TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

• Verfasst von: Ratz, Leonie [VerfasserIn]
• Verfasst von: Laible, Mark [VerfasserIn]
• Verfasst von: Kacprzyk, Łukasz Antoni [VerfasserIn]
• Verfasst von: Wittig-Blaich, Stephanie Maritta [VerfasserIn]
• Verfasst von: Tolstov, Yanis [VerfasserIn]
• Verfasst von: Duensing, Stefan [VerfasserIn]
• Verfasst von: Altevogt, Peter [VerfasserIn]
• Verfasst von: Klauck, Sabine [VerfasserIn]
• Verfasst von: Sültmann, Holger [VerfasserIn]
• Titel: TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells
• Verf.angabe: Leonie Ratz, Mark Laible, Lukasz A. Kacprzyk, Stephanie M. Wittig-Blaich, Yanis Tolstov, Stefan Duensing, Peter Altevogt, Sabine M. Klauck, Holger Sültmann
• E-Jahr: 2017
• Jahr: 6 March 2017
• Umfang: 16 S.
• Fussnoten: Im Titel ist "TMPRSS2:ERG" kursiv geschrieben ; Gesehen am 11.04.2018
• Titel Quelle: Enthalten in: OncoTarget
• Ort Quelle: [Erscheinungsort nicht ermittelbar] : Impact Journals LLC, 2010
• Jahr Quelle: 2017
• Band/Heft Quelle: 8(2017), 15, Seite 25115-25130
• ISSN Quelle: 1949-2553
• DOI: doi:10.18632/oncotarget.15931
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1571911189

Abstract

TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and -β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.