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Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

Abstract

Wnt5a is a representative ligand that activates the β-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/β-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the β-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and β-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and β-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of β-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research and for Scientific Research on Priority Areas from the Ministry of Education, Science, and Culture of Japan (2007, 2008, 2009), The YASUDA Medical Foundation (2006) and Uehara Memorial Foundation (2008).

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Correspondence to A Kikuchi.

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

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Yamamoto, H., Oue, N., Sato, A. et al. Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. Oncogene 29, 2036–2046 (2010). https://doi.org/10.1038/onc.2009.496

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