Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells

Exp Cell Res. 2001 Jun 10;266(2):239-49. doi: 10.1006/excr.2000.5229.

Abstract

Invasion is a defining event in carcinoma progression. In general, invasive carcinoma is characterized by an epithelial-fibroblastoid conversion associated with loss of cell-cell adhesion receptors such as E-cadherin and beta-catenin. We report here that TGF-beta1 promotes the invasiveness by modulating the alterations of cellular plasticity including a loss of cell-cell contact in Ras-transformed epithelial cells. In order to examine the role of TGF-beta1 in the Ras-induced responses, intestinal epithelial cells expressing a conditionally activated Ha-Ras(Val12) (RIE-iRas cells) were used in this study. Induced expression of activated Ha-Ras(Val12) caused morphologic transformation of the RIE-iRas cells with an increase in vimentin expression and a decrease of E-cadherin levels. There was also redistribution of beta-catenin from the cytoplasm to the nucleus after the induction of Ras. TGF-beta1 treatment enhanced both the decrease in E-cadherin levels and the redistribution of beta-catenin. Interestingly, the activation of Ras markedly decreased the level of TGF-beta receptor type II (TbetaRII) in RIE-iRas cells. However, the expression of plasminogen activator inhibitor-1, which is known to be transcriptionally induced by TGF-beta1, was strongly induced by TGF-beta1 despite the marked downregulation of TbetaRII. The induction of Ha-Ras(Val12) markedly increased the invasiveness in RIE-iRas cells, as evaluated by a collagen type I-coated Boyden-chamber assay, and the Ras-mediated invasiveness was significantly enhanced by TGF-beta1 treatment. Expression of a dominant-negative form of TbetaRII in the RIE-iRas cells abrogated both growth-inhibitory and invasion responses to TGF-beta1. Collectively, these results suggest that TGF-beta1 and oncogenic Ras collaborate in promoting cellular invasiveness in intestinal epithelial cells. The enhancement of invasiveness was correlated with decreased E-cadherin levels and subcellular distribution of beta-catenin. The enhancement of oncogenic Ras-mediated cell transformation by TGF-beta1 occurs via TbetaRII.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adherens Junctions / drug effects
  • Cadherins / metabolism
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Line, Transformed
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Cytoskeletal Proteins / metabolism
  • Down-Regulation
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Neoplasm Invasiveness*
  • Oncogene Protein p21(ras) / genetics*
  • Oncogene Protein p21(ras) / metabolism
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Trans-Activators*
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • beta Catenin

Substances

  • Cadherins
  • Cytoskeletal Proteins
  • Plasminogen Activator Inhibitor 1
  • Receptors, Transforming Growth Factor beta
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • beta Catenin
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Oncogene Protein p21(ras)