Targeting the CNOT2/VEGF pathway by Cornin attenuates angiogenesis and invasion in cervical cancer cells

Cornin, a bioactive iridoid glycoside isolated from Cornus officinalis, has been reported to exhibit cardioprotective and pro-apoptotic activities. However, its antitumor mechanism in cervical cancer remains largely unknown. In this study, we investigated the antiangiogenic and anti-invasive effects of Cornin, focusing on the CNOT2-VEGF signaling axis. Cornin showed limited cytotoxicity in SiHa, HeLa, and CaSki cervical cancer cells but significantly downregulated CNOT2, N-cadherin, VEGF, and Snail expression in HeLa and SiHa cells. Functional analyses revealed that CNOT2 silencing suppressed wound healing activity, while Cornin treatment markedly inhibited cell migration, invasion, and VEGF secretion in HeLa cells. VEGF luciferase reporter and cycloheximide chase assays confirmed that Cornin reduced VEGF transcription and protein stability in a time-dependent manner. Furthermore, Cornin inhibited tube formation in HUVECs and angiogenesis in the chick chorioallantoic membrane (CAM) model. TCGA analysis showed that CNOT2 expression was elevated in cervical cancer tissues and positively correlated with VEGF expression (r = 0.35). This association was further supported by immunoprecipitation analysis demonstrating a physical interaction between CNOT2 and VEGF in HeLa cells. Mechanistically, ectopic CNOT2 expression upregulated VEGF, whereas its depletion suppressed VEGF expression. Collectively, these findings highlight the CNOT2-VEGF axis as a crucial mediator in antiangiogenic and anti-invasive effects of Cornin in cervical cancer, suggesting Cornin as a potent natural inhibitor of tumor angiogenesis and invasion.