This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Perturbation in the normal differentiation process during peripheral neural development leads to neuroblastoma, a childhood cancer of peripheral nervous system. More than 50% of children with neuroblastoma have metastatic or aggressive disease with poor overall prognosis. Thus, identification of novel molecular targets involved in the development of neuroblastoma is of clinical importance. Our studies have shown that expression of a cell surface protease called dipeptidyl peptidase IV (DPPIV) is significantly decreased in neuroblastoma cells as compared to normal neural crest derived cells. Furthermore, restoration of DPPIV expression in neuroblastoma cells leads to their differentiation, apoptosis, and suppression of their tumoigenic potential. It is well established that secreted proteins/peptides play a pivotal role in regulatingthese processes. Interestingly, DPPIV is present on cell plasma membrane as well as in secreted form and DPPIV is shown to regulate the activities and levels of some of the secreted mitogenic peptides. Thus, it is likely that DPPIV functions as tumor suppressor gene by modulating the spectrum of proteins secreted by tumor cells, rendering their microenvironment less supportive of the survival and spread of tumor cells. Thus identification of secreted proteins that are regulated by DPPIV in neuroblastoma cells is of importance. Based on these data, we hypothesize that DPPIV differentially regulates the expression of proteins or peptides with growth inhibitory and stimulatory functions. Our current proposal is aimed at identifying the differentially expressed secreted peptides by employing proteomic technologies. We will adapt stable isotopic labeling with amino acids in cell culture (SILAC) technology to identify and quantify proteins differentially expressed or released into the extracellular media by a pair of undifferentiated and differentiated NB cell lines. These studies will be carried out in collaboration with faculty members of VGN proteomic core facility. Our proposed studies are expected to identify the novel peptides with prognostic, diagnostic and/or therapeutic value. Also, results from the proposed studies may contribute significantly to better understanding of biology of neuroblastoma.
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