Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma
| Autor: | Shirong Chang, Heidi V. Russell, M. John Hicks, Jose Diaz-Miron, Andrew Ludwig, Susan Burlingame, Jed G. Nuchtern, Catherine L. Wesson, Ningling Ge, Javed Khan, Eugene S. Kim, Jianhua Yang, Xiao-Ying Shang, Sanjeev A. Vasudevan |
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| Rok vydání: | 2009 |
| Předmět: |
MAPK/ERK pathway
Cancer Research medicine.medical_treatment Molecular Sequence Data Biology Transfection Article Neuroblastoma Cell Line Tumor medicine Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Cells Cultured Cell Proliferation Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Base Sequence Oncogene Kinase Cell growth Growth factor Computational Biology Membrane Proteins medicine.disease Neoplasm Proteins Cell biology Secretory protein Oncology Cell culture |
| Zdroj: | Molecular Cancer Therapeutics. 8:2478-2489 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-08-1132 |
| Popis: | 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] |
| Databáze: | OpenAIRE |
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