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IGFBP2 potentiates nuclear EGFR–STAT3 signaling

Oncogene volume 35, pages 738–747 (2016)Cite this article

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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.

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Acknowledgements

We thank Dr Oliver Bogler, Dr Zhimin Lu, Dr Frederick Lang, Dr Paul Chiao and Dr Tapio Visakorpi for their helpful comments and discussions and Kathryn L Hale, Department of Scientific Publications at MD Anderson Cancer Center, for editing the manuscript. We thank Ville Kytölä for contributions to the immunohistochemical association analyses. This work was partially supported by grants from the US National Institutes of Health (CA098503, CA141432 and CA143835 to WZ and GNF and U24 CA143835 to WZ), by funding for the Cancer Systems Informatics Center from the National Foundation for Cancer Research (to WZ), by NIH/NCI grant P30CA016672 to MD Anderson Cancer Center supporting the Flow Cytometry and Cellular Imaging Core Facility and by the Finnish Funding Agency for Technology and Innovation Finland Distinguished Professor program and the Academy of Finland (grant 259038 to KG). WKC is a Fellow of the National Foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Y Chua, Y Liu, K J Granberg, L Hu, M J Annala, D E Cogdell, M Verploegen, L M Moore, G N Fuller & W Zhang

  2. The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    C Y Chua, G N Fuller & W Zhang

  3. ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Seattle, WA/Houston, TX, USA

    Y Liu, G N Fuller & W Zhang

  4. Department of Signal Processing, Tampere University of Technology, Tampere, Finland

    K J Granberg & M J Annala

  5. Institute of Biomedical Technology, University of Tampere, Tampere, Finland

    K J Granberg, M J Annala & M Nykter

  6. Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland

    H Haapasalo

  7. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

    M Verploegen

  8. Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA

    W K Cavenee

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Chua, C., Liu, Y., Granberg, K. et al. IGFBP2 potentiates nuclear EGFR–STAT3 signaling. Oncogene 35, 738–747 (2016). https://doi.org/10.1038/onc.2015.131

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