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-β1 (TGF-β1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-β1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-β1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-β1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Animals
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Autocrine Communication*
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Cell Movement*
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Epithelial-Mesenchymal Transition*
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Female
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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Humans
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Male
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Neoplasm Metastasis
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Neoplasms / genetics
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Neoplasms / metabolism*
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Neoplasms / pathology
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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PC-3 Cells
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Phenotype
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Phosphorylation
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Signal Transduction*
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Smad2 Protein / genetics
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Smad2 Protein / metabolism*
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Time Factors
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism*
Substances
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MYC protein, human
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Nuclear Proteins
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PSPC1 protein, human
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Proto-Oncogene Proteins c-myc
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RNA-Binding Proteins
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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TGFB1 protein, human
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Transforming Growth Factor beta1
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paraspeckle protein 1, mouse