Abstract
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.
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.
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Neuropilin-2 / metabolism*
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / genetics
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / metabolism*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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RNA Interference
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RNA, Small Interfering
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Signal Transduction / genetics
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Transcription, Genetic
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Transcriptional Activation
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Transplantation, Heterologous
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
Substances
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BMI1 protein, human
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Neuropilin-2
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RNA, Small Interfering
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Polycomb Repressive Complex 1
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Receptor, IGF Type 1
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JNK Mitogen-Activated Protein Kinases
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PTEN Phosphohydrolase
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PTEN protein, human