A disintegrin and metalloproteinase-17 (ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and cancer. ADAM17 promotes neural progenitor cell migration and contributes to neurogenesis after stroke and breast cancer growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to glioma progression. To this end, we examined the role of ADAM17 in the proliferation, invasion, and tube formation of U87 human glioma cells in vitro and tumor growth in vivo. Stable transfection of the U87 cell line with either a plasmid for over-expression of human ADAM17, or a siRNA to ADAM17 was employed in this study to establish high- or low-ADAM17 expression in glioma cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high-ADAM17 expression and the activated PI3K-AKT pathway, respectively. Proliferation of glioma cells were tested by thiazolyl blue tetrazolium bromide (MTT) assay, bromodeoxyuridine incorporation assay, growth curve, and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of U87 cells to penetrate the extracellular matrix (ECM). A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in U87 cells under different ADAM17 expression levels were tested by Western blot. Our data show that ADAM17 promotes the U87 malignant phenotype by increased proliferation, invasion, angiogenesis, and in vivo tumor growth. Tumor growth in nude mice was significantly inhibited by ADAM17 inhibitor and A17-shRNA in vivo transfection. TGF-α, VEGF secretion, and VEGF expression was increased by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2, and LY294002 in U87 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2, and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with U87 cell malignant phenotype changes. This study suggests ADAM17 contributes to glioma progression through activation of the EGFR-PI3K-AKT signal pathway.
pan class="Gene">A disintegrin and metalloproteinase-17 (n>an class="Gene">ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and cancer. ADAM17 promotes neural progenitor cell migration and contributes to neurogenesis after stroke and breast cancer growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to glioma progression. To this end, we examined the role of ADAM17 in the proliferation, invasion, and tube formation of U87humanglioma cells in vitro and tumor growth in vivo. Stable transfection of the U87 cell line with either a plasmid for over-expression of humanADAM17, or a siRNA to ADAM17 was employed in this study to establish high- or low-ADAM17 expression in glioma cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high-ADAM17 expression and the activated PI3K-AKT pathway, respectively. Proliferation of glioma cells were tested by thiazolyl blue tetrazolium bromide (MTT) assay, bromodeoxyuridine incorporation assay, growth curve, and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of U87 cells to penetrate the extracellular matrix (ECM). A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in U87 cells under different ADAM17 expression levels were tested by Western blot. Our data show that ADAM17 promotes the U87 malignant phenotype by increased proliferation, invasion, angiogenesis, and in vivo tumor growth. Tumor growth in nude mice was significantly inhibited by ADAM17 inhibitor and A17-shRNA in vivo transfection. TGF-α, VEGF secretion, and VEGF expression was increased by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2, and LY294002 in U87 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2, and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with U87 cell malignant phenotype changes. This study suggests ADAM17 contributes to glioma progression through activation of the EGFR-PI3K-AKT signal pathway.
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