ZEB1 Enhances Transendothelial Migration and Represses the Epithelial Phenotype of Prostate Cancer Cells
ZEB1 Enhances Transendothelial Migration and Represses the Epithelial Phenotype of Prostate Cancer Cells
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DOI：
10.1091/mbc.e08-10-1076
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发表时间：
2009-04-15
影响因子：
3.3
通讯作者：
Henry, Michael D.
中科院分区：
文献类型：
--
作者：
Drake, Justin M.;Strohbehn, Garth;Henry, Michael D.
转移性定植包括癌细胞在微血管中沉积或粘附，随后这些细胞通过内皮迁移到次要器官部位。为了进一步研究这一过程，我们在体外分析了人PC-3前列腺癌细胞的跨内皮迁移。我们分离了一个细胞亚群，TEM4-18，它更有效地穿过内皮屏障，但令人惊讶的是，在体外其他情况下，比亲代PC-3细胞的侵袭性更小。重要的是，在小鼠转移定殖模型中，TEM4-18细胞比PC-3细胞更具侵袭性。这些细胞的芯片和FACS分析显示，许多先前与白细胞运输和癌细胞外溢相关的基因表达不变或下调。相反，TEM4-18细胞表现出上皮-间质转化（EMT）的特征分子标记，包括E-cadherin表达的明显缺失和E-cadherin抑制因子ZEB1的上调。在TEM4-18细胞中沉默ZEB1导致E-cadherin增加和跨内皮迁移减少。TEM4-18细胞也表达n -钙粘蛋白，这对于增加跨内皮迁移是必要的，但不是充分的。我们的研究结果将EMT在前列腺癌细胞转移中的作用扩展到跨内皮迁移，并暗示ZEB1和N-cadherin参与了这一过程。
Metastatic colonization involves cancer cell lodgment or adherence in the microvasculature and subsequent migration of those cells across the endothelium into a secondary organ site. To study this process further, we analyzed transendothelial migration of human PC-3 prostate cancer cells in vitro. We isolated a subpopulation of cells, TEM4-18, that crossed an endothelial barrier more efficiently, but surprisingly, were less invasive than parental PC-3 cells in other contexts in vitro. Importantly, TEM4-18 cells were more aggressive than PC-3 cells in a murine metastatic colonization model. Microarray and FACS analysis of these cells showed that the expression of many genes previously associated with leukocyte trafficking and cancer cell extravasation were either unchanged or down-regulated. Instead, TEM4-18 cells exhibited characteristic molecular markers of an epithelial-to-mesenchymal transition (EMT), including frank loss of E-cadherin expression and up-regulation of the E-cadherin repressor ZEB1. Silencing ZEB1 in TEM4-18 cells resulted in increased E-cadherin and reduced transendothelial migration. TEM4-18 cells also express N-cadherin, which was found to be necessary, but not sufficient for increased transendothelial migration. Our results extend the role of EMT in metastasis to transendothelial migration and implicate ZEB1 and N-cadherin in this process in prostate cancer cells.