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NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma

Oncogene volume 34, pages 5069–5079 (2015)Cite this article

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Abstract

Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.

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Acknowledgements

We thank Yiqun Zhang for technical assistance and Dr Neha Parikh for her assistance with figure layout and design. This work was supported by The Cancer Prevention and Research Institute of Texas (to SZ, T-KM, CL, PR, JH, LK, CJC, LAD, JTY), WWW.W Foundation, Inc. (QuadW) (to JTY), The St Baldrick’s Foundation (to JTY), the Sarcoma Foundation of America (to LAD), NIH R01 CA123238 (to AMCB) and NCI/NIH grant P30 CA125123 (to CJC).

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Authors and Affiliations

  1. Department of Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA

    S Zhao, L Kurenbekova, Y Gao, A Roos, P Rao, T-K Man, C Lau, L A Donehower & J T Yustein

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    A Roos, L A Donehower & J T Yustein

  3. Dan L. Duncan Cancer Center Division of Biostatistics, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    C J Creighton

  4. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    J Hicks

  5. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA

    A M C Brown

  6. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA

    S N Jones

  7. Department of Pathology and The Sarcoma Research Center at The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A J Lazar

  8. Department of Surgical Oncology and The Sarcoma Research Center at The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Ingram

  9. Department of Cancer Biology at The Ohio State University, Columbus, OH, USA

    D Lev

  10. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

    L A Donehower

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Correspondence to J T Yustein.

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Zhao, S., Kurenbekova, L., Gao, Y. et al. NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma. Oncogene 34, 5069–5079 (2015). https://doi.org/10.1038/onc.2014.429

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