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Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

Oncogene volume 28, pages 3197–3208 (2009)Cite this article

Abstract

The receptor tyrosine kinase Ror2 regulates cell migration by acting as a receptor or co-receptor for Wnt5a. Although Wnt5a has been implicated in the invasiveness of several types of tumors, the role of Ror2 in tumor invasion remains elusive. Here we show that osteosarcoma cell lines SaOS-2 and U2OS show invasive properties in vitro by activating Wnt5a/Ror2 signaling in a cell-autonomous manner. The suppressed expression of either Wnt5a or Ror2 in osteosarcoma cells inhibits cell invasiveness accompanying decreased invadopodia formation. Gene-expression profiling identified matrix metalloproteinase 13 (MMP-13) as one of the genes whose expression is downregulated in SaOS-2 cells following suppression of Ror2 expression. Reduced expression or activity of MMP-13 suppresses invasiveness of SaOS-2 cells. Moreover, expression of MMP-13 and cell invasiveness by Wnt5a/Ror2 signaling can be abrogated by an inhibitor of the Src-family protein tyrosine kinases (SFKs), suggesting the role of the SFKs in MMP-13 expression through Wnt5a/Ror2 signaling. We further show that activation of an SFK is inhibited by the suppressed expression of Ror2. Collectively, these results indicate that Wnt5a/Ror2 signaling involves the activation of a SFK, leading to MMP-13 expression, and that constitutively active Wnt5a/Ror2 signaling confers invasive properties on osteosarcoma cells in a cell-autonomous manner.

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Acknowledgements

We thank M Endo for critical reading of the paper. We also thank K Mizuno for pEYFP-Actin. This work was supported by a Grant-in-Aid for Scientific Research in Priority Areas (YM), a Grant-in-Aid for Scientific Research (B) (YM), a Grant from the Global Center of Excellence Program ‘Education and Research on Signal Transduction Medicine in the Coming Generation’ (YM), a Grant-in-Aid for Young Scientists (B) (MN) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, a Grant from Hyogo Science and Technology Association (MN) and a Grant from Takeda Science Foundation (MN).

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Authors and Affiliations

  1. Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

    M Enomoto, S Hayakawa, S Itsukushima, D Y Ren, M Nishita & Y Minami

  2. Department of Pediatrics, Graduate School of Medicine, Kobe University, Kobe, Japan

    M Enomoto & M Matsuo

  3. Osaka Bioscience Institute, Osaka, Japan

    K Tamada & T Takumi

  4. Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    C Oneyama & M Okada

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  1. M Enomoto
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  2. S Hayakawa
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  3. S Itsukushima
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  4. D Y Ren
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  5. M Matsuo
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  6. K Tamada
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  7. C Oneyama
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  8. M Okada
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  9. T Takumi
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  10. M Nishita
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  11. Y Minami
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Correspondence to M Nishita or Y Minami.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Enomoto, M., Hayakawa, S., Itsukushima, S. et al. Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene 28, 3197–3208 (2009). https://doi.org/10.1038/onc.2009.175

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  • DOI: https://doi.org/10.1038/onc.2009.175

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