Regulation of epithelial cell migration and tumor formation by beta-catenin signaling

Exp Cell Res. 2002 Oct 15;280(1):119-33. doi: 10.1006/excr.2002.5630.

Abstract

Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. beta-catenin plays a dual role in this process: as a member of adherens junctions it is essential to link cadherins to the cytoskeleton thereby allowing tight intercellular adhesion, and as a member of the Wnt-signaling pathway, beta-catenin is translocated into the nucleus and serves together with the LEF1/TCF-transcription factors to drive gene expression necessary for the epithelial-to-mesenchymal transition (EMT). Activated beta-catenin signaling has been implicated in the genesis of a variety of tumors. Here we demonstrate a pivotal function for beta-catenin signaling in epithelial cell migration and tumorigenesis. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) induce beta-catenin signaling under conditions where they stimulate cell motility. Ectopic expression of either stabilized beta-catenin or a regulatable form of activated beta-catenin induces cell migration in different cell types and cooperates with EGF and HGF in this process. Activation of beta-catenin signaling induces expression of the new target gene osteopontin during migration. Cells expressing stabilized beta-catenin also exhibit significantly increased capability to form tumors in a nude mouse xenograft model. The data suggest that a critical threshold of beta-catenin signaling, activated by cooperative mechanisms, may be important during the EMT and tumorigenesis.

MeSH terms

  • Animals
  • Aphidicolin / pharmacology
  • Carcinoma / pathology
  • Cell Line
  • Cell Movement / physiology*
  • Cycloheximide / pharmacology
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / physiology*
  • Gene Targeting
  • Mice
  • Mice, Nude
  • Neoplasms / etiology*
  • Osteopontin
  • Protein Synthesis Inhibitors / pharmacology
  • Rats
  • Sialoglycoproteins / metabolism
  • Signal Transduction*
  • Trans-Activators / metabolism*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / pathology
  • beta Catenin

Substances

  • CTNNB1 protein, mouse
  • Ctnnb1 protein, rat
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Protein Synthesis Inhibitors
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • Spp1 protein, rat
  • Trans-Activators
  • beta Catenin
  • Osteopontin
  • Aphidicolin
  • Epidermal Growth Factor
  • Cycloheximide