title: Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells.
abstract: Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analyzed for gene regulatory activity and the expression pattern of APC and GSK3β at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activated APC and AXIN2 promoter activities via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration.
authors: Department of Pathology, Sygehus Syd Naestved, Naestved 4700, Denmark.
authors: Anders Krüger
authors: AK
authors: Olsen
authors: Mehmet
authors: M
authors: Coskun
authors: Michael
authors: M
authors: Bzorek
authors: Michael Holmsgaard
authors: MH
authors: Kristensen
authors: Erik Thomas
authors: ET
authors: Danielsen
authors: Steffen
authors: S
authors: Jørgensen
authors: Jørgen
authors: J
authors: Olsen
authors: Ulla
authors: U
authors: Engel
authors: Susanne
authors: S
authors: Holck
authors: Jesper Thorvald
authors: JT
authors: Troelsen
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060466:Axin Protein / Q000096:biosynthesis*; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: C555337:APC protein, human; C491761:AXIN2 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3