ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation.
ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation.
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DOI：
10.4161/cbt.8.11.8539
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发表时间：
2009-06
影响因子：
3.6
通讯作者：
Chopp M
中科院分区：
文献类型：
--
作者：
Zheng X;Jiang F;Katakowski M;Zhang ZG;Lu QE;Chopp M
去整合素和金属蛋白酶-17(ADAM17)参与了几种膜结合生长因子和细胞因子的蛋白水解性胞外结构域脱落。在某些病理条件下，如中风、胶质瘤等，ADAM17的表达和活性增加。ADAM17促进神经前体细胞迁移，有助于卒中后卒中诱导的神经发生和脑肿瘤的生长和侵袭。在本研究中，我们试图阐明ADAM17是否促进乳腺癌的进展及其机制。为此，我们研究了ADAM17在体外对MDA-MB-231乳腺癌细胞增殖、侵袭和管状形成的作用。分别用人ADAM17高表达的质粒和ADAM17的siRNA稳定地转染人乳腺癌细胞株MDA-MB-231，以建立ADAM17高表达或低表达的乳腺癌细胞。用ADAM17抑制剂TAPI-2和PI3K-AKT抑制剂LY294002阻断ADAM17的高表达或PI3K-AKT通路的激活，以探讨ADAM17的作用机制。采用四甲基偶氮唑盐比色法、溴脱氧尿嘧啶核苷掺入法、生长曲线法和硫代罗丹明B法检测乳腺癌细胞的增殖情况。采用Matrigel侵袭实验检测MDA-MB-231细胞穿透细胞外基质的能力。进行Matrigel管形成实验以测试毛细管形成能力。用Western印迹和ELISA法检测不同ADAM17表达水平下，细胞内EGFR-PI3K-Akt通路的激活情况。我们的数据表明，ADAM17通过增加增殖、侵袭和血管生成来促进MDA-MB-231的恶性表型。ADAM17siRNA、Tapi-2和LY294002均可抑制ADAM17siRNA、Tapi-2和LY294002对α分泌和表达的影响。ADAM17激活，而ADAM17 siRNA、TAPI-2和LY294002失活EGFR-PI3K-AKT信号通路，与MDA-MB-231细胞恶性表型变化相关。本研究提示ADAM17通过激活EGFR-PI3K-AKT信号通路参与乳腺癌的进展。
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 glioma. ADAM17 promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis after stroke and brain tumor growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to breast cancer progression and its mechanisms. To this end, we examined the role of ADAM17 in the proliferation, invasion, and tube formation of MDA-MB-231 breast cancer cells in vitro. Stable transfection of the MDA-MB-231 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 breast cancer cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high ADAM17 expression or the activated PI3K-AKT pathway. Proliferation of MDA-MB-231 breast cancer cells were tested by MTT, Bromodeoxyuridine incorporation assay, growth curve, and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of MDA-MB-231 cells to penetrate the Extra Cellular Matrix. A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in MDA-MB-231 cells under different ADAM17 expression levels were tested by Western blot and ELISA. Our data show that ADAM17 promotes the MDA-MB-231 malignant phenotype by increased proliferation, invasion and angiogenesis. TGF-α, VEGF secretion and VEGF expression was increasing by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2, and LY294002 in MDA-MB-231 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2, and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with MDA-MB-231 cell malignant phenotype changes. This study suggests ADAM17 contributes to breast cancer progression through activation of the EGFR-PI3K-AKT signal pathway.
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影响因子：
4.8
作者：
Buxbaum, JD;Liu, KN;Black, RA
通讯作者：
Black, RA
影响因子：
15.9
作者：
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通讯作者：
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影响因子：
50.5
作者：
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DOI：
10.1016/j.bbapap.2007.09.008
发表时间：
2008-01-01
影响因子：
3.2
作者：
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通讯作者：
Liu, Ling-Zhi
影响因子：
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作者：
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通讯作者：
Chopp, Michael