Abstract
BackgroundStem cell antigen-1 (Sca-1 or Ly6A) is a glycosyl phostidylinositol (GPI)-anchored cell surface protein associated with both stem and progenitor activity, as well as tumor initiating-potential. However, at present the functional role for Sca-1 is poorly defined.Methodology/Principal FindingsTo investigate the role of Sca-1 in mammary tumorigenesis, we used a mammary cell line derived from a MMTV-Wnt1 mouse mammary tumor that expresses high levels of endogenous Sca-1. Using shRNA knockdown, we demonstrate that Sca-1 expression controls cell proliferation during early tumor progression in mice. Functional limiting dilution transplantations into recipient mice demonstrate that repression of Sca-1 increases the population of tumor propagating cells. In scratch monolayer assays, Sca-1 enhances cell migration. In addition, knockdown of Sca-1 was shown to affect cell adhesion to a number of different extracellular matrix components. Microarray analysis indicates that repression of Sca-1 leads to changes in expression of genes involved in proliferation, cell migration, immune response and cell organization.Conclusions/SignificanceSca-1 exerts marked effects on cellular activity and tumorgenicity both in vitro and in vivo. A better understanding of Sca-1 function may provide insight into the broader role of GPI-anchored cell surface proteins in cancer.
Highlights
Stem cell antigen-1 (Sca-1 or Ly6A) is a member of the Ly6 family of glycosyl phostidylinositol (GPI)-anchored cell surface proteins
Stem Cell Antigen-1 (Sca-1) promotes cell migration Sca-1 is localized to lipid rafts [2] similar to urokinase plasminogen activator receptor (UPAR), another well-characterized Ly6 family member
Sca-1 is widely accepted as a stem/progenitor cell marker in normal mouse tissues [3,13,14,15]
Summary
Stem cell antigen-1 (Sca-1 or Ly6A) is a member of the Ly6 family of glycosyl phostidylinositol (GPI)-anchored cell surface proteins. Sca-1 has been long associated with murine stem/ progenitor cells [1] and is localized to lipid rafts where it regulates signaling complexes [2]. Functional studies using Sca-1-null mice have revealed several phenotypes. Interferon-stimulated hematopoietic stem cells (HSCs) upregulate Sca-1 in a Stat1-dependent manner. Minor defects in lineage skewing were observed in the hematopoietic system of Sca-1-null mice. Osteoporosis and reduced muscle size were observed in aging Sca-1-null mice. Sca-1 is necessary for matrix metalloproteinase (MMP) activity during muscle repair. Stem cell antigen-1 (Sca-1 or Ly6A) is a glycosyl phostidylinositol (GPI)-anchored cell surface protein associated with both stem and progenitor activity, as well as tumor initiating-potential. At present the functional role for Sca is poorly defined
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