uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells.
uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells.
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DOI：
10.1083/jcb.200701092
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发表时间：
2007-07-30
期刊：
影响因子：
--
通讯作者：
Gonias SL
中科院分区：
文献类型：
--
作者：
Lester RD;Jo M;Montel V;Takimoto S;Gonias SL
缺氧激活促进细胞存活的遗传程序;然而，在癌症中，它可能促进侵袭和转移。在这项研究中，我们表明，乳腺癌细胞培养在1.0%O2表现出的变化与上皮间质转化（EMT）一致。Snail易位到细胞核，E-钙粘蛋白从质膜丢失。波形蛋白表达、细胞迁移、基质胶侵袭和胶原重塑增加。缺氧诱导的EMT伴随着尿激酶型纤溶酶原激活物受体（uPAR）表达的增加和uPAR下游细胞信号传导因子（包括Akt和Rac 1）的激活。糖原合成酶激酶-3 β被磷酸化，Snail表达增加。低氧诱导的EMT被uPAR基因沉默阻断，并被常氧下uPAR过表达模拟。拮抗Rac 1或磷脂酰肌醇3-激酶也抑制缺氧时与EMT相关的细胞特性的发展。将乳腺癌细胞植入鸡胚绒毛尿囊膜并用CoCl 2处理，以模拟缺氧，表现出扩散增加。我们的结论是，在缺氧，uPAR激活不同的细胞信号通路，协同诱导EMT，并可能促进癌症转移。
Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. In this study, we show that breast cancer cells cultured in 1.0% O2 demonstrate changes consistent with epithelial–mesenchymal transition (EMT). Snail translocates to the nucleus, and E-cadherin is lost from plasma membranes. Vimentin expression, cell migration, Matrigel invasion, and collagen remodeling are increased. Hypoxia-induced EMT is accompanied by increased expression of the urokinase-type plasminogen activator receptor (uPAR) and activation of cell signaling factors downstream of uPAR, including Akt and Rac1. Glycogen synthase kinase-3β is phosphorylated, and Snail expression is increased. Hypoxia-induced EMT is blocked by uPAR gene silencing and mimicked by uPAR overexpression in normoxia. Antagonizing Rac1 or phosphatidylinositol 3-kinase also inhibits development of cellular properties associated with EMT in hypoxia. Breast cancer cells implanted on chick chorioallantoic membranes and treated with CoCl2, to model hypoxia, demonstrate increased dissemination. We conclude that in hypoxia, uPAR activates diverse cell signaling pathways that cooperatively induce EMT and may promote cancer metastasis.
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影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
6.2
作者：
Conley, Barbara A.;Wright, John J.;Kummar, Shivaani
通讯作者：
Kummar, Shivaani
影响因子：
5.8
作者：
Harrison, L;Blackwell, K
通讯作者：
Blackwell, K
DOI：
10.1083/jcb.200409067
发表时间：
2005-01-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bachelder RE;Yoon SO;Franci C;de Herreros AG;Mercurio AM
通讯作者：
Mercurio AM