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

Autor:	Patil SS; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Gokulnath P; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Bashir M; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Shwetha SD; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Jaiswal J; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Shastry AH; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Arimappamagan A; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Santosh V; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.)., Kondaiah P; Molecular Reproduction, Development and Genetics department, Indian Institute of Science, Bangalore, India (S.S.P., P.G., M.B., P.K.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (S.D.S., J.J., V.S.); Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.H.S.); Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India (A.A.).
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2016 Nov; Vol. 18 (11), pp. 1487-1497. Date of Electronic Publication: 2016 Apr 03.
DOI:	10.1093/neuonc/now053
Abstrakt:	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 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. Methods: Regulation of the β-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 β-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 β-catenin and regulation of its nuclear functions involving integrin-mediated inactivation of GSK3β. 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 β-catenin was associated with worse prognosis (P = .001) in GBM patients. Conclusion: IGFBP-2 potentiates GBM tumor growth by the activation of the β-catenin pathway through its C-terminal domain, and their coexpression possibly contributes to worse patient prognosis. (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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