Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and GFR expression and activity contributes to the pathogenesis of many types of cancer. However, the mechanisms responsible for control of GFR expression in tumor cells are not well understood, and the roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of these tumors, and in the response of tumors to treatment have not been clearly delineated. The gene for the ubiquitin ligase UBE4B is located in the chromosome 1p36 region commonly deleted in neuroblastoma tumors and therefore may function as a tumor suppressor gene. We have identified a significant association between UBE4B gene expression and neuroblastoma patient outcomes. UBE4B interacts with endosomal proteins required for GFR trafficking and degradation, suggesting a previously uncharacterized functional link between GFR trafficking and neuroblastoma pathogenesis. However, the function of UBE4B and the role of UBE4B-mediated GFR trafficking in neuroblastoma tumor cells are unknown. We believe that UBE4B expression and function will mediate the growth of neuroblastoma tumors and their sensitivity to treatment through regulation of GFR trafficking. Our goals with these studies are therefore to evaluate the relevance of UBE4B expression and function in children with neuroblastoma and its roles in neuroblastoma tumor cell proliferation and responses to treatment. To achieve these goals, we propose a series of experiments which will determine 1) the association of UBE4B expression with neuroblastoma patient prognostic factors and outcomes, 2) the role of UBE4B activity in GFR trafficking in neuroblastoma tumor cells, and 3) the role of UBE4B in neuroblastoma tumor cell resistance to treatment.
In Aim 1, we will evaluate the association of UBE4B protein expression with GFR expression and with patient outcomes and clinical prognostic factors in tumor samples obtained from the Texas Children's Cancer Center tissue bank.
In Aim 2, we will use neuroblastoma tumor cell lines and xenograft models to evaluate the mechanisms by which UBE4B regulates GFR trafficking and affects neuroblastoma cell proliferation and survival.
In Aim 3 we will evaluate the roles of UBE4B and GFR trafficking in the sensitivity and resistance of neuroblastoma tumor cells to treatment. These studies will provide important information about the functions of UBE4B and the role of UBE4B- mediated GFR trafficking in neuroblastoma tumor growth and chemoresistance. With the critical need for new treatment options for children with neuroblastoma, the results from this research will provide important information leading to improved outcomes for children with neuroblastoma.
Children with high-risk neuroblastoma have extremely poor survival rates despite intensive therapy, and therefore these children need new strategies for treatment. We believe that the UBE4B protein may play a role in neuroblastoma tumor cell survival, growth, and response to treatment through regulation of growth factor receptor expression in tumor cells. In this proposal, we will investigate this potential role of UBE4B with the goals of determining the association of UBE4B with the survival of children with neuroblastoma, the mechanisms through which UBE4B affects patient survival, and the effects of UBE4B on the sensitivity of neuroblastoma tumors to treatment.
