PSPC1 mediates TGF-β1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis

NATURE CELL BIOLOGY(2018)

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摘要
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- β 1 (TGF- β 1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF- β 1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF- β 1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1–Smads–TGF- β 1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.
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关键词
Cancer,Cell signalling,Epithelial–mesenchymal transition,Metastasis,Life Sciences,general,Cell Biology,Cancer Research,Developmental Biology,Stem Cells
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