Abstract
Neuropilin-1 (NRP-1) was first described as a coreceptor implicated in neuronal guidance that bound members of the semaphorin/collapsin family. NRP-1 is also expressed in endothelial cells and is believed to promote angiogenesis by acting as a coreceptor with vascular endothelial growth factor (VEGF) receptor 2. Recent studies suggest that NRP-1 can function through both a VEGF-dependent and VEGF-independent fashion. Expression of NRP-1 has been shown in many human tumors, including pancreatic adenocarcinomas. The exact role of NRP-1 in tumor cells is unknown, particularly in cells that lack the NRP-1 coreceptors VEGF receptor 2 and Plexin-A1. To discern the regulatory role(s) of NRP-1 in pancreatic adenocarcinoma that lack these coreceptors, we overexpressed both full-length NRP-1 and a deletion form of NRP-1 that does not interact with semaphorin or VEGF. Overexpression of either isoform reduced several key tumorigenic properties, including anchorage-independent cell growth and migration in vitro, and resulted in reduced tumor incidence and tumor volume in vivo. Conversely, reduction of NRP-1 expression by small interfering RNA targeting led to enhanced tumor growth. Thus, NRP-1 may play distinct growth regulatory roles in different tumor types, and altering NRP-1 expression or function may be a means of influencing the growth of pancreatic cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Animals
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Movement / physiology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Male
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Mice
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Mice, Nude
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / deficiency*
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Neuropilin-1 / antagonists & inhibitors
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Neuropilin-1 / biosynthesis
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Neuropilin-1 / genetics
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Neuropilin-1 / physiology*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Phosphorylation
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Protein Isoforms
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Small Interfering / genetics
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Receptors, Cell Surface / biosynthesis
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Receptors, Cell Surface / deficiency*
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Semaphorin-3A / biosynthesis
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Up-Regulation
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
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Vascular Endothelial Growth Factor Receptor-2 / deficiency*
Substances
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Nerve Tissue Proteins
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PLXNA1 protein, human
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Protein Isoforms
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Receptors, Cell Surface
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SEMA3A protein, human
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Semaphorin-3A
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Vascular Endothelial Growth Factor A
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Neuropilin-1
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Vascular Endothelial Growth Factor Receptor-2
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases