RESUMO
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.
Assuntos
Comunicação Autócrina , Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Células PC-3 , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/genética , Proteína Smad2/genética , Proteína Smad3/genética , Fatores de Tempo , Fator de Crescimento Transformador beta1/genéticaRESUMO
Breast cancer is the most universal cancer in women, but the medications for breast cancer usually cause serious side effects and offer no effective treatment for triple-negative breast cancer. Here, we investigated the growth inhibitory effects of gallic acid (GA), (-)-epigallocatechin gallate (EGCG), or 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5GG) combined with quercetin (Que) on breast cancer cells. In this study, we tested the combined effects of these compounds on estrogen receptor (ER)/human epidermal growth factor 2 (Her2)-negative (MDA-MB-231), ER-positive/Her2-negative (BT483), and ER-negative/Her2-positive (AU565) breast cancer cells. After treatment of each cell line with these compounds, we found that Que combined with 5GG induced S-phase arrest and apoptosis in MDA-BM-231 cells through downregulation of S-phase kinase protein 2 expression, but induced G2/M-phase arrest and apoptosis in AU565 cells through downregulation of Her2 expression. Additionally, Que combined with 5GG was more effective in inhibiting MDA-MB-231 cell growth than Que combined with EGCG (5GG analogue) or GA. The combination of 5GG and Que can offer great potential for the chemoprevention of ER-negative breast cancer.