ETS-1 protein regulates vascular endothelial growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3.
ABSTRACT Matrix metalloproteinase-mediated degradation of extracellular matrix is a crucial event for invasion and metastasis of malignant cells. The expressions of matrix metalloproteinases (MMPs) are regulated by different cytokines and growth factors. VEGF, a potent angiogenic cytokine, induces invasion of ovarian cancer cells through activation of MMPs. Here, we demonstrate that invasion and scattering in SKOV-3 cells were induced by VEGF through the activation of p38 MAPK and PI3K/AKT pathways. VEGF induced the expression of MMP-2, MMP-9, and MMP-13 and hence regulated the metastasis of SKOV-3 ovarian cancer cells, and the activities of these MMPs were reduced after inhibition of PI3K/AKT and p38 MAPK pathways. Interestingly, VEGF induced expression of ETS-1 factor, an important trans-regulator of different MMP genes. ETS-1 bound to both MMP-9 and MMP-13 promoters. Furthermore, VEGF acted through its receptor to perform the said functions. In addition, VEGF-induced MMP-9 and MMP-13 expression and in vitro cell invasion were significantly reduced after knockdown of ETS-1 gene. Again, VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. VEGF enriched ETS-1 in the nuclear fraction in a dose-dependent manner. VEGF-induced expression of ETS-1 and its nuclear localization were blocked by specific inhibitors of the PI3K and p38 MAPK pathways. Therefore, based on these observations, it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. The study provides a mechanistic insight into the prometastatic functions of VEGF-induced expression of relevant MMPs.
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ABSTRACT: BackgroundBoth transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins’ correlation and their clinical significance in colorectal cancerous tissues.ResultsThe specimens were arranged into microarray using the immunohistochemistry method to investigate the expression of integrin αvβ6 and transcriptional factor Ets-1 in these tissues. Among the 158 tissue specimens, 36.07% were positive for αvβ6 expression, and 57.59% were positive for Ets-1 expression. There were obvious statistical differences existed regarding differentiation, N stage, M stage and TNM stage between αvβ6 and Ets-1 positively and negatively expressing tumors. The correlation analysis confirmed the expression of αvβ6 and Ets-1 were positively correlated in colorectal cancer. The Kaplan-Meier survival analysis showed that patients who were both αvβ6 and Ets-1 positive relapsed earlier than those who were both αvβ6 and Ets-1 negative; and the former group had much shorter survival time than the latter. And Cox model indicated that αvβ6 and Ets-1 were the independent prognostic factors (RR = 2.175, P = 0.012 and RR = 3.903, P < 0.001).ConclusionsThe expression of αvβ6 and Ets-1 were positively correlated, and their expression degrees were associated with the differentiation, N stage, M stage and TNM stage of the tumors. Hence, the combination of αvβ6 and Ets-1 can be used as a prognostic marker in colorectal cancer, especially for the early stage.09/2014; 4(1):53. DOI:10.1186/2045-3701-4-53
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ABSTRACT: We previously reported that β6 integrin played an important role in the progression of colon cancer. In this study, we demonstrated that β6 integrin induced the expression of MMP-3/MMP-9 and the invasion of colon cancer cells. Moreover, that function was abolished by the inhibition of ERK/MAPK pathways or knockdown of ETS1, an important transcription factor of MMP genes. Here, we showed that β6 induced phosphorylation of ETS1 via the ERK/MAPK pathways, through which the MMP-3/MMP-9 promoters were stimulated, thereby leading to the up-regulation of MMP-3/MMP-9, and subsequent the invasion of colon cancer cells.Cancer Letters 08/2014; 354(2). DOI:10.1016/j.canlet.2014.08.017 · 5.02 Impact Factor
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ABSTRACT: Purpose:To investigate the exact mechanism by which keratocytes promote corneal neovascularization. Methods:The expression of MMP13, CD146, VEGFa, VEGFc, VEGFr2 and VEGFr3 by normal and alkali-burned rat corneas was determined by qRT-PCR and/or Western blot analysis, or in situ hybridization. Corneal neovascularization was observed under slit lamp microscope and evaluated by Immunohistochemistry. The cells which expressed MMP13 in corneas were determined by sequential immunohistochemistry and in situ hybridization. The degradation of typeⅠcollagen was evaluated by detection of hydroxyproline content and western blot analysis. Effects of VEGFa and VEGFc on MMP13 expression were determined by luciferase reporter assay for MMP13 promoter and primary keratocytes culture. Results:MMP13 was predominantly expressed by epithelial cells in normal rat corneas but by cells in corneal stromas after alkali burns. The formation of new blood vessels was consistent with MMP13 expression and attenuated by selective MMP13 inhibitor in alkali-burned corneas. Keratocytes was the major cells expressing MMP13 in corneal stromas after alkali burns. Through MMP13 expression, keratocytes directly degraded collagen type I to create stromal spaces into which were convenient for newly formed blood vessels growth. MMP13 expression and collagen type I degradation by keratocytes were induced VEGFc through VEGFr3 and inhibited by antibodies for VEGFc and VEGFr3. Conclusions:Keratocytes could directly degrade type I collagen and create stromal spaces to promote corneal neovascularization through VEGFc/VEGFr3-induced MMP13 expression.Investigative Ophthalmology & Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14746 · 3.66 Impact Factor