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CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor TFPI in a c Src dependent fashion

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Niveau: Supérieur, Doctorat, Bac+8
RESEARCH PAPER CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion Niko Bretz • Aurelia Noske • Sascha Keller • Natalie Erbe-Hofmann • Thomas Schlange • Alexei V. Salnikov • Gerd Moldenhauer • Glen Kristiansen • Peter Altevogt Received: 22 June 2011 / Accepted: 5 September 2011 Springer Science+Business Media B.V. 2011 Abstract CD24 is a glycosyl-phosphatidylinositol- anchored protein with mucin-type structure that resides exclusively in membrane microdomains. CD24 is often highly expressed in carcinomas and correlates with poor prognosis. Experimentally, the over-expression or deple- tion of CD24 alters cell proliferation, adhesion, and inva- sion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these cellular effects. Here we have studied the mechanism of CD24-dependent cell invasion using transient CD24 knock-down or over-expression in human cancer cell lines. We show that CD24 depletion reduced tumor cell invasion and up-regulated expression of Tissue Factor Pathway Inhibitor 2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block metastases formation and tumor cell invasion. Over-expression of CD24 in A125 cells resulted in reduced TFPI-2 expression and enhanced invasion. We provide evidence that the activity of c-Src is reduced upon CD24 knock-down.

  • cell lysates using

  • cd24 knock-down

  • cd24

  • tfpi

  • using transient

  • tumor cell


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Clin Exp Metastasis DOI 10.1007/s10585-011-9426-4 R E S E A R C H P A P E R
CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion Niko Bretz Aurelia Noske Sascha Keller Natalie Erbe-Hofmann Thomas Schlange Alexei V. Salnikov Gerd Moldenhauer Glen Kristiansen Peter Altevogt
Received: 22 June 2011 / Accepted: 5 September 2011 Springer Science+Business Media B.V. 2011
Abstract CD24 is a glycosyl-phosphatidylinositol-anchored protein with mucin-type structure that resides exclusively in membrane microdomains. CD24 is often highly expressed in carcinomas and correlates with poor prognosis. Experimentally, the over-expression or deple-tion of CD24 alters cell proliferation, adhesion, and inva-sion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these cellular effects. Here we have studied the mechanism of CD24-dependent cell invasion using transient CD24 knock-down or over-expression in human cancer cell lines. We show that CD24 depletion reduced tumor cell invasion and up-regulated expression of Tissue Factor Pathway Inhibitor 2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block metastases formation and tumor cell invasion. Over-expression of CD24 in A125 cells resulted in reduced TFPI-2 expression and enhanced Electronic supplementary material The online version of this article (doi: 10.1007/s10585-011-9426-4 ) contains supplementary material, which is available to authorized users. N. Bretz S. Keller N. Erbe-Hofmann A. V. Salnikov G. Moldenhauer P. Altevogt ( & ) Tumor Immunology Programme D015, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany e-mail: P.Altevogt@dkfz.de A. Noske G. Kristiansen Institute of Clinical Pathology, University Hospital Zurich, Zurich, Switzerland T. Schlange Bayer Healthcare AG, Wuppertal, Germany
invasion. We provide evidence that the activity of c-Src is reduced upon CD24 knock-down. The silencing of c-Src, similar to CD24, was able to enhance TFPI-2 expression and reduce tumor cell invasion. An inverse expression of CD24 and TFPI-2 was observed by immunohistochemical analysis of primary breast cancers ( N = 1,174). TFPI-2 expression was highest in CD24 negative samples and lowered with increasing CD24 expression. Patients with a CD24 low/TFPI-2 high phenotype showed significantly better survival compared to CD24 high/TFPI-2 low patients. Our results provide evidence that CD24 can reg-ulate cell invasion via TFPI-2 and suggests a role of c-Src in this process. Keywords CD24 Cell invasion c-Src Lipid-rafts Abbreviations BrCa Breast carcinoma mAb Monoclonal antibody GPI Glycosyl phosphatidylinositol GAPDH Glycerinaldehyde 3 0 phosphate-dehydrogenease TMA Tissue microarray TFPI-2 Tissue factor pathway inhibitor-2 pAb Polyclonal antibody ECM Extracellular matrix Introduction CD24 is a mucin-like, highly N- and O- glycosylated, GPI-anchored membrane protein of 31 amino acids in humans and 27 in mice [ 1 3 ]. Due to its extensive decoration with carbohydrates, human CD24 appears by SDS-PAGE with a molecular weight of 30–70 kDa [ 4 ]. Because of these properties, CD24 in mouse and humans was identified as a 1 3