Regular Articles
Requirement of the Akt/β-Catenin Pathway for Uterine Carcinosarcoma Genesis, Modulating E-Cadherin Expression Through the Transactivation of Slug

https://doi.org/10.2353/ajpath.2009.081018Get rights and content

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/β-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 β-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 β-catenin. In endometrial cancer cell lines, active Akt induced the stabilization of nuclear β-catenin through the phosphorylation of GSK-3β, and this, in turn, led to the transactivation of Slug, which was mediated by nuclear β-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/β-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.

Cited by (0)

Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant 20590352).

Supplementary material for this article can be found on http://ajp.amjpathol.org.

View Abstract