Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines

Konkuk University, Sŏul, Seoul, South Korea
Oncogene (Impact Factor: 8.46). 04/2007; 26(10):1468-76. DOI: 10.1038/sj.onc.1209926
Source: PubMed


Cell migration and angiogenesis are key steps in tumor metastasis. However, the mechanism of migration regulated by vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is not completely understood. This study examined the relationship between VEGF and migration, along with the mechanism involved in the VEGF-regulated migration of human gastric cancer cells. The level of cell migration was increased by recombinant human (rh)VEGF-165 in the VEGF receptor-2-expressing SNU-601 cells. Interleukin (IL)-18 is associated with the malignant progression of tumors. Accordingly, this study examined the effect of IL-18 on the migration of cancer cells in order to identify the factors involved in VEGF-enhanced migration. Inhibiting IL-18 markedly reduced the level of VEGF-enhanced migration, and IL-18 increased cell migration directly through filamentous-actin polymerization and tensin downregulation. It was confirmed that rhVEGF-165 increased IL-18 production significantly. An antioxidant and an extracellular signal-regulated kinase (ERK)1/2-specific inhibitor blocked rhVEGF-165-enhanced IL-18 production. Accordingly, rhVEGF-165 increased the generation of region of interest (ROI) and activated the ERK1/2 pathway. These results suggest that rhVEGF-165 enhances IL-18 production via the generation of ROI and ERK1/2 phosphorylation, which results in the increased migration of gastric cancer cells.

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    • "In addition, the pro-inflammatory micro-environment such as IL-1β production may also contribute to this process [19]. Our study found that M.hy induced IL-1β promoted migration and invasion of the gastric cancer cells, while M.hy induced IL-18 did not contribute to the migration and invasion of gastric cancer cells, which was different from other reports [26], [27]. A possible explanation is that IL-18 may have promoted gastric cancer cells migration and invasion via the regulation of CD70, CD44 and VEGF expression in immune cells, which deserves our further investigation [26]. "
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    ABSTRACT: Mycoplasma hyorhinis (M.hyorhinis, M.hy) is associated with development of gastric and prostate cancers. The NLRP3 inflammasome, a protein complex controlling maturation of important pro-inflammatory cytokines interleukin (IL)-1β and IL-18, is also involved in tumorigenesis and metastasis of various cancers. To clarify whether M.hy promoted tumor development via inflammasome activation, we analyzed monocytes for IL-1β and IL-18 production upon M.hy challenge. When exposed to M.hy, human monocytes exhibited rapid and robust IL-1β and IL-18 secretion. We further identified that lipid-associated membrane protein (LAMP) from M.hy was responsible for IL-1β induction. Applying competitive inhibitors, gene specific shRNA and gene targeted mice, we verified that M.hy induced IL-1β secretion was NLRP3-dependent in vitro and in vivo. Cathepsin B activity, K(+) efflux, Ca(2+) influx and ROS production were all required for the NLRP3 inflammasome activation by M.hy. Importantly, it is IL-1β but not IL-18 produced from macrophages challenged with M.hy promoted gastric cancer cell migration and invasion. Our data suggest that activation of the NLRP3 inflammasome by M.hy may be associated with its promotion of gastric cancer metastasis, and anti-M.hy therapy or limiting NLRP3 signaling could be effective approach for control of gastric cancer progress.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Higher expression levels of IL-18 have been detected in various cancer cells, such as those in gastric cancer (Ye et al., 2007) and breast cancer (Eissa et al., 2005). Further analysis has shown that IL-18 promotes the expression of vascular endothelial growth factor and degradation of the extracellular matrix to accelerate the process of cancer angiogenesis and migration (Alexandrakis et al., 2004; Jung et al., 2006; Cho et al., 2006; Kim et al., 2007). The data obtained recently also indicated that IL-18 interacts with phosphorylation ERK1/2 (Amin et al., 2007), p38 MAPK, and endogenous oxygen species (reactive oxygen intermediate)signaling pathways (Jung et al., 2006) to induce the apoptosis of immune cells in the tumor immune escape (Yoon et al., 2004). "
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    ABSTRACT: Interleukin-18 (IL-18) has been implicated in a wide variety of cellular functions that affect the biological response to tumors. However, there is insufficient evidence to prove that IL-18 gene variants are associated with risk of prostate cancer. We examined a possible association between two promoter polymorphisms, -137G/C (rs187238) and -607C/A (rs1946518), in the IL-18 gene and prostate cancer occurrence and prognosis in Han Chinese. We used a high-resolution melting method to genotype these two polymorphisms in 375 Chinese Han patients with prostate cancer and in 400 age-matched healthy controls. A hundred and eighty-one prostate cancer patients who had been receiving androgen deprivation therapy, including operational and medical castration, were enrolled to follow-up in this study. Carriers of the GG genotype of the -137G/ C polymorphism had a 2.165-times higher risk of prostate cancer progression than carriers of GC [95% confidence interval (CI) = 1.270-3.687]. Patients with the GG genotype at clinical stages III and IV also had significantly lower rates of progression-free survival (relative risk = 2.174, 95%CI = 1.211-3.906). However, we found no significant association of genotype or allele distributions of these two polymorphisms with occurrence of prostate cancer. We conclude that there is evidence that the IL-18 gene promoter polymorphism -137G/ C influences the prognosis of prostate cancer patients in androgen deprivation therapy, although neither of the two SNPs contributes to prostate cancer development.
    Full-text · Article · Mar 2013 · Genetics and molecular research: GMR
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    • "Similarly, the dual eVect of IL-18 in tumor progression is illustrated by its ability to stimulate natural killer and T cells which eliminate nascent tumor cells on the one hand, yet to display pro-carcinogenic functions on the other, that include promotion of VEGF production , which itself stimulates IL-18 mRNA synthesis in a dose-dependent manner. (Kim et al. 2007). IL-18 also induces MMP-9 expression, and may thereby be a signiWcant player in tumor cell migration, invasion and metastasis (Park et al. 2007). "
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    ABSTRACT: It is well established that interactions between tumor cells and the host tissue stroma play a key role in determining whether and how any given solid malignancy will develop. In most cases, tumor cells hijack stromal cell functions for their own benefit and ultimately dictate the rules of engagement to the host tissue microenvironment. However, the contribution of the different stromal cell components to tumor growth remains to be clarified. Because most solid tumors are accompanied by a local inflammatory response, it has long been thought that inflammation and carcinogenesis are related. If formal proof that cancer can be initiated by inflammation in the absence of exogenous carcinogens is still lacking, there is abundant evidence that the inflammatory response can play a central role in modulating tumor growth and progression. This review will discuss some of the mechanisms whereby inflammation can both enhance and inhibit tumor growth.
    Preview · Article · Nov 2008 · Histochemie
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