title: Cooperation of Sox4 with β-catenin/p300 complex in transcriptional regulation of the Slug gene during divergent sarcomatous differentiation in uterine carcinosarcoma.
abstract: BACKGROUND
  Uterine carcinosarcoma (UCS) represents a true example of cancer associated with epithelial-mesenchymal transition (EMT), which exhibits cancer stem cell (CSC)-like traits. Both Sox and β-catenin signal transductions play key roles in the regulation of EMT/CSC properties, but little is known about their involvement in UCS tumorigenesis. Herein, we focused on the functional roles of the Sox/β-catenin pathway in UCSs.
  
  
  METHODS
  EMT/CSC tests and transfection experiments were carried out using three endometrial carcinoma (Em Ca) cell lines. Immunohistochemical investigation was also applied for a total of 32 UCSs.
  
  
  RESULTS
  Em Ca cells cultured in STK2, a serum-free medium for mesenchymal stem cells, underwent changes in morphology toward an EMT appearance through downregulation of E-cadherin, along with upregulation of Slug, known as a target gene of β-catenin. The cells also showed CSC properties with an increase in the aldehyde dehydrogenase (ALDH) 1(high) activity population and spheroid formation, as well as upregulation of Sox4, Sox7, and Sox9. Of these Sox factors, overexpression of Sox4 dramatically led to transactivation of the Slug promoter, and the effects were further enhanced by cotransfection of Sox7 or Sox9. Sox4 was also able to promote β-catenin-mediated transcription of the Slug gene through formation of transcriptional complexes with β-catenin and p300, independent of TCF4 status. In clinical samples, both nuclear β-catenin and Slug scores were significantly higher in the sarcomatous elements as compared to carcinomatous components in UCSs, and were positively correlated with Sox4, Sox7, and Sox9 scores.
  
  
  CONCLUSIONS
  These findings suggested that Sox4, as well as Sox7 and Sox9, may contribute to regulation of EMT/CSC properties to promote development of sarcomatous components in UCSs through transcriptional regulation of the Slug gene by cooperating with the β-catenin/p300 signal pathway.
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. dm13008y@st.kitasato-u.ac.jp.
authors: Hisako
authors: H
authors: Inoue
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. hitakaha@med.kitasato-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Takahashi
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. mhashimu@med.kitasato-u.ac.jp.
authors: Miki
authors: M
authors: Hashimura
authors: Department of Immunology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. eshima@med.kitasato-u.ac.jp.
authors: Koji
authors: K
authors: Eshima
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. platysmanejp@yahoo.co.jp.
authors: Masashi
authors: M
authors: Akiya
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. matsumoto@med.kitasato-u.ac.jp.
authors: Toshihide
authors: T
authors: Matsumoto
authors: Department of Pathology, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. msaegusa@med.kitasato-u.ac.jp.
authors: Makoto
authors: M
authors: Saegusa
mesh_terms: D000818:Animals; D002296:Carcinosarcoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000096:biosynthesis* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D055758:SOX9 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D055751:SOXC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D055760:SOXF Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C000604407:SNAI1 protein, human; C083431:SOX4 protein, human; C484456:SOX7 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055751:SOXC Transcription Factors; D055760:SOXF Transcription Factors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human