Document Detail


Knock-down of plasminogen-activator inhibitor-1 enhances expression of E-cadherin and promotes epithelial differentiation of human pancreatic adenocarcinoma cells.
MedLine Citation:
PMID:  22331587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
High levels of plasminogen activator inhibitor-1 (PAI-1), which is produced by stromal, endothelial, and cancer cells and has multiple complex effects on cancers, correlate with poor cancer prognosis. To more definitively study the role of endogenously produced PAI-1 in human pancreatic adenocarcinoma (PAC) PANC-1 cell line biology, we used anti-PAI-1 shRNA to create stable PAI-1 deficient cells (PD-PANC-1s). PD-PANC-1s exhibited a heterogeneous morphology. While the majority of cells exhibited a cuboidal shape similar to the parental PANC-1 or the vector-infected control cells, numerous large cells with long filopodia and a neuronal-like appearance were observed. Although both Vector-control cells and PD-PANC-1s expressed mRNAs that are characteristic of mesenchymal, neural, and epithelial phenotypes, epithelial marker RNAs were up-regulated (e.g., E-cadherin, 32-fold) whereas mesenchymal marker RNAs were down-regulated (e.g., Thy1, ninefold) in PD-PANC-1s, suggesting mesenchymal-to-epithelial transition. Neural markers exhibited both up- and down-regulation. Immunocytochemistry indicated that epithelial-like PD-PANC-1s expressed E-cadherin and β-catenin in significantly more cells, while neural-like cells exhibited robust expression of organized β-3-tubulin. PAI-1 and E-cadherin were rarely co-expressed in the same cells. Indeed, examination of PAI-1 and E-cadherin mRNAs expression in additional cell lines yielded clear inverse correlation. Indeed, infection of Colo357 PAC cells (that exhibit high expression of E-cadherin) with PAI-1-expressing adenovirus led to a marked decrease in E-cadherin expression and to enhanced migration of cells from clusters. Our results suggest that endogenous PAI-1 suppresses expression of E-cadherin and differentiation in PAC cells in vitro, supporting its negative impact on tumor prognosis.
Authors:
Monica Lupu-Meiri; Elizabeth Geras-Raaka; Ruth Lupu; Hagit Shapira; Judith Sandbank; Liora Segal; Marvin C Gershengorn; Yoram Oron
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  227     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-07-23     Completed Date:  2012-10-03     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3621-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma* / metabolism,  pathology
Cadherins / genetics,  metabolism
Cell Differentiation / genetics*
Cell Line, Tumor
Epithelial-Mesenchymal Transition*
Epithelium* / growth & development,  metabolism
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Mesoderm / cytology,  growth & development,  metabolism
Pancreatic Neoplasms / metabolism
Plasminogen Activator Inhibitor 1 / genetics,  metabolism*
beta Catenin / metabolism
Grant Support
ID/Acronym/Agency:
ZIA DK011007-11/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Cadherins; 0/Plasminogen Activator Inhibitor 1; 0/beta Catenin
Comments/Corrections

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