Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer.
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.
Cheung
L W T
LW
School of Biological Sciences, University of Hong Kong, Hong Kong, PR China.
Leung
P C K
PC
Wong
A S T
AS
D015820:Cadherins / Q000502:physiology*; D051177:Catenins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology*; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; C107953:RAC1 protein, human; D007987:Gonadotropin-Releasing Hormone; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000095002:Delta Catenin; C000722347:CTNND1 protein, human