HOXC8-Dependent Cadherin 11 Expression Facilitates Breast Cancer Cell Migration through Trio and Rac.
HOXC8-Dependent Cadherin 11 Expression Facilitates Breast Cancer Cell Migration through Trio and Rac.
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DOI：
10.1177/1947601911433129
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Huang, Shuang
中科院分区：
文献类型：
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作者：
Li, Yong;Guo, Zijing;Huang, Shuang
HOXC 8表达在不同的癌症类型中上调，并且高水平的HOXC 8通常与侵袭性/转移性表型相关。我们以前报道过HOXC 8的存在对于乳腺癌细胞的迁移和转移是必不可少的。然而，HOXC 8调节细胞迁移的潜在分子机制尚不清楚。在这里，我们证明了HOXC 8的存在是所需的钙粘蛋白11（CDH 11）在乳腺癌细胞中的表达和HOXC 8调节细胞迁移是由CDH 11介导的。为了了解HOXC 8-CDH 11轴在细胞迁移中的作用，我们发现，耗尽HOXC 8或CDH 11减少了肌动蛋白为基础的膜皱褶的形成，细胞迁移所必需的事件。HOXC 8-或CDH 11-敲除细胞中膜皱褶的丧失显然是由Rac活性降低引起的，因为异位表达活性Rac 1恢复细胞骨架重组。CDH 11与Rac GEF Trio进行物理交互。我们表明，三是负责大多数的内源性Rac活性在迁移性乳腺癌细胞。由于CDH 11的敲低阻止了Trio的质膜定位，因此我们的研究表明，CDH 11可能在将Trio募集到质膜中方面发挥作用，其中Trio激活Rac，导致细胞迁移。这项研究揭示了一种新的HOXC 8-CDH 11-Trio-Rac信号传导轴，该轴对乳腺癌细胞迁移有显着贡献。
HOXC8 expression is upregulated in diverse cancer types, and a high level of HOXC8 is often associated with the aggressive/metastatic phenotypes. We previously reported that the presence of HOXC8 is essential for breast cancer cell migration and metastasis. However, the underlying molecular mechanism of HOXC8 regulation of cell migration is unclear. Here, we demonstrate that the presence of HOXC8 is required for cadherin 11 (CDH11) expression in breast cancer cells and that HOXC8 regulation of cell migration is mediated by CDH11. To understand the role of HOXC8-CDH11 axis in cell migration, we show that depleting either HOXC8 or CDH11 diminishes the formation of actin-based membrane ruffles, an event essential for cell migration. The loss of membrane ruffles in HOXC8- or CDH11-knockdown cells is apparently caused by reduced Rac activity because ectopically expressing active Rac1 restores cytoskeleton reorganization. CDH11 physically interacts with Trio, a Rac GEF. We show that Trio is responsible for the majority of endogenous Rac activity in migratory breast cancer cells. Because knockdown of CDH11 prevents the plasma membrane localization of Trio, our study indicates that CDH11 may play a role in recruiting Trio to the plasma membrane where Trio activates Rac, leading to cell migration. This study reveals a novel HOXC8-CDH11-Trio-Rac signaling axis that contributes significantly to breast cancer cell migration.