5743

PTGS2

BACKGROUND: Transforming growth factor beta (TGF-beta) acts as a tumor promoter by inducing epithelial-mesenchymal transition (EMT), which leads to a motile phenotype, enabling invasion and metastasis of cancer cells. cancer-related inflammation, mediated by prostaglandins, has been proposed as a critical mechanism in conversion of benign cells to malignant. OBJECTIVE: Induction of cyclooxygenase 2 (COX-2), producer of prostaglandins, is thought to be a prerequisite for TGF-beta-induced EMT in benign cells. We used HaCaT derivatives, representative of skin cancer progression, to investigate TGF-beta1 mediated EMT response, and the role of COX-2 in it. METHODS: Effect of TGF-beta1 was investigated by analyzing cell proliferation, morphology and protein expression. Chemotaxis and scratch-wound assays were used to study migration. RESULTS: TGF-beta1 caused proliferation arrest of benign and malignant HaCaT cells, and changed the epithelial morphology of benign and low-grade malignant cells, but not metastatic cells, to mesenchymal spindle-shape. epithelial junction proteins ZO-1 and E-cadherin were downregulated in all cell lines in response to TGF-beta1, but mesenchymal markers were not induced, suggesting a partial EMT response. COX-2 and migration were induced only in benign HaCaT derivatives. Malignant derivatives did not induce COX-2 in response to TGF-beta 1 treatment, thus emphasizing the role of inflammation in EMT response of benign cells. CONCLUSIONS: TGF-beta1 operates via distinct mechanisms in inducing EMT and metastasis, and supporting this we show that TGF-beta1 induces COX-2 and promotes the migration of benign cells, but does not further augment the migration of malignant cells, indicating their resistance to TGF-beta1 in the context of motility.CI - 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

epithelial to mesenchymal transition (EMT) is an intricate process by which epithelial cells loose epithelial characteristics and acquire a mesenchymal-like phenotype. EMT and cyclooxygenase 2 (COX-2) expression are related to tumor invasion and metastasis. The tumor microenvironment plays a major role in tumor progression and the induction of EMT. Here, we investigated the relationship between EMT and COX-2 expression as well as tumor-associated macrophages (TAM) and CD10-positive stromal cells during the development of cutaneous squamous neoplastic lesion. We performed immunohistochemical staining for vimentin, E-cadherin, beta-catenin, COX-2, CD68, and CD10 in 41 cases of squamous cell cancers (SCC), 20 of Bowen's disease, 30 of actinic keratosis, and 30 samples of normal skin. SCC cells showed significantly increased vimentin expression and reduced expression of membranous E-cadherin and beta-catenin compared with cells in precursor lesions and in normal skin. COX-2 expression was also markedly increased in SCC cells. E-cadherin expression was positively correlated with beta-catenin expression and inversely correlated with COX-2 expression in SCC cells. The number of TAM and CD10-positive stromal cells increased from the normal skin to precursor lesions and SCC cells. The number of TAM and of CD10-positive stromal cells did not correlate with the expression of E-cadherin, beta-catenin, COX-2, and vimentin in SCC cells. We suggest that cutaneous SCC cells show EMT, which appears to be correlated with COX-2 expression but not with stromal CD10 expression and TAM.

AIMS: Determination of prognostic parameters that are predictive of survival of gastric cancer (GC) may allow better identification of patients who could benefit from current chemotherapy regimens. To assess the correlation between tumour progression and epithelial-mesenchymal transition (EMT), we assayed the expression levels of selected molecules involved in EMT [CD44, transforming growth factor (TGF)-alpha, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-7, MMP-9 and C-X-C chemokine receptor (CXCR4)], and correlated these with overall patient survival (OS) and disease stage. METHODS AND RESULTS: Medical records and pathological biopsy results of 137 patients with GC were evaluated retrospectively. Spearman's correlation analysis showed that expression of CXCR4 was correlated significantly with the expression of all other proteins studied. In contrast, COX-2 expression correlated significantly with the expression of only MMP-7 (P = 0.011), MMP-9 (P = 0.015) and CXCR4 (P = 0.013). We observed significant negative correlations between OS and the expression of TGF-alpha (P = 0.017), COX-2 (P < 0.001), CXCR4 (P = 0.010), MMP-7 (P = 0.020) and MMP-9 (P = 0.015). On multivariate analysis, only COX-2 was an independent prognostic factor for OS [hazard ratio (HR) = 3.34; 95% confidence interval (CI): 1.43-9.75; P = 0.002). CONCLUSIONS: COX-2, TGF-alpha, MMP-7, MMP-9 and CXCR4 are associated with poor OS in gastric cancer.CI - (c) 2012 Blackwell Publishing Ltd.

Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells.

Many studies have highlighted the correlation between the increase of bisphenol A (BPA) level in the environment and the incidence of tumor in humans. In human carcinogenesis, the overexpression of cyclooxygenase-2 (COX-2) and epithelial-mesenchymal transition (EMT) are closely related with tumor development. In this study, human endometrial carcinoma cells line (RL95-2) was used to investigate whether BPA can induce EMT and COX-2 expression. The results show that BPA increased growth rate and colony-forming efficiency in a dose-dependent manner, induced EMT and COX-2 gene expression and promoted the migration and invasion ability of RL95-2 cells. Furthermore, our study showed that the expression of COX-2 was essential for BPA-induced cell migration and invasion. The results of this study provide new insights into the mechanism of endometrial cancer cell growth and invasion and potential therapeutic strategy.CI - Copyright (c) 2015 Elsevier Inc. All rights reserved.

Platelets are activated by the interaction with cancer cells and release enhanced levels of lipid mediators [such as thromboxane (TX)A2 and prostaglandin (PG)E2, generated from arachidonic acid (AA) by the activity of cyclooxygenase (COX)-1], granule content, including ADP and growth factors, chemokines, proteases and Wnt proteins. Moreover, activated platelets shed different vesicles, such as microparticles (MPs) and exosomes (rich in genetic material such as mRNAs and miRNAs). These platelet-derived products induce several phenotypic changes in cancer cells which confer high metastatic capacity. A central event involves an aberrant expression of COX-2 which influences cell-cycle progression and contribute to the acquisition of a cell migratory phenotype through the induction of epithelial mesenchymal transition genes and down-regulation of E-cadherin expression. The identification of novel molecular determinants involved in the cross-talk between platelets and cancer cells has led to identify novel targets for anti-cancer drug development.CI - (c) 2015 Authors.

BACKGROUND: The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non-small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met. METHODS: Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF. RESULTS: Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment. CONCLUSIONS: In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.