Dysregulation of E-cadherin by oncogenic Ras in intestinal epithelial cells is blocked by inhibiting MAP kinase.
BACKGROUND
Mutations in oncogenic Ras contribute to colorectal tumorigenesis. Loss of the cell adhesion protein E-cadherin is associated with tumor invasion and metastasis.


METHODS
Expression of oncogenic Ras was induced in intestinal epithelial cells. Changes in cell morphology, E-cadherin protein expression, and E-cadherin localization were examined by light microscopy, Western blot, and immunofluorescence respectively. Expression of E-cadherin in human colorectal tumors was examined by immunohistochemistry.


RESULTS
Induction of oncogenic Ras results in an epithelial to mesenchymal transformation with loss of membranous E-cadherin expression and mis-localization to the cytoplasm. Removal of Ras stimulus or blockade of the MAP kinase pathway allowed reversion to a normal cellular phenotype and return of E-cadherin to the cell membrane. Loss of or decreased expression of E-cadherin was observed in seven of eight colorectal tumors.


CONCLUSIONS
Oncogenic Ras contributes to malignant transformation and altered E-cadherin expression in intestinal epithelial cells. Similar dysregulation of E-cadherin is found in human colorectal tumors. Ras effects on E-cadherin are critical to malignant transformation in our in-vitro model and may be an important event in human colorectal tumors.
Department of Surgery, Vanderbilt University Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA.
Carl R
CR
Schmidt
M Kay
MK
Washington
Y J
YJ
Gi
Robert J
RJ
Coffey
R Daniel
RD
Beauchamp
A Scott
AS
Pearson
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D051381:Rats
D002070:Butadienes; D015820:Cadherins; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases