PSPC1 mediates TGF-ß1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis.
Nat Cell Biol
; 20(4): 479-491, 2018 04.
Article
em En
| MEDLINE
| ID: mdl-29593326
ABSTRACT
Activation of metastatic reprogramming is critical for tumour metastasis. However, more detailed knowledge of the underlying mechanism is needed to enable targeted intervention. Here, we show that paraspeckle component 1 (PSPC1), identified in an aberrant 13q12.11 locus, is upregulated and associated with poor survival in patients with cancer. PSPC1 promotes tumorigenesis, epithelial-to-mesenchymal transition (EMT), stemness and metastasis in multiple cell types and in spontaneous mouse cancer models. PSPC1 is the master activator for transcription factors of EMT and stemness and accompanies c-Myc activation to facilitate tumour growth. PSPC1 increases transforming growth factor-ß1 (TGF-ß1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-ß1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-ß1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-ß1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Proteínas Nucleares
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Transdução de Sinais
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Movimento Celular
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Proteínas de Ligação a RNA
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Comunicação Autócrina
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Proteína Smad2
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Proteína Smad3
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Fator de Crescimento Transformador beta1
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Transição Epitelial-Mesenquimal
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article