Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer
Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer
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DOI：
10.1038/onc.2009.523
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Wong, A. S. T.
中科院分区：
文献类型：
--
作者：
Cheung, L. W. T.;Leung, P. C. K.;Wong, A. S. T.
促性腺激素释放激素(GnRH)受体在卵巢癌中的表达经常升高，但其在卵巢癌转移中的潜在作用才刚刚开始被揭示。钙粘附素转换是肿瘤发生过程中的关键步骤，尤其是在转移过程中。在这里，我们发现GnRH是E-到P-钙粘素转换的诱导者，这让人想起在卵巢肿瘤进展过程中看到的情况。无论E-钙粘蛋白的表达如何，P-钙粘蛋白的过度表达显著增强，而P-钙粘蛋白的表达下调则减少了迁移和侵袭，提示P-钙粘蛋白的不适当表达参与了侵袭性表型的形成。P-钙粘素的这些作用是通过激活Rho GTP酶rac1和cdc42，通过在细胞质中积累p120连环蛋白(p120(CTN))来实现的。使用p120(CTN)小干扰RNA或嵌合钙粘素分别抑制p120(CTN)的表达和胞浆定位，可显著抑制细胞的迁移和侵袭，并伴随着rac1和CDc42激活的降低，证实其作用是p120(CTN)特异性的。同样，迁移/侵袭表型可以被显性负值的rac1和cdc42的表达所逆转。这些结果首次确认钙粘素转换和p120(CTN)信号是GnRH功能的重要靶点，并且是卵巢癌侵袭性和肿瘤进展的新介质。Oncogene(2010)29,2427-2440；doi：10.1038/onc.2009.523；2010年2月1日在线发布
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 (p120(ctn)) in the cytoplasm. The use of p120(ctn) small interfering RNA or chimeric cadherin construct to inhibit p120(ctn) 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 p120(ctn) 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 p120(ctn) signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer. Oncogene (2010) 29, 2427-2440; doi:10.1038/onc.2009.523; published online 1 February 2010