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      VEGF-Targeted RNA Interference Suppresses Angiogenesis and Tumor Growth of Retinoblastoma

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          Abstract

          Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors for tumor angiogenesis which has been verified to be involved in neovascularization of retinoblastoma. Here, we sought to explore whether RNA interference (RNAi) targeting VEGF could inhibit retinoblastoma angiogenesis and tumor growth. Stable transfection of the two human retinoblastoma cell lines SO-RB50 and HXO-RB44 with VEGF-targeted small interfering RNA (siRNA) expression plasmid significantly inhibited VEGF expression determined by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay and Western blot, whereas the control transfection showed no effects. The chemically synthesized VEGF siRNA dramatically suppressed tumor angiogenesis (CD34 immunohistochemistry) and tumor growth in the SO-RB50 subcutaneous xenograft model. Significant downregulation of VEGF expression both on messenger RNA and protein levels in VEGF-siRNA-treated SO-RB50 subcutaneous xenograft was confirmed by real-time PCR and Western blot compared to control. Our data demonstrate the suppression function on angiogenesis and tumor growth of retinoblastoma by VEGF-targeted RNAi. This novel therapeutic strategy promises to play a part in the clinical management of retinoblastoma.

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          Most cited references 15

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.

            Vascular endothelial growth factor (VEGF) has been shown to promote neovascularization in animal models and, more recently, in human subjects. This feature has been assumed to result exclusively from its direct effects on fully differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in both angiogenesis and vasculogenesis during fetal development, we investigated the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics for postnatal neovascularization. Indeed, we observed an increase in circulating EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone marrow-derived EPCs resulted in increased differentiated EPCs in vitro and augmented corneal neovascularization in vivo. These findings thus establish a novel role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis.
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              Gene silencing in mammals by small interfering RNAs.

              Among the 3 billion base pairs of the human genome, there are approximately 30,000-40,000 protein-coding genes, but the function of at least half of them remains unknown. A new tool - short interfering RNAs (siRNAs) - has now been developed for systematically deciphering the functions and interactions of these thousands of genes. siRNAs are an intermediate of RNA interference, the process by which double-stranded RNA silences homologous genes. Although the use of siRNAs to silence genes in vertebrate cells was only reported a year ago, the emerging literature indicates that most vertebrate genes can be studied with this technology.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2007
                March 2007
                02 February 2007
                : 39
                : 2
                : 108-115
                Affiliations
                Departments of aOphthalmology and bOral Pathology, Ninth People’s Hospital, and cDepartment of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
                Article
                99247 Ophthalmic Res 2007;39:108–115
                10.1159/000099247
                17284938
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 32, Pages: 8
                Categories
                Original Paper

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