Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma
- 1 August 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 8 (8), 2478-2489
- https://doi.org/10.1158/1535-7163.mct-08-1132
Abstract
Secreted proteins such as growth factors, cytokines, and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma-derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting, we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18-kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA, sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MAP/ERK kinase 1/2 inhibitors, which diminish ERK1/2 phosphorylation, results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK1/2 activation results in a reversal of the growth-inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway. [Mol Cancer Ther 2009;8(8):2478–89]Keywords
Other Versions
This publication has 36 references indexed in Scilit:
- Neuroblastoma-derived secretory protein messenger RNA levels correlate with high-risk neuroblastomaJournal of Pediatric Surgery, 2007
- Credentialing Preclinical Pediatric Xenograft Models Using Gene Expression and Tissue Microarray AnalysisCancer Research, 2007
- Oncogenic rearrangements of the NTRK1/NGF receptorCancer Letters, 2006
- MKP-8, a novel MAPK phosphatase that inhibits p38 kinaseBiochemical and Biophysical Research Communications, 2005
- Insulin-like growth factors and neoplasiaNature Reviews Cancer, 2004
- N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cellsOncogene, 2002
- Insulin-like growth factor I stimulates motility in human neuroblastoma cellsOncogene, 2001
- Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic AcidNew England Journal of Medicine, 1999
- Neuroblastoma: a clinical challenge and biologic puzzleCA: A Cancer Journal for Clinicians, 1995
- Association between High Levels of Expression of the TRK Gene and Favorable Outcome in Human NeuroblastomaNew England Journal of Medicine, 1993