Journal Article

Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models

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 and Michael E. Cox

in Carcinogenesis

Volume 33, issue 12, pages 2558-2567
Published in print December 2012 | ISSN: 0143-3334
Published online October 2012 | e-ISSN: 1460-2180 | DOI:
Integrin-linked kinase as a target for ERG-mediated invasive properties  in prostate cancer models

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  • Clinical Cytogenetics and Molecular Genetics


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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.

Journal Article.  6308 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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