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Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis
- Publication Year :
- 2016
- Publisher :
- Oxford University Press, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Cancer Research
Integrins
medicine.medical_treatment
Mice, Nude
Biology
Insulin-like growth factor-binding protein
Receptor, IGF Type 1
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Basic and Translational Investigation
Glioma
Cell Line, Tumor
medicine
Animals
Humans
beta Catenin
Gene knockdown
Glycogen Synthase Kinase 3 beta
Brain Neoplasms
Growth factor
Receptors, Somatomedin
medicine.disease
Prognosis
Survival Analysis
Insulin-Like Growth Factor Binding Protein 2
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Immunohistochemistry
Heterografts
Neurology (clinical)
Signal transduction
Stem cell
Glioblastoma
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....003e22f25d2ebdd5a22f2b39052a47fe