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

Publisher: Irl Press At Oxford University Press Country of Publication: England NLM ID: 8008055 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2180 (Electronic) Linking ISSN: 01433334 NLM ISO Abbreviation: Carcinogenesis Subsets: MEDLINE

Publication: Oxford : Irl Press At Oxford University Press
Original Publication: [New York, IRL Press]

Prostatic Neoplasms/*pathology ; Protein Serine-Threonine Kinases/*physiology ; Trans-Activators/*physiology; Animals ; Azo Compounds/pharmacology ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Humans ; Lymphoid Enhancer-Binding Factor 1/physiology ; Male ; Mice ; Neoplasm Invasiveness ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Pyrazoles/pharmacology ; Snail Family Transcription Factors ; Transcription Factors/physiology ; Transcriptional Regulator ERG

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.

Mol Cancer Ther. 2005 Aug;4(8):1146-56. (PMID: 16093430)
Cancer Res. 2007 Sep 1;67(17):7991-5. (PMID: 17804708)
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2105-10. (PMID: 18245377)
J Cell Sci. 2008 Oct 1;121(Pt 19):3121-32. (PMID: 18799788)
Clin Cancer Res. 2001 Jul;7(7):1987-91. (PMID: 11448915)
Nature. 1996 Jan 4;379(6560):91-6. (PMID: 8538749)
PLoS One. 2011;6(7):e21650. (PMID: 21747944)
Clin Cancer Res. 2008 Aug 1;14(15):4719-25. (PMID: 18676740)
In Vitro Cell Dev Biol Anim. 1995 Jan;31(1):14-24. (PMID: 7535634)
Blood. 2001 Dec 1;98(12):3332-9. (PMID: 11719371)
Oncogene. 2000 Aug 3;19(33):3811-5. (PMID: 10949937)
Endocr Relat Cancer. 2005 Sep;12(3):631-43. (PMID: 16172196)
Oncogene. 2005 May 19;24(22):3596-605. (PMID: 15782140)
Nat Genet. 2009 May;41(5):619-24. (PMID: 19396168)
Cancer Res. 2006 Sep 1;66(17):8337-41. (PMID: 16951139)
Cancer Res. 2006 Jan 1;66(1):393-403. (PMID: 16397254)
J Cell Biol. 2008 Feb 25;180(4):681-9. (PMID: 18283114)
Kidney Int. 2010 Aug;78(4):363-73. (PMID: 20505657)
J Clin Invest. 2009 Jun;119(6):1420-8. (PMID: 19487818)
Oncogene. 2005 May 26;24(23):3847-52. (PMID: 15750627)
BMC Cancer. 2008 Aug 11;8:230. (PMID: 18694509)
Nat Genet. 2009 May;41(5):524-6. (PMID: 19396167)
Eur Urol. 2009 Aug;56(2):275-86. (PMID: 19409690)
J Cell Biol. 1994 Feb;124(4):619-26. (PMID: 8106557)
J Biol Chem. 2002 Oct 18;277(42):39209-16. (PMID: 12161443)
Urology. 2007 Oct;70(4):630-3. (PMID: 17991527)
Cancer Res. 2010 Sep 1;70(17):6735-45. (PMID: 20713528)
Bioessays. 2001 Oct;23(10):912-23. (PMID: 11598958)
Nat Rev Cancer. 2008 Jul;8(7):497-511. (PMID: 18563191)
Cancer Biol Ther. 2007 Jan;6(1):40-5. (PMID: 17172822)
Cancer Res. 2005 Jul 15;65(14):5991-5; discussion 5995. (PMID: 16024595)
Oncogene. 2008 Sep 11;27(40):5348-53. (PMID: 18542058)
Cancer Res. 2008 Apr 1;68(7):2391-9. (PMID: 18381447)
Oncogene. 2007 Jul 5;26(31):4596-9. (PMID: 17237811)
Cancer Res. 2005 Dec 15;65(24):11649-57. (PMID: 16357176)
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21276-81. (PMID: 22123976)
Dev Dyn. 2008 Oct;237(10):2737-47. (PMID: 18773488)
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4374-9. (PMID: 9539744)
Nat Methods. 2007 Apr;4(4):359-65. (PMID: 17396127)
Carcinogenesis. 1997 Jun;18(6):1215-23. (PMID: 9214605)
Cancer Res. 2009 Apr 15;69(8):3332-8. (PMID: 19351848)
APMIS. 2009 Mar;117(3):196-204. (PMID: 19245592)
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3207-12. (PMID: 10716737)
Cancer Res. 2008 May 15;68(10):3584-90. (PMID: 18483239)
Neoplasia. 2008 Feb;10(2):177-88. (PMID: 18283340)
Expert Rev Anticancer Ther. 2008 Jan;8(1):33-42. (PMID: 18095881)
Science. 2005 Oct 28;310(5748):644-8. (PMID: 16254181)
Eur J Cancer. 2005 Nov;41(16):2462-78. (PMID: 16213704)
Cancer Res. 2001 Aug 15;61(16):6064-72. (PMID: 11507055)
J Urol. 1991 Sep;146(3):881-6. (PMID: 1714974)
Mod Pathol. 2008 Dec;21(12):1451-60. (PMID: 18500259)
Oncogene. 2001 Jan 4;20(1):133-40. (PMID: 11244511)
J Clin Pathol. 2007 Nov;60(11):1238-43. (PMID: 17259299)
Oncogene. 2008 Jan 10;27(3):253-63. (PMID: 17637754)
Cancer Res. 2008 Jan 1;68(1):73-80. (PMID: 18172298)
Matrix Biol. 2010 Apr;29(3):161-5. (PMID: 20018240)
Nucleic Acids Res. 2004 Oct 21;32(18):5693-702. (PMID: 15498926)

P50CA097186 United States CA NCI NIH HHS; Canada Canadian Institutes of Health Research

0 (Azo Compounds)
0 (ERG protein, human)
0 (LEF1 protein, human)
0 (Lymphoid Enhancer-Binding Factor 1)
0 (Pyrazoles)
0 (QLT 0267)
0 (Snail Family Transcription Factors)
0 (Trans-Activators)
0 (Transcription Factors)
0 (Transcriptional Regulator ERG)
EC 2.7.1.- (integrin-linked kinase)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)

Date Created: 20121003 Date Completed: 20130308 Latest Revision: 20211203

20250114

PMC3510737

10.1093/carcin/bgs285

23027626