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HGF upregulates CXCR4 expression in gliomas via NF-κB: implications for glioma cell migration

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

Invasion is a hallmark of malignant gliomas and is the main reason for therapeutic failure and recurrence of the tumor. CXCR4 is a key chemokine receptor implicated in glioma cell migration whose expression is regulated by hypoxia. Here, we report that hepatocyte growth factor (HGF) upregulated CXCR4 protein expression in glioma cells. HGF pre-treatment increased migration of U87MG and LN229 glioma cells towards the CXCR4 ligand, stromal cell-derived factor-1α (SDF-1α). AMD3100, a CXCR4 inhibitor, inhibited the increased migration of HGF pre-treated LN229 glioma cells towards SDF-1α. Following exposure to HGF and hypoxia, both cell lines showed nuclear translocation of NF-κB (p65). The HGF- and hypoxia-induced nuclear translocation of NF-κB (p65) involved phosphorylation and degradation of IκB-α. Knock-down of NF-κB expression inhibited the induction of CXCR4 expression in response to HGF, but not to hypoxia. However, knock-down of NF-κB expression inhibited the induction of CXCR4 expression in response to hypoxia in the presence of HGF. NF-κB mediated migration towards SDF-1α in response to HGF. Knock-down of NF-κB expression resulted in decreased migration of HGF pre-treated glioma cells towards SDF-1α. Therefore, HGF upregulates CXCR4 expression via NF-κB and leads to enhanced migration. To our knowledge, this is the first report to show that a crosstalk mediated by NF-κB exists between the SDF-1α/CXCR4 and HGF/c-Met axes relevant to glioma cell migration. These findings imply that effective inhibition of glioma invasion should be directed against several ligand/receptor signaling pathways.

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Abbreviations

HGF:

Hepatocyte growth factor

SDF-1α:

Stromal cell-derived factor-1α

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Acknowledgments

This work was supported by the National Institutes of Health grant R01 CA100426.

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Authors and Affiliations

  1. Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, NY, USA

    Mine Esencay & David Zagzag

  2. Department of Pathology, MSB-130, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA

    Elizabeth W. Newcomb & David Zagzag

  3. Division of Neuropathology, New York University School of Medicine, New York, NY, USA

    David Zagzag

  4. Department of Neurosurgery, New York University School of Medicine, New York, NY, USA

    David Zagzag

  5. New York University Cancer Institute, New York University School of Medicine, New York, NY, USA

    Elizabeth W. Newcomb & David Zagzag

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  1. Mine Esencay
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  2. Elizabeth W. Newcomb
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Correspondence to David Zagzag.

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Esencay, M., Newcomb, E.W. & Zagzag, D. HGF upregulates CXCR4 expression in gliomas via NF-κB: implications for glioma cell migration. J Neurooncol 99, 33–40 (2010). https://doi.org/10.1007/s11060-010-0111-2

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  • DOI: https://doi.org/10.1007/s11060-010-0111-2

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