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Integrin-linked kinase is an essential mediator of ERG-induced epithelial-to-mesenchymal transition in prostate cancer models

University of British Columbia

Approximately 50% of human prostate cancers carry a gene fusion involving the 5' untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an ETS transcription factor. Exogenous expression of ERG in human prostatic epithelial cell lines (PrECs) promotes phenotypic changes associated with epithelial-to-mesenchymal transition (EMT), a process implicated in the invasion and metastasis of carcinomas. To gain insight into the biological mechanism by which ERG promotes EMT, I used two immortalized PrECs stably infected with a lentiviral vector expressing a Flag epitope-tagged ERG3 (fERG-PrECs). qRT-PCR and Western blotting show that integrin-linked kinase (ILK) mRNA and protein levels are increased in fERG-PrECs. The mesenchymal markers and downstream effectors of ILK, LEF-1 and Snail, are also upregulated in fERG-PrECs. Depletion of ILK expression by siRNA or inhibition of its activity with a highly selective small molecule inhibitor, QLT-0267, results in a substantial decrease in ERG-mediated upregulation of Snail and LEF-1. Furthermore, I show that inhibition of ILK activity impairs the in vitro invasive properties and suppresses the anchorage-independent growth of fERG-PrECs. In conclusion, I have provided novel insights into critical pathways by which aberrant ERG expression may promote prostate cancer progression. In particular, I presented evidence to support the hypothesis that ERG-mediated oncogenesis in prostate cancer involves activation of ILK signaling, leading to key cancer-promoting phenotypic effects, such as EMT.

Text

2011-03-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/33063

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/