title: The APC tumor suppressor is required for epithelial cell polarization and three-dimensional morphogenesis.
abstract: The Adenomatous Polyposis Coli (APC) tumor suppressor has been previously implicated in the control of apical-basal polarity; yet, the consequence of APC loss-of-function in epithelial polarization and morphogenesis has not been characterized. To test the hypothesis that APC is required for the establishment of normal epithelial polarity and morphogenesis programs, we generated APC-knockdown epithelial cell lines. APC depletion resulted in loss of polarity and multi-layering on permeable supports, and enlarged, filled spheroids with disrupted polarity in 3D culture. Importantly, these effects of APC knockdown were independent of Wnt/β-catenin signaling, but were rescued with either full-length or a carboxy (c)-terminal segment of APC. Moreover, we identified a gene expression signature associated with APC knockdown that points to several candidates known to regulate cell-cell and cell-matrix communication. Analysis of epithelial tissues from mice and humans carrying heterozygous APC mutations further supports the importance of APC as a regulator of epithelial behavior and tissue architecture. These data also suggest that the initiation of epithelial-derived tumors as a result of APC mutation or gene silencing may be driven by loss of polarity and dysmorphogenesis.
authors.affiliation: Department of Biological Sciences and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Alyssa C
authors.initials: AC
authors.lastname: Lesko
authors.affiliation: University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL 60637, USA.
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Goss
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Schwertner
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Imge
authors.initials: I
authors.lastname: Hulur
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine - South Bend, South Bend, IN 46617, USA; Department of Biological Sciences and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: jrprospe@iupui.edu.
authors.forename: Jenifer R
authors.initials: JR
authors.lastname: Prosperi
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018929:Cell Culture Techniques; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D004285:Dogs; D004847:Epithelial Cells / Q000502:physiology*; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation / Q000502:physiology
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein
keywords: Adenomatous Polyposis Coli; Epithelial polarity; Madin–Darby Canine Kidney