| Autor: |
López-Moncada F; Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile.; School of Medical Technology, Austral University of Chile, Puerto Montt 5504335, Chile., Torres MJ; Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile., Lavanderos B; Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile., Cerda O; Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile., Castellón EA; Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile., Contreras HR; Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile. |
| Abstrakt: |
Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial-mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway. |
