Cytoplasmic PML promotes TGF-β-associated epithelial-mesenchymal transition and invasion in prostate cancer

Autor: Amanda K. Miles, Catherine Johnson, G Hulman, Richard Parkinson, Desmond G. Powe, Tarik Regad, Magdalena Elżbieta Buczek, Robert C. Rees, J Hulman, William J.F. Green, David J. Boocock, G. van Schalkwyk, Alan Graham Pockley
Rok vydání: 2015
Předmět:
0301 basic medicine
Male
Cancer Research
Cytoplasm
Epithelial-Mesenchymal Transition
Immunoblotting
Active Transport
Cell Nucleus
Receptor
Transforming Growth Factor-beta Type I
Receptors
Cytoplasmic and Nuclear
Kaplan-Meier Estimate
Smad2 Protein
Karyopherins
Promyelocytic Leukemia Protein
Protein Serine-Threonine Kinases
Metastasis
03 medical and health sciences
Prostate cancer
Promyelocytic leukemia protein
Cell Movement
Transforming Growth Factor beta
Cell Line
Tumor
Genetics
medicine
Humans
Neoplasm Invasiveness
Epithelial–mesenchymal transition
Smad3 Protein
Phosphorylation
Molecular Biology
Cell Nucleus
biology
Cancer
Prostatic Neoplasms
Transforming growth factor beta
medicine.disease
Hedgehog signaling pathway
030104 developmental biology
Cancer cell
Immunology
biology.protein
Cancer research
RNA Interference
Original Article
Receptors
Transforming Growth Factor beta
Signal Transduction
Zdroj: Oncogene
Europe PubMed Central
ISSN: 1476-5594
0950-9232
Popis: Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.
Databáze: OpenAIRE
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