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Keywords:

  • β-catenin;
  • LEF-1;
  • DLD1;
  • MDCK;
  • HCE cells;
  • epithelial-mesenchymal transformation

Abstract

Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, β-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. β-catenin has been shown to activate LEF-1 transcription during EMT induced in vitro by c-Fos. Here, we ask whether or not LEF-1 directly introduced into epithelial cells in an adenovirus construct can induce EMT. In normal epithelial cell lines, such as HCE and MDCK cells, that contain functional APC, nuclear β-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks β-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic β-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear β-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear β-catenin. This EMT is reversible if the LEF-1 virus is removed. Thus, our results demonstrate that LEF-1 can induce EMT directly when its transcription activity is activated by stable nuclear β-catenin. Normal adult epithelial cells appear to use APC to keep β-catenin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/β-catenin-induced EMT.