Abstract. expression by melanoma cells may influence their metastatic capabilities. tetramethylpyrazine (tMp) from Ligusticum wallichil Franch. possesses anti-inflammatory and antitumor activities. It has recently been suggested that autocrine IL-8 may play a role in tumor cell survival, invasion and migration. the role of tMp in association with IL-8 in the tumor cell migratory process remains unclear. the purpose of the present study was to determine whether TMP influences the migratory ability of a human ovarian carcinoma cell line (sKOV3) via regulation of IL-8 expression in vitro. Cell counts showed that treatment of sKOV3 with tMp (25-100 µg/ml) for 24 h did not decrease cell numbers, while an effect of tMp on the down-regulation of the expression of IL-8 was observed. In addition, migration of sKOV3 cells was suppressed after treatment with tMp (25-100 µg/ml) for 24 h. therefore, expression of IL-8 by sKOV3 cells correlates with their metastatic potential. Western blot analysis revealed that erK1/2 and p38 phosphorylation was blocked by tMp. Furthermore, IL-8 mrNA expression was inhibited significantly after co-incubation with PD98059 (erK inhibitor) and sB203580 (p38 inhibitor), respectively. Notably, these changes were the results of activator protein-1 (Ap-1) activity suppression rather than that of NF-κB. Our data suggest that tMp may inhibit tumor cell invasion and migration, at least in part, through its down-regulation of IL-8 expression. Our results provide evidence that anti-inflammation plays an important role in integrative cancer therapies. IntroductionThe functional relationship between inflammation and cancer is widely accepted. Inflammation is a critical component of tumor progression, such as tumor cell metastasis (1). Metastasis, a complex and multiple process in which tumor cells spread from the primary site to distant organs, is one of the most common causes of morbidity and mortality in patients with ovarian carcinoma. the migratory capacity of cancer cells can be regulated by various factors including growth factors and cytokines (2), such as CXC-chemokine IL-8 (CXCL-8), a pro-inflammatory cytokine initially described as a neutrophil and monocyte chemoattactant, which modulates monocyte adhesion to endothelium and vascular smooth muscle cell migration (3-5). A direct correlation has also been demonstrated between overexpressed IL-8 and the increased metastasis of tumor cells (6-8). Evidence has confirmed that tumor cells are able to respond to the autocrine release of IL-8, which enables tumor cells to have an additional growth and progression advantage (9). De Larco et al (10) reported that the concentration gradient of IL-8 produced by tumor cells, which is higher at the primary tumor site than that at noncancerous sites, promotes distant metastasis of tumor cells. Moreover, IL-8 can recruit neutrophils to the primary tumor site through its chemoattractant capacity. In response to IL-8, the recruited neutrophils release proteases and heparanase which hydrolyze components of the ext...
Background: The present study aimed to explore the role of ZIC4 in human liver cancer.Methods: Illumina450 genome-wide methylation data was downloaded from The Cancer Genome Atlas for 50 available liver tumor/surrounding pairs. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, survival and apoptosis. The effects of EZH2 and ZIC4 on tumor growth were also investigated through in vivo xenograft and orthotopic implantation experiments. Results: ZIC4 was hypermethylated in liver cancer tissues and cell lines. EZH2 knockdown and DZNep mediated H3K27me3 contributes to ZIC4 expression. The antitumor effect of EZH2 knockdown on hepatocellular carcinoma growth, metastasis and epithelial-mesenchymal transition progression in vitro were rescued by sh-ZIC4. Downregulation of ZIC4 also rescued the antitumor effect of DZNep in vivo.Conclusions: Epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in human liver cancer and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
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