Transforming growth factor-β1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells

被引:65
作者
Fujimoto, K
Sheng, H
Shao, J
Beauchamp, RD
机构
[1] Vanderbilt Univ, Med Ctr, Med Ctr N CC2306, Dept Surg, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Dept Cell Biol, Nashville, TN 37232 USA
[4] Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA
关键词
TGF-beta; Ras; invasiveness; epithelial-fibroblastoid conversion; E-cadherin; beta-catenin; TGF-beta receptor type II; intestinal epithelial cells;
D O I
10.1006/excr.2000.5229
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (T beta RII) 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 T beta RII. 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 T beta RII 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 T beta RII. (C) 2001 Academic Press.
引用
收藏
页码:239 / 249
页数:11
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