Linked Life Data

15994966

Source:http://linkedlifedata.com/resource/pubmed/id/15994966

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2005-7-4
pubmed:abstractText
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 1alpha (HIF-1alpha). Exposure of wild-type HT1080 cells to 1% hypoxia resulted in HIF-1alpha 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-1alpha 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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5881-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15994966-Animals, pubmed-meshheading:15994966-Cell Growth Processes, pubmed-meshheading:15994966-Cell Hypoxia, pubmed-meshheading:15994966-Cell Line, Tumor, pubmed-meshheading:15994966-DNA-Binding Proteins, pubmed-meshheading:15994966-Fibrosarcoma, pubmed-meshheading:15994966-Gene Expression Regulation, Neoplastic, pubmed-meshheading:15994966-Humans, pubmed-meshheading:15994966-Hypoxia-Inducible Factor 1, pubmed-meshheading:15994966-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:15994966-Mice, pubmed-meshheading:15994966-Mice, Nude, pubmed-meshheading:15994966-Neoplasm Transplantation, pubmed-meshheading:15994966-Neovascularization, Pathologic, pubmed-meshheading:15994966-Nuclear Proteins, pubmed-meshheading:15994966-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:15994966-RNA, Small Interfering, pubmed-meshheading:15994966-RNA Interference, pubmed-meshheading:15994966-Transcription Factors, pubmed-meshheading:15994966-Transfection, pubmed-meshheading:15994966-Transplantation, Heterologous, pubmed-meshheading:15994966-Up-Regulation, pubmed-meshheading:15994966-Vascular Endothelial Growth Factor A
pubmed:year
2005
pubmed:articleTitle
Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A.
pubmed:affiliation
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural