Cyclopiane Suppresses Gastric Cancer Invasion and Angiogenesis via the CYR61/αvβ3 Integrin/NF-κB Pathway.
4 affiliations
- 1Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
- 2Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
- 3Anhui Public Health Clinical Center, Hefei, China.
- 4Department of Ophthalmology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract
Background
Cysteine-rich angiogenic inducer 61 (CYR61), a matricellular protein, has been implicated in gastric cancer aggressiveness through activation of integrin-mediated NF-κB signaling; however, effective pharmacological strategies targeting this axis remain limited. Cyclopiane, a bioactive small-molecule compound, has shown potential anti-tumor activity, but its role and underlying mechanisms in gastric cancer have not been fully elucidated. This study aimed to investigate whether Cyclopiane suppresses gastric cancer invasion and angiogenesis via modulation of the CYR61/αvβ3 integrin/NF-κB signaling pathway.Methods
Human gastric cancer cell lines AGS and MKN45 were treated with increasing concentrations of Cyclopiane. Cell viability was assessed using MTT assays, while invasive capacity was evaluated using Matrigel-coated Transwell assays. TUNEL staining was used to assess changes in apoptosis in tumor cells. The expression of invasion-, angiogenesis-, and inflammation-related proteins was analyzed by Western blot (WB) and enzyme-linked immunosorbent assay (ELISA). Transcriptomic profiling of AGS cells treated with Cyclopiane versus vehicle control was performed to identify differentially expressed genes and enriched signaling pathways. CYR61 overexpression was achieved via adeno-associated virus (AAV-CYR61), with its pathway involvement further validated using integrin αvβ3 antagonists. The conventional anticancer drug 5-fluorouracil (5-FU) was employed to compare Cyclopiane's therapeutic effects. In vivo experiments utilized a nude mouse xenograft model to evaluate changes in tumor growth, angiogenesis, and inflammatory responses following Cyclopiane treatment.Results
We found that Cyclopiane significantly reduced cell viability, invasive capacity of AGS and MKN45 cells and promoted apoptosis in a dose-dependent manner, with its high-dose effects comparable to those of 5-FU. Transcriptomic analysis revealed that Cyclopiane downregulated CCN1/CYR61, ITGAV and ITGB3 expression, with pathway enrichment identifying integrin signaling, ECM-receptor interaction, focal adhesion and NF-κB pathways as the top modulated terms. In vivo experiments demonstrated that Cyclopiane significantly inhibited tumor growth and progression. Both in vivo and in vitro studies showed Cyclopiane significantly downregulated vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and MMP-9 expression while inhibiting integrin αvβ3 expression and NF-κB activation, as evidenced by reduced phosphorylation levels of p65 and IκBα. Overexpression of CYR61 partially reversed the inhibition of invasion, angiogenic factor production, and NF-κB signaling mediated by Cyclopiane. The αvβ3/αvβ5 integrin antagonist Cilengitide also exhibited tumor-suppressive effects, and the co-treatment of Cyclopiane with Cilengitide achieved the strongest tumor-suppressive effect.Conclusion
These findings suggest that modulation of the CYR61/integrin/NF-κB signaling axis contributes, at least in part, to the anti-invasive and anti-angiogenic effects of Cyclopiane in preclinical gastric cancer models. Further studies are required to establish its molecular target specificity, safety, selectivity, and translational potential.
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BibTeX
@article{zhang2026cyclopiane,
title = {{Cyclopiane Suppresses Gastric Cancer Invasion and Angiogenesis via the CYR61/αvβ3 Integrin/NF-κB Pathway.}},
author = {Yingfeng Zhang and Hongjun Tian and Song Wang and Feng Lin and Weixiang Li and Runben Jiang and Zhengxuan Jiang and Wenbin Wang},
journal = {Cancer medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72352},
url = {https://europepmc.org/article/MED/42902874},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Cyclopiane Suppresses Gastric Cancer Invasion and Angiogenesis via the CYR61/αvβ3 Integrin/NF-κB Pathway.
AU - Yingfeng Zhang
AU - Hongjun Tian
AU - Song Wang
AU - Feng Lin
AU - Weixiang Li
AU - Runben Jiang
AU - Zhengxuan Jiang
AU - Wenbin Wang
PY - 2026
DA - 2026/10/01
JO - Cancer medicine
DO - 10.1002/cam4.72352
UR - https://europepmc.org/article/MED/42902874
AB - Background Cysteine-rich angiogenic inducer 61 (CYR61), a matricellular protein, has been implicated in gastric cancer aggressiveness through activation of integrin-mediated NF-κB signaling; however, effective pharmacological strategies targeting this axis remain limited. Cyclopiane, a bioactive small-molecule compound, has shown potential anti-tumor activity, but its role and underlying mechanisms in gastric cancer have not been fully elucidated. This study aimed to investigate whether Cyclopiane suppresses gastric cancer invasion and angiogenesis via modulation of the CYR61/αvβ3 integrin/NF-κB signaling pathway.Methods Human gastric cancer cell lines AGS and MKN45 were treated with increasing concentrations of Cyclopiane. Cell viability was assessed using MTT assays, while invasive capacity was evaluated using Matrigel-coated Transwell assays. TUNEL staining was used to assess changes in apoptosis in tumor cells. The expression of invasion-, angiogenesis-, and inflammation-related proteins was analyzed by Western blot (WB) and enzyme-linked immunosorbent assay (ELISA). Transcriptomic profiling of AGS cells treated with Cyclopiane versus vehicle control was performed to identify differentially expressed genes and enriched signaling pathways. CYR61 overexpression was achieved via adeno-associated virus (AAV-CYR61), with its pathway involvement further validated using integrin αvβ3 antagonists. The conventional anticancer drug 5-fluorouracil (5-FU) was employed to compare Cyclopiane's therapeutic effects. In vivo experiments utilized a nude mouse xenograft model to evaluate changes in tumor growth, angiogenesis, and inflammatory responses following Cyclopiane treatment.Results We found that Cyclopiane significantly reduced cell viability, invasive capacity of AGS and MKN45 cells and promoted apoptosis in a dose-dependent manner, with its high-dose effects comparable to those of 5-FU. Transcriptomic analysis revealed that Cyclopiane downregulated CCN1/CYR61, ITGAV and ITGB3 expression, with pathway enrichment identifying integrin signaling, ECM-receptor interaction, focal adhesion and NF-κB pathways as the top modulated terms. In vivo experiments demonstrated that Cyclopiane significantly inhibited tumor growth and progression. Both in vivo and in vitro studies showed Cyclopiane significantly downregulated vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and MMP-9 expression while inhibiting integrin αvβ3 expression and NF-κB activation, as evidenced by reduced phosphorylation levels of p65 and IκBα. Overexpression of CYR61 partially reversed the inhibition of invasion, angiogenic factor production, and NF-κB signaling mediated by Cyclopiane. The αvβ3/αvβ5 integrin antagonist Cilengitide also exhibited tumor-suppressive effects, and the co-treatment of Cyclopiane with Cilengitide achieved the strongest tumor-suppressive effect.Conclusion These findings suggest that modulation of the CYR61/integrin/NF-κB signaling axis contributes, at least in part, to the anti-invasive and anti-angiogenic effects of Cyclopiane in preclinical gastric cancer models. Further studies are required to establish its molecular target specificity, safety, selectivity, and translational potential.
SN - 2045-7634
ER -