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(-)-Epigallocatechin-3-O-gallate (EGCG), a primary green tea polyphenol, has powerful iron scavengers, belongs to the family of flavonoids with antioxidant properties, and can be used to prevent cancer. Urokinase-type plasminogen activator receptors (uPARs) are glycosylphosphatidylinositol (GPI)-anchored cell membrane receptors that have crucial roles in cell invasion and metastasis of several cancers including bladder cancer. The mechanism of action of EGCG on uPAR expression has not been reported clearly yet. In this study, we investigated the effect of EGCG on interleukin (IL)-1β-induced cell invasion and uPAR activity in T24 human bladder cancer cells. Interestingly, nuclear factor (NF)-κB and activator protein (AP)-1 transcription factors were critically required for IL-1β-induced high uPAR expression, and EGCG suppressed the transcriptional activity of both the ERK1/2 and JNK signaling pathways with the AP-1 subunit c-Jun. EGCG blocked the IL-1β-stimulated reactive oxygen species (ROS) production, in turn suppressing NF-κB signaling and anti-invasion effects by inhibiting uPAR expression. These results suggest that EGCG may exert at least part of its anticancer effect by controlling uPAR expression through the suppression of ERK1/2, JNK, AP-1, and NF-κB.

Sulforaphane (SFN) is a naturally occurring isothiocyanate that is abundant in many cruciferous vegetables, such as broccoli and cauliflower, and it has been observed to exert numerous biological activities. In the present study, we investigate the effect of SFN on eNOS, a key regulatory enzyme of vascular homeostasis and underlying intracellular pathways, in human endothelial EA.hy926 cells. The results indicate that SFN treatment significantly increases NO production and eNOS phosphorylation in a time- and dose-dependent fashion and also augments Akt phosphorylation in a time- and dose-dependent manner. Meanwhile, pretreatment with LY294002 (a specific PI3K inhibitor) suppresses the phosphorylation of eNOS and NO production. Furthermore, SFN time- and dose-dependently induces the phosphorylation of Src kinase, a further upstream regulator of PI3K, while PP2 pretreatment (a specific Src inhibitor) eliminates the increase in phosphorylated Akt, eNOS and the production of NO derived from eNOS. Overall, the present study uncovers a novel effect of SFN to stimulate eNOS activity in EA.hy926 cells by regulating NO bioavailability. These findings provide clear evidence that SFN regulates eNOS activity and NO bioavailability, suggesting a promising therapeutic candidate to prevent endothelial dysfunction, atherosclerosis and other cardiovascular diseases.

Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy.

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d'origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment., Competing Interests: The authors declare no conflict of interest.

Cell invasion is a crucial mechanism of cancer metastasis and malignancy. Matrix metalloproteinase-9 (MMP-9) is an important proteolytic enzyme involved in the cancer cell invasion process. High expression levels of MMP-9 in gastric cancer positively correlate with tumor aggressiveness and have a significant negative correlation with patients' survival times. Recently, mechanisms suppressing MMP-9 by phytochemicals have become increasingly investigated. Chrysin, a naturally occurring chemical in plants, has been reported to suppress tumor metastasis. However, the effects of chrysin on MMP-9 expression in gastric cancer have not been well studied. In the present study, we tested the effects of chrysin on MMP-9 expression in gastric cancer cells, and determined its underlying mechanism. We examined the effects of chrysin on MMP-9 expression and activity via RT-PCR, zymography, promoter study, and western blotting in human gastric cancer AGS cells. Chrysin inhibited phorbol-12-myristate 13-acetate (PMA)-induced MMP-9 expression in a dose-dependent manner. Using AP-1 decoy oligodeoxynucleotides, we confirmed that AP-1 was the crucial transcriptional factor for MMP-9 expression. Chrysin blocked AP-1 via suppression of the phosphorylation of c-Jun and c-Fos through blocking the JNK1/2 and ERK1/2 pathways. Furthermore, AGS cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by chrysin and MMP-9 antibody. Our results suggest that chrysin may exert at least part of its anticancer effect by controlling MMP-9 expression through suppression of AP-1 activity via a block of the JNK1/2 and ERK1/2 signaling pathways in gastric cancer AGS cells.

Helicobacter pylori (H. pylori) is a major etiological factor in the development of gastric cancer. Large-scale epidemiological studies have confirmed the strong association between H. pylori infection and both cancer development and progression. Interleukin-8 (IL-8) is overexpressed in gastric mucosa exposed to H. pylori. The expression of IL-8 directly correlates with a poor prognosis in gastric cancer. IL-8 is multifunctional. In addition to its potent chemotactic activity, it can induce proliferation and migration of cancer cells. In this review, we focus on recent insights into the mechanisms of IL-8 signaling associated with gastric cancer. The relationship between IL-8 and H. pylori is discussed. We also summarize the current therapeutics against IL-8 in gastric cancer., (© 2013 Baishideng Publishing Group Co., Limited. All rights reserved.)

Overexpression of recepteur d'Origine nantais (RON) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between RON and uPAR in gastric cancer is unclear. The present study investigated the effect of macrophage-stimulating protein (MSP, the RON ligand) on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. uPAR messenger RNA expression was induced by MSP in a time- and concentration-dependent manner. MSP also induced uPAR promoter activity. The introduction of RON-specific small interfering RNA (siRNA) significantly affected the MSP-induced uPAR transcription. Deleted and site-directed mutagenesis studies demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the MSP-induced uPAR expression. Studies with expression vectors encoding mutated-type NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the MSP-induced uPAR expression. In addition, MSP induced the activation of extracellular signal-regulated kinase-1/2 (Erk-1/2), c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Dominant-negative mutants (K97M and TAM67) and specific inhibitors of Erk-1/2 and JNK were able to suppress the MSP-induced uPAR expression. AGS cells pretreated with MSP showed a remarkably enhanced invasiveness, which was partially abrogated by siRNA-targeted RON and uPAR-neutralizing antibodies. The above results suggest that MSP induces uPAR expression via MAPK, AP-1 and NF-κB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.