Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug.

Uterine carcinosarcomas (UCSs) are considered to represent true examples of the epithelial-mesenchymal transition. Akt plays a key role in the induction of epithelial-mesenchymal transition, but little is known about its involvement in tumorigenesis. Here we examined the functional roles of the Akt/beta-catenin pathway in UCSs. In clinical samples, phospho-Akt (pAkt) expression was found to be significantly increased in mesenchymal compared with epithelial components, exhibiting both positive and negative correlations with nuclear beta-catenin and E-cadherin, respectively. Expression levels of the transcription factor Slug were also significantly up-regulated in the mesenchymal components and strongly correlated with both pAkt and nuclear beta-catenin. In endometrial cancer cell lines, active Akt induced the stabilization of nuclear beta-catenin through the phosphorylation of GSK-3beta, and this, in turn, led to the transactivation of Slug, which was mediated by nuclear beta-catenin. Moreover, Slug overexpression itself caused repression of E-cadherin, with subtle changes in cell morphology. In addition, knockdown of the retinoblastoma gene product (Rb) up-regulated pAkt and repressed E-cadherin, consistent with the in vivo finding of significantly decreased Rb expression in mesenchymal components. These findings suggest that changes in the Akt/beta-catenin pathway, as well as alterations in Rb expression, may be essential for both the establishment and maintenance of phenotypic characteristics of UCSs, playing key roles in the regulation of E-cadherin through the transactivation of the Slug gene.