PT  - JOURNAL ARTICLE
AU  - Vasudevan, Sanjeev A.
AU  - Shang, Xiaoyi
AU  - Chang, Shirong
AU  - Ge, Ningling
AU  - Diaz-Miron, Jose L.
AU  - Russell, Heidi V.
AU  - Hicks, M. John
AU  - Ludwig, Andrew D.
AU  - Wesson, Catherine L.
AU  - Burlingame, Susan M.
AU  - Kim, Eugene S.
AU  - Khan, Javed
AU  - Yang, Jianhua
AU  - Nuchtern, Jed G.
TI  - Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma
AID  - 10.1158/1535-7163.MCT-08-1132
DP  - 2009 Aug 01
TA  - Molecular Cancer Therapeutics
PG  - 2478--2489
VI  - 8
IP  - 8
4099  - http://mct.aacrjournals.org/content/8/8/2478.short
4100  - http://mct.aacrjournals.org/content/8/8/2478.full
SO  - Mol Cancer Ther2009 Aug 01; 8
AB  - 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]