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.
Saegusa
Makoto
M
Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. msaegusa@med.kitasato-u.ac.jp
Hashimura
Miki
M
Kuwata
Takeshi
T
Okayasu
Isao
I
D015153:Blotting, Western; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002296:Carcinosarcoma / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000096:biosynthesis*
D015820:Cadherins; D016160:Retinoblastoma Protein; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt