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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, 2 Vascular Biology Program and Department of Surgery, Boston Children's Hospital, 3 Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; and 4 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Requests for reprints: Sam S. Yoon, Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-4241; Fax: 617-724-3895; E-mail: syoon{at}partners.org.
Vascular endothelial cell growth factor A (VEGF-A) and hypoxia play important roles in tumor angiogenesis. VEGF-A gene expression is up-regulated in tumors under hypoxic conditions, yet it is unclear how such up-regulation will affect the efficacy of RNA interference strategies targeting VEGF-A. Four potential short interfering RNA (siRNA) sequences for the VEGF-A gene were cloned into expression plasmids and transfected into HT1080 human fibrosarcoma cells. Stable transfection of these plasmids decreased VEGF-A mRNA levels and protein secretion by up to 99%. Our analysis of >100 hypoxia-related genes using oligonucleotide microarrays of 38 human sarcoma samples and 14 normal tissues identified distinctly different patterns of expression between sarcomas and normal tissues as assessed by hierarchical clustering analysis. Numerous hypoxia-related genes were significantly up-regulated in sarcomas including hypoxia-inducible factor 1
(HIF-1). Exposure of wild-type HT1080 cells to 1% hypoxia resulted in HIF-1 up-regulation and a 74% increase in VEGF-A secretion as compared with secretion under normoxic conditions. Surprisingly, stable cell lines expressing VEGF-A siRNAs silenced VEGF-A expression equally well in hypoxia and normoxia. S.c. injection of cells with VEGF-A siRNAs into athymic nude mice led to slower-growing tumors, decreased blood vessel density, and greater apoptosis when compared with controls. Immunofluorescence analysis of tumor sections revealed areas of HIF-1 nuclear expression, suggesting areas of hypoxia, in both control tumors and VEGF-suppressed tumors. We conclude that hypoxia plays an important role in human sarcomas but hypoxic up-regulation of VEGF-A expression does not attenuate the efficacy of VEGF-A RNA interference.
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