Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
复制标题
DOI：
10.1084/jem.20071082
复制
发表时间：
2007-11-26
期刊：
影响因子：
--
通讯作者：
Karsan A
中科院分区：
文献类型：
--
作者：
Leong KG;Niessen K;Kulic I;Raouf A;Eaves C;Pollet I;Karsan A
Jagged 1和Notch 1的异常表达与乳腺癌预后不良相关然而，Jagged 1和/或Notch过度表达预示预后不良的原因尚不清楚。我们确定Slug，一种转录抑制因子，作为一种新的Notch靶点，并表明Slug水平升高与各种人类癌症中Jagged 1表达增加相关。Slug对于Notch介导的E-钙粘蛋白抑制至关重要，从而导致β-连环蛋白激活和对失巢凋亡的抵抗。在异种移植Slug阳性/E-cadherin阴性乳腺肿瘤中抑制配体诱导的Notch信号传导促进细胞凋亡并抑制肿瘤生长和转移。这种反应与Slug表达下调、E-钙粘蛋白再表达和活性β-连环蛋白抑制相关。我们的研究结果表明，配体诱导的Notch激活，通过诱导Slug，促进肿瘤的生长和转移，其特征在于上皮间质转化和抑制失巢凋亡。
Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.
登录
查看更多内容
影响因子：
2.5
作者：
Hatsell, S;Rowlands, T;Cowin, P
通讯作者：
Cowin, P
影响因子：
4.4
作者：
Bermejo-Rodríguez, C;Pérez-Caro, M;Sánchez-García, I
通讯作者：
Sánchez-García, I
影响因子：
8
作者：
Imatani, A;Callahan, R
通讯作者：
Callahan, R
影响因子：
6
作者：
Frierson, HF;Ei-Naggar, AK;Hampton, GM
通讯作者：
Hampton, GM
影响因子：
6
作者：
Linn, SC;West, RB;van de Rijn, M
通讯作者：
van de Rijn, M