Oncogenic Ras dominates overexpression of E-cadherin in malignant transformation of intestinal epithelial cells.

Schmidt CR, Gi YJ, Coffey RJ, Beauchamp RD, Pearson AS
Surgery. 2004 136 (2): 303-9

PMID: 15300195 · DOI:10.1016/j.surg.2004.05.004

BACKGROUND - Loss of the adherens junction protein E-cadherin is a critical event during Ras-mediated transformation of intestinal epithelial cells. The purpose of our study was to determine if overexpression of E-cadherin prevents Ras-induced malignant transformation and suppresses cell growth.

METHODS - Rat intestinal epithelial cells were constructed with a mutated human Ha-RasVal12 cDNA. In these cells, Ras is constitutively expressed or induced by addition of isopropyl-1-thio-B-D-galactopyranoside. Cells were transfected with a bicistronic retroviral system that expressed green fluorescent protein alone or this protein and human E-cadherin. E-cadherin expression was measured by Western blot analysis, and localization by immunofluorescence. Anchorage-independent growth in soft agar was examined as well as tumor growth in nude mice.

RESULTS - After Ras induction, endogenous E-cadherin was downregulated, whereas overexpression of human E-cadherin was sustained. Oncogenic Ras dominated overexpression of E-cadherin by causing malignant transformation and E-cadherin mislocalization. Ras also promoted growth in soft agar and tumors in nude mice despite E-cadherin overexpression.

CONCLUSIONS - Oncogenic Ras subverts the tumor suppressor activity of E-cadherin in Ras-transformed intestinal epithelial cells by downregulating endogenous E-cadherin and mislocalizing transfected E-cadherin. The role of E-cadherin as a tumor suppressor in intestinal malignancies may be restricted by mutated or overactive Ras.

Copyright 2004 Elsevier Inc.

MeSH Terms (11)

Animals Cadherins Cells, Cultured Cell Transformation, Neoplastic Genes, ras Intestinal Mucosa Intestinal Neoplasms Mice Mice, Nude Rats Transfection

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