title: ZEB1 coordinately regulates laminin-332 and {beta}4 integrin expression altering the invasive phenotype of prostate cancer cells.
abstract: Metastasis involves the invasion of cancer cells across both the extracellular matrix and cellular barriers, and an evolving theme is that epithelial-to-mesenchymal transition (EMT) may mediate invasive cellular behavior. Previously, we isolated and analyzed a subpopulation of PC-3 prostate cancer cells, TEM4-18, and found that these cells both invaded an endothelial barrier more efficiently and exhibited enhanced metastatic colonization in vivo. Transendothelial migration of these cells depended on expression of ZEB1, a known regulator of EMT. Surprisingly, these cells were much less invasive than parental PC-3 cells in assays that involve matrix barriers. Here, we report that TEM4-18 cells express significantly reduced levels of two subunits of laminin-332 (β3 and γ2) and that exogenous laminin-332, or co-culture with laminin-332-expressing cells, rescues the in vitro invasion phenotype in these cells. Stable knockdown of ZEB1 in prostate cancer cells up-regulated LAMC2 and ITGB4 mRNA and protein and resulted in a concomitant increase in Transwell migration. Using chromatin immunoprecipitation (ChIP), we show that ZEB1 directly interacts with the promoters of LAMC2 and ITGB4. These results provide a novel molecular basis for reduced laminin-332 observed in clinical prostate cancer specimens and demonstrate a context-dependent role for EMT in invasive cellular behavior.
authors: Departments of Molecular Physiology and Biophysics, Roy J and Lucille ACarver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Justin M
authors: JM
authors: Drake
authors: J Matthew
authors: JM
authors: Barnes
authors: Joshua M
authors: JM
authors: Madsen
authors: Frederick E
authors: FE
authors: Domann
authors: Christopher S
authors: CS
authors: Stipp
authors: Michael D
authors: MD
authors: Henry
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D002843:Chromatin / Q000378:metabolism; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry*; D008297:Male; D009362:Neoplasm Metastasis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D039663:Integrin beta4; D007797:Laminin; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1