NT-3/TRK-C regulated proteins in the biology of medulloblastoma

Abstract

12519 Background: Medulloblastoma (MB) is the most common malignant childhood brain tumor. Because of its high risk of leptomeningeal dissemination, standard postoperative treatment includes craniospinal irradiation and chemotherapy. Such treatment produces significant sequelae including neurocognitive dysfunction, endocrine and growth disturbances. These therapy-induced morbidities warrant a novel less toxic approach possibly targeting key molecules within specific pathways of medulloblastoma biology. Recent reports identified high neurotrophin receptor TrkC mRNA expression as a powerful independent predictor of a favorable survival outcome in MB patients. However, the role of activated TrkC receptors in the development and biology of MB remains unclear. Methods: To determine downstream effector proteins of TrkC signaling, the medulloblastoma cell line DAOY was stably transfected with a vector containing the full-length TrkC cDNA sequence or an empty vector control. Accounting for the complexity of ligand-induced changes in cellular pathways and effector proteins, we investigated proteomic changes at multiple time points for up to 48 hrs following neurotrophin-3 induced TrkC receptor activation. Results: We identified 18 proteins differentially expressed: Caldesmon; Cathepsin D; Metastasis inhibition factor nm23; Multidrug resistance-associated protein Mgr1-Ag; Vimentin; Vinculin; Superoxide dismutase (Mn); Glutathione S-transferase P; Stathmin, Lamin A/C, Valosin-containing protein, Annexin A1; ULIP protein; DJ-1 protein; Fascin; Mitofilin; Heterogeneous nuclear ribonucleoprotein H and K. Conclusion: The proteins affected play substantial roles in differentiation, migration, invasion, proliferation, apoptosis and drug resistance. Almost all of the proteins have been described as being essential in the pathogenesis of different solid tumors, but have not been related to MB pathogenesis so far. No significant financial relationships to disclose.