Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways
Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways
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DOI：
10.1158/0008-5472.can-07-2938
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Weinberg, Robert A.
中科院分区：
文献类型：
--
作者：
Onder, Tamer T.;Gupta, Piyush B.;Weinberg, Robert A.
上皮粘附分子E-钙粘蛋白的丢失被认为是通过破坏细胞间接触而使转移成为可能，这是转移性播散的早期步骤。为了进一步研究这一概念的分子基础，我们使用两种方法来抑制E-cadherin功能，区分E-cadherin的细胞间粘附和细胞内信号传导功能。尽管细胞-细胞接触的单独破坏不能使转移成为可能，但E-钙粘蛋白蛋白的丢失通过诱导上皮向间充质转化、侵袭性和抗失巢凋亡而使转移成为可能。我们发现E-钙粘蛋白结合伴侣β-连环蛋白是必要的，但不是足够的，诱导这些表型。此外，基因表达分析表明，E-钙粘蛋白的损失导致多种转录因子的诱导，其中至少有一个，扭曲，是必要的E-钙粘蛋白损失诱导的转移。这些发现表明，E-钙粘蛋白在肿瘤中的损失有助于通过诱导广泛的转录和功能变化的转移性传播。
Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contacts-an early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whereas the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness, and anoikis resistance. We find the E-cadherin binding partner beta-catenin to be necessary, but not sufficient, for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss-induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes.