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Cancer Discov. 2012 Oct;2(10):906-21. doi: 10.1158/2159-8290.CD-12-0085. Epub 2012 Jul 9.

VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer.

Author information

1
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. hira.goel@umassmed.edu

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.

PMID:
22777769
PMCID:
PMC4205964
DOI:
10.1158/2159-8290.CD-12-0085
[Indexed for MEDLINE]
Free PMC Article

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