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The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Objective

Wnt signalling pathways regulate proliferation, motility and survival in a variety of human cell types. Dickkopf 1 (DKK1) gene codes for a secreted Wnt inhibitory factor. It functions as tumour suppressor gene in breast cancer and as a pro-apoptotic factor in glioma cells. In this study, we aimed to demonstrate whether the different expression of DKK1 in human glioma-derived cells is dependent on microenvironmental factors like hypoxia and regulated by the intercellular crosstalk with bone-marrow-derived mesenchymal stem cells (bmMSCs).

Methods

Glioma cell line U87-MG, three cell lines from human glioblastoma grade IV (glioma-derived mesenchymal stem cells) and three bmMSCs were selected for the experiment. The expression of DKK1 in cell lines under normoxic/hypoxic environment or co-culture condition was measured using real-time PCR and enzyme-linked immunoadsorbent assay. The effect of DKK1 on cell migration and proliferation was evaluated by in vitro wound healing assays and sulphorhodamine assays, respectively.

Results

Glioma-derived cells U87-MG displayed lower DKK1 expression compared with bmMSCs. Hypoxia led to an overexpression of DKK1 in bmMSCs and U87-MG when compared to normoxic environment, whereas co-culture of U87-MG with bmMSCs induced the expression of DKK1 in both cell lines. Exogenous recombinant DKK1 inhibited cell migration on all cell lines, but did not have a significant effect on cell proliferation of bmMSCs and glioma cell lines.

Conclusion

In this study, we showed for the first time that the expression of DKK1 was hypoxia dependent in human malignant glioma cell lines. The induction of DKK1 by intracellular crosstalk or hypoxia stimuli sheds light on the intense adaption of glial tumour cells to environmental alterations.

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Acknowledgments

This work was generously supported the SYSTHER/INREMOS projects on Systems Biology Tools development for cell Therapy and Drug Development (Con. No.: 3211-06-000539; 2006-2011), funded by the German and Slovenian Federal Ministries of Education and Research and the SFB 824 (Deutsche Forschungsgemeinschaft). Peng Fu was supported by China Scholarship Council (No. 2009616010).

Conflict of interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled, ‘The expression of Wnt-inhibitor Dickkopf 1 (DKK1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas’.

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Authors and Affiliations

  1. Tumour-Biological Laboratory, Department of Neurosurgery, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany

    Ke-Tai Guo, Peng Fu, Jörg-Christian Tonn & Christian Schichor

  2. Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Peng Fu

  3. AG Bioinformatics, Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany

    Kathrin Juerchott & Joachim Selbig

  4. Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia

    Helena Motaln & Tamara Lah

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  1. Ke-Tai Guo
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  2. Peng Fu
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  3. Kathrin Juerchott
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Corresponding authors

Correspondence to Ke-Tai Guo or Peng Fu.

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Ke-Tai Guo and Peng Fu have contributed equally to this work.

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Guo, KT., Fu, P., Juerchott, K. et al. The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas. J Cancer Res Clin Oncol 140, 1261–1270 (2014). https://doi.org/10.1007/s00432-014-1642-2

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  • DOI: https://doi.org/10.1007/s00432-014-1642-2

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