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Cigarette smoke, specifically the nicotine contained within, has been shown to correlate closely with cell invasion and strategies to downregulate their expression may ultimately be of clinical utility. Matrix metalloproteinase-9 (MMP-9) is critically involved in the cell invasion and metastasis processes. Since nicotine plays a crucial role in the regulation of MMP-9 expression, the investigation of plant-derived compounds capable of modulating nicotine-induced signaling is an issue of concern. In this study, the effects of (-)-epigallocatechin-3-gallate (EGCG), a major green tea catechin, on nicotine-induced cell invasion and MMP-9 activity in ECV304 human endothelial cells were examined. EGCG treatment was found to reduce the MMP-9 expression and transcriptional activity in a dose-dependent manner. EGCG inhibited nicotine-activated production of reactive oxygen species (ROS), which are known as important signaling molecules to activate MMP-9. To further study the mechanisms for the EGCG-mediated regulation of MMP-9, the transcription factors NF-κB and AP-1 activities were examined. EGCG suppressed the nicotine-induced NF-κB and AP-1 activation. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated MMP-9 expression. EGCG also abrogated the nicotine-induced activation of AP-1 subunits c-fos and c-jun. The above studies demonstrate that EGCG may exert at least part of its anti-invasive effect in ECV304 human endothelial cells by controlling MMP-9 expression through the suppression of ROS, NF-κB and AP-1.

Abnormal accumulation and activation of the recepteur d'origine nantais (RON) has been implicated in epithelial tumor carcinogenesis. In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG), the major green tea catechin, on the induction of RON and tumor growth in human gastric cancer. EGCG inhibited phorbol 12-myristate 13-acetate (PMA)-induced RON expression and reduced RON transcriptional activity. However, (-)-epigalloca-techin (EGC), (-)-epicatechin gallate (ECG) and (-)‑epicatechin (EC) did not affect RON expression. Experiments with deleted and site-directed mutagenesis of the RON promoter indicated that Egr-1 binding sites in the RON promoter may be the EGCG‑response element acting as a cis-element in gastric cancer cells. EGCG also inhibited PMA-induced Egr-1 expression and DNA binding in a dose-dependent manner. Furthermore, gastric cancer cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by EGCG and siRNA-targeted RON and Egr-1. EGCG significantly reduced tumor growth in an in vivo tumor model, whereas RON expression was downregulated. These results suggest that EGCG may exert at least part of its anticancer effect by controlling RON expression through suppression of Egr-1 activation.