppressed proliferation, invasion, and migration while promoting apoptosis in GC cells. At the selected treatment concentration, quercetin showed stronger inhibitory effects on GC cells than on GES-1 cells. Serpine1 expression was upregulated in GC cells and downregulated after quercetin treatment. Serpine1 knockdown inhibited GC cell proliferation, colony formation, migration, invasion, and angiogenic potential, while promoting apoptosis. Conversely, Serpine1 overexpression enhanced GC proliferation, invasion, and migration and inhibited apoptosis, whereas quercetin counteracted these effects. Quercetin also reduced angiogenesis-related factors (VEGFA, FGF-2, and FGF-7) in GC cells and decreased HUVEC angiogenesis-associated proteins (VEGFR-2, CD31, and VE-cadherin). These findings suggest that the anti-GC and anti-angiogenic effects of quercetin are mediated, at least in part, through targeting Serpine1.

Our experimental results demonstrate that quercetin inhibits GC progression by targeting Serpine1 to suppress angiogenesis in vitro. Serpine1 represents a potential therapeutic target for GC treatment with quercetin, providing a new research direction for future treatment strategies.