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Deletion of Yin Yang 1 Protein in Osteosarcoma Cells on Cell Invasion and CXCR4/Angiogenesis and Metastasis

¹ Department of General Pathology, Division of Clinical Pathology, ² Chair of Human Pathology and Department of Chemical Biology and Physics, ³ Regional Center of Craniofacial Malformations-MRI and Odontostomatology, and ⁴ Department of Experimental Medicine, 1st School of Medicine, II University of Naples; ⁵ Unit of Animal Facility, Fondazione G. Pascale National Institute of Tumours, Naples, Italy and ⁶ Division of Anesthesiology and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California

Requests for reprints: Claudio Napoli, Department of General Pathology, Division of Clinical Pathology, 1st School of Medicine, II University of Naples, Via Luigi de Crecchio, 7, Complesso S. Andrea delle Dame, Naples 80138, Italy. Phone: 39-081-5667567; Fax: 39-081-450169; E-mail: claudio.napoli{at}unina2.it.

Key Words: Angiogenesis • CXCR4 • Osteosarcoma • Cell cycle • VEGF • YY1

We know that the Yin Yang 1 protein (YY1) overexpression is positively and strongly correlated with the degree of malignancy of bone tumors. Therefore, we questioned whether we could influence cell invasiveness by deleting YY1 in human osteosarcoma cells (SaOs-2), as tested in Matrigel-coated filters and metastasis implantation of such osteosarcoma cells in vivo, by serial analysis with nuclear magnetic resonance. Moreover, we focused our work on the chemokine receptor CXCR4 and its inhibition by T22 antibody, as well as on systemic (direct in vivo assay) and computer-assisted imaging of angiogenesis-related metastasis. Results showed that cell invasiveness and metastasis implantation by wild-type SaOs-2 cells, as evaluated by histology and immunohistochemistry, are associated with up-regulation of CXCR4 expression, which in turn was significantly reduced by T22. In addition, deletion of YY1 (siRNAYY1-SaOs-2) induced a significant decrease of cell invasion and metastasis growth. This phenomenon was associated with decreased vascular endothelial growth factor (VEGF)/angiogenesis and a complex rearrangement of the gene expression profile as evaluated by microarray analysis. In conclusion, YY1 and VEGF/CXCR4 seem to intervene in the pathogenesis of the malignant phenotype of osteosarcoma by acting on cell invasiveness and metastasis growth. [Cancer Res 2008;68(6):1797–808]