TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells
| Autor: | Mark Laible, Yanis Tolstov, Leonie Ratz, Holger Sültmann, Peter Altevogt, Sabine M. Klauck, Stefan Duensing, Lukasz A. Kacprzyk, Stephanie M. Wittig-Blaich |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Epithelial-Mesenchymal Transition Oncogene Proteins Fusion Transcription Genetic Activin Receptors Type II ALK1 TGF-β signaling Models Biological p38 Mitogen-Activated Protein Kinases TMPRSS2 Smad7 Protein Fusion gene 03 medical and health sciences Prostate cancer 0302 clinical medicine Transcriptional Regulator ERG Transforming Growth Factor beta Cell Line Tumor LNCaP medicine Humans Epithelial–mesenchymal transition beta Catenin business.industry Serine Endopeptidases EMT Wnt signaling pathway Genetic Variation Prostatic Neoplasms Cancer prostate cancer medicine.disease TMPRSS2:ERG fusion variants Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Immunology Cancer research business Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.15931 |
| Popis: | // Leonie Ratz 1 , Mark Laible 1, 5 , Lukasz A. Kacprzyk 1, 6 , Stephanie M. Wittig-Blaich 1, 7 , Yanis Tolstov 2 , Stefan Duensing 2 , Peter Altevogt 3, 4 , Sabine M. Klauck 1 , Holger Sultmann 1 1 Cancer Genome Research Group, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany 2 Department of Urology, Section of Molecular Urooncology, University Hospital Heidelberg, 69120 Heidelberg, Germany 3 Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 4 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, 68135 Mannheim, Germany 5 Present address: BioNTech Diagnostics GmbH, 55131 Mainz, Germany 6 Present address: UGA Biopharma GmbH, 16761 Hennigsdorf, Germany 7 Present address: Institute of Comparative Molecular Endocrinology (CME), University of Ulm, 89081 Ulm, Germany Correspondence to: Holger Sultmann, email: h.sueltmann@dkfz.de Keywords: TMPRSS2:ERG fusion variants, TGF-β signaling, ALK1, EMT, prostate cancer Received: November 25, 2016 Accepted: February 15, 2017 Published: March 06, 2017 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. |
| Databáze: | OpenAIRE |
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