Document Detail


Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models.
MedLine Citation:
PMID:  23027626     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.
Authors:
Daiana D Becker-Santos; Yubin Guo; Mazyar Ghaffari; Elaine D Vickers; Melanie Lehman; Manuel Altamirano-Dimas; Arusha Oloumi; Junya Furukawa; Manju Sharma; Yuzhuo Wang; Shoukat Dedhar; Michael E Cox
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-01
Journal Detail:
Title:  Carcinogenesis     Volume:  33     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-03-08     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  2558-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Azo Compounds / pharmacology
Cell Line, Tumor
Epithelial-Mesenchymal Transition
Humans
Lymphoid Enhancer-Binding Factor 1 / physiology
Male
Mice
Neoplasm Invasiveness
Prostatic Neoplasms / pathology*
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  physiology*
Pyrazoles / pharmacology
Trans-Activators / physiology*
Transcription Factors / physiology
Grant Support
ID/Acronym/Agency:
P50CA097186/CA/NCI NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Azo Compounds; 0/ERG protein, human; 0/LEF1 protein, human; 0/Lymphoid Enhancer-Binding Factor 1; 0/Pyrazoles; 0/QLT 0267; 0/Trans-Activators; 0/Transcription Factors; 0/snail family transcription factors; EC 2.7.1.-/integrin-linked kinase; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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