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Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Oncogene volume 29, pages 2427–2440 (2010)Cite this article

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Abstract

Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E- to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120ctn) in the cytoplasm. The use of p120ctn small interfering RNA or chimeric cadherin construct to inhibit p120ctn expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120ctn specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120ctn signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.

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Acknowledgements

We thank Drs N Auersperg, A Hall, and C Gottardi for cell lines and plasmids. This work was supported by Canadian Institutes of Health Research grant (PCK Leung), and by Hong Kong Research Grant Council Grant 778108 and HKU Outstanding Young Researcher Award (AST Wong).

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Authors and Affiliations

  1. School of Biological Sciences, University of Hong Kong, Hong Kong, PR China

    L W T Cheung & A S T Wong

  2. Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada

    P C K Leung

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  1. L W T Cheung
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  2. P C K Leung
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  3. A S T Wong
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Correspondence to A S T Wong.

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Cheung, L., Leung, P. & Wong, A. Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. Oncogene 29, 2427–2440 (2010). https://doi.org/10.1038/onc.2009.523

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