title: Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Patil
authors.affiliation: 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.).
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gokulnath
authors.affiliation: 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.).
authors.forename: Mohsin
authors.initials: M
authors.lastname: Bashir
authors.affiliation: 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.).
authors.forename: Shivayogi D
authors.initials: SD
authors.lastname: Shwetha
authors.affiliation: 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.).
authors.forename: Janhvi
authors.initials: J
authors.lastname: Jaiswal
authors.affiliation: 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.).
authors.forename: Arun H
authors.initials: AH
authors.lastname: Shastry
authors.affiliation: 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.).
authors.forename: Arivazhagan
authors.initials: A
authors.lastname: Arimappamagan
authors.affiliation: 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.).
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
authors.affiliation: 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.).
authors.forename: Paturu
authors.initials: P
authors.lastname: Kondaiah
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000175:diagnosis / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C000597236:IGF1R protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D016023:Integrins; D017451:Receptors, Somatomedin; D051176:beta Catenin; D017526:Receptor, IGF Type 1; D000071679:Glycogen Synthase Kinase 3 beta
keywords: GBM prognosis; GSK3β; IGFBP-2 C-domain; β-catenin signaling