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Insulin-like growth factor binding protein-2 regulates beta-catenin signaling pathway in glioma cells and contributes to poor patient prognosis

Patil, Shilpa S and Gokulnath, Priyanka and Bashir, Mohsin and Shwetha, Shivayogi D. and Jaiswal, Janhvi and Shastry, Arun H. and Arimappamagan, Arivazhagan and Santosh, Vani and Kondaiah, Paturu (2016) Insulin-like growth factor binding protein-2 regulates beta-catenin signaling pathway in glioma cells and contributes to poor patient prognosis. In: NEURO-ONCOLOGY, 18 (11). pp. 1487-1497.

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Official URL: http://dx.doi.org/10.1093/neuonc/now053

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 beta-catenin by IGFBP-2 in breast cancer and the crucial role of beta-catenin pathway in glioma invasion, proliferation and maintenance of glioma stem cells, the mechanism of regulation of beta-catenin by IGFBP-2, and its role in GBM prognosis was studied. Methods. Regulation of the beta-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 beta-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 beta-catenin and regulation of its nuclear functions involving integrin-mediated inactivation of GSK3 beta. 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 beta-catenin was associated with worse prognosis (P = .001) in GBM patients. Conclusion. IGFBP-2 potentiates GBM tumor growth by the activation of the beta-catenin pathway through its C-terminal domain, and their coexpression possibly contributes to worse patient prognosis.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the OXFORD UNIV PRESS INC, JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Depositing User: Id for Latest eprints
Date Deposited: 07 Dec 2016 05:54
Last Modified: 07 Dec 2016 05:54
URI: http://eprints.iisc.ac.in/id/eprint/55545

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