title: IGFBP2 potentiates nuclear EGFR-STAT3 signaling.
abstract: Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also unclear. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of epidermal growth factor receptor (EGFR), which subsequently activates signal transducer and activator of transcription factor 3 (STAT3) signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioblastoma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from The Cancer Genome Atlas database for human glioma. A high level of all three proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient data set. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by two distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Chua
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Seattle, WA/Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
authors.forename: K J
authors.initials: KJ
authors.lastname: Granberg
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Haapasalo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Annala
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Cogdell
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Verploegen
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Moore
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.|ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Seattle, WA/Houston, TX, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.|ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Seattle, WA/Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors