Targeting gastrin-releasing peptide suppresses neuroblastoma progression via upregulation of PTEN signaling.

Paul P, Qiao J, Kim KW, Romain C, Lee S, Volny N, Mobley B, Correa H, Chung DH
PLoS One. 2013 8 (9): e72570

PMID: 24039782 · PMCID: PMC3767701 · DOI:10.1371/journal.pone.0072570

We have previously demonstrated the role of gastrin-releasing peptide (GRP) as an autocrine growth factor for neuroblastoma. Here, we report that GRP silencing regulates cell signaling involved in the invasion-metastasis cascade. Using a doxycycline inducible system, we demonstrate that GRP silencing decreased anchorage-independent growth, inhibited migration and neuroblastoma cell-mediated angiogenesis in vitro, and suppressed metastasis in vivo. Targeted inhibition of GRP decreased the mRNA levels of oncogenes responsible for neuroblastoma progression. We also identified PTEN/AKT signaling as a key mediator of the tumorigenic properties of GRP in neuroblastoma cells. Interestingly, PTEN overexpression decreased GRP-mediated migration and angiogenesis; a novel role for this, otherwise, understated tumor suppressor in neuroblastoma. Furthermore, activation of AKT (pAKT) positively correlated with neuroblastoma progression in an in vivo tumor-metastasis model. PTEN expression was slightly decreased in metastatic lesions. A similar phenomenon was observed in human neuroblastoma sections, where, early-stage localized tumors had a higher PTEN expression relative to pAKT; however, an inverse expression pattern was observed in liver lesions. Taken together, our results argue for a dual purpose of targeting GRP in neuroblastoma--1) decreasing expression of critical oncogenes involved in tumor progression, and 2) enhancing activation of tumor suppressor genes to treat aggressive, advanced-stage disease.

MeSH Terms (23)

Animals Cell Adhesion Cell Line, Tumor Cell Movement Disease Progression Enzyme Activation Gastrin-Releasing Peptide Gene Knockdown Techniques Humans Human Umbilical Vein Endothelial Cells Liver Neoplasms Male Mice Mice, Nude Neoplasm Transplantation Neovascularization, Pathologic Neuroblastoma Phenotype Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase RNA, Small Interfering RNA Interference Signal Transduction

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