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Insulin-like growth factor binding protein-2 regulates ?-catenin signaling pathway in glioma cells and contributes to poor patient prognosis.
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ABSTRACT: Background
Upregulation of insulin-like growth factor binding protein 2 (IGFBP-2) is often associated with aggressiveness of glioblastoma (GBM) and contributes to poor prognosis for GBM patients. In view of the regulation of ?-catenin by IGFBP-2 in breast cancer and the crucial role of ?-catenin pathway in glioma invasion, proliferation and maintenance of glioma stem cells, the mechanism of regulation of ?-catenin by IGFBP-2, and its role in GBM prognosis was studied.Methods
Regulation of the ?-catenin pathway was studied by immunocytochemistry, Western blot analysis, luciferase assays, and real-time RT-PCR. The role of IGFBP-2 was studied by subcutaneous tumor xenografts in immunocompromised mice using glioma cells engineered to express IGFBP-2 and its domains. GBM patient tumor tissues (n = 112) were analyzed for expression of IGFBP-2 and ?-catenin by immunohistochemistry. Survival analysis was performed employing Cox regression and Kaplan-Meier survival analyses.Results
IGFBP-2 knockdown in U251, T98G, and U373 or overexpression in LN229 and U87 cells revealed a role for IGFBP-2 in stabilization of ?-catenin and regulation of its nuclear functions involving integrin-mediated inactivation of GSK3?. Similar results were obtained upon overexpression of the C-terminal domain of IGFBP-2 but not the N-terminal domain. Subcutaneous xenograft tumors overexpressing either full-length or the C-terminal domain of IGFBP-2 showed larger volume as compared with controls. Coexpression of high levels of IGFBP-2 and ?-catenin was associated with worse prognosis (P = .001) in GBM patients.Conclusion
IGFBP-2 potentiates GBM tumor growth by the activation of the ?-catenin pathway through its C-terminal domain, and their coexpression possibly contributes to worse patient prognosis.
SUBMITTER: Patil SS
PROVIDER: S-EPMC5063512 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
Publications
Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis.
Neuro-oncology 20160403 11
<h4>Background</h4>Upregulation of insulin-like growth factor binding protein 2 (IGFBP-2) is often associated with aggressiveness of glioblastoma (GBM) and contributes to poor prognosis for GBM patients. In view of the regulation of β-catenin by IGFBP-2 in breast cancer and the crucial role of β-catenin pathway in glioma invasion, proliferation and maintenance of glioma stem cells, the mechanism of regulation of β-catenin by IGFBP-2, and its role in GBM prognosis was studied.<h4>Methods</h4>Regu ...[more]