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Originally published as MBoC in Press, 10.1091/mbc.E08-10-1076 on February 18, 2009

Vol. 20, Issue 8, 2207-2217, April 15, 2009

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ZEB1 Enhances Transendothelial Migration and Represses the Epithelial Phenotype of Prostate Cancer Cells

Justin M. Drake*, Garth Strohbehn*, Thomas B. Bair{dagger}, Jessica G. Moreland{ddagger}, and Michael D. Henry*,§

Departments of *Molecular Physiology and Biophysics, §Pathology, {ddagger}Pediatrics, and {dagger}DNA Facility, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242

Submitted October 28, 2008; Revised January 21, 2009; Accepted February 9, 2009
Monitoring Editor: Richard O. Hynes

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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-10-1076) on February 18, 2009.

Address correspondence to: Michael D. Henry (michael-henry{at}uiowa.edu)

Abbreviations used: BLI, bioluminescent imaging; EMT, epithelial-to-mesenchymal transition; HMVEC-L, human microvascular endothelial cell from lung; qPCR, quantitative PCR.






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