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

Abstract

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/␤-catenin pathway in UCSs. In clinical samples, phosphoAkt (pAkt) expression was found to be significantly increased in mesenchymal compared with epithelial components, exhibiting both positive and negative correlations with nuclear ␤-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 ␤-catenin. In endometrial cancer cell lines, active Akt induced the stabilization of nuclear ␤-catenin through the phosphorylation of GSK-3␤, and this, in turn, led to the transactivation of Slug, which was mediated by nuclear ␤-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/␤-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

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

“…Expression differences between tumor components were reported previously, but exact percentages are lacking. 24 Previously, positive nuclear b-catenin immunostaining was detected in 86% of uterine carcinosarcomas, 41 which is higher compared with our result. However, this study population was smaller (n ¼ 7) and different techniques for immunohistochemistry analysis were used.…”

“…Above-mentioned results are in line with other studies and confirm the monoclonal origin of uterine carcinosarcomas. 8,9,[23][24][25] The ER and PR are important in growth, differentiation and function of reproductive tissues. In the past decade, two subtypes of ER (ER-a and ER-b) and PR (PR-A and PR-B) have been discovered.…”

“…3 To date, only two studies reported on this subject in uterine carcinosarcomas. 24,41 To determine the function of the aberrant Wnt signaling in carcinosarcomas of the uterus, we determined b-catenin and cyclin D1 expression (which is a direct target gene of b-catenin). In our population, nuclear b-catenin expression was present in 11% and 13% in the epithelial and mesenchymal component of carcinosarcomas, respectively.…”

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

“…Previous studies have shown that activated RAS can increase Snail2 expression in rat intestinal epithelial cells (Schmidt et al, 2005) and that Snail2 expression can be induced by multiple RAS effector pathways, by Raf and ERK (Conacci-Sorrell et al, 2003;Wang et al, 2007) and also by AKT (Saegusa et al, 2009). Snail2 knockdown does have a relatively modest effect on E-cadherin mRNA, even in cells without RAS activation, suggesting that there is at least some activity of Snail2 independent of elevated RAS signalling.…”

Sox4 functions as a positive regulator of β-catenin signaling through upregulation of TCF4 during morular differentiation of endometrial carcinomas

“…[17][18][19][20] In addition, siRNAs for Sox4, as well as the negative controls, were transfected using siPORT NeoFX transfection agent (Ambion, Austin, TX) according to the manufacturers' instructions. 25 RT-PCR Amplification was carried out in the exponential phase (20-28 cycles) to allow comparison among cDNAs synthesized from identical reactions, using specific primers (Supplementary Table S1). Primers for the GAPDH gene were also applied as described previously.…”