Transforming growth factor-β1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells
Transforming growth factor-β1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells
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DOI：
10.1006/excr.2000.5229
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发表时间：
2001-06-10
影响因子：
3.7
通讯作者：
Beauchamp, RD
中科院分区：
文献类型：
--
作者：
Fujimoto, K;Sheng, H;Beauchamp, RD
侵袭是癌症进展中的决定性事件。一般而言，浸润性癌的特征在于上皮-成纤维细胞样转化，其与细胞-细胞粘附受体如E-钙粘蛋白和β-连环蛋白的丧失相关。我们在这里报告说，TGF-β 1通过调节细胞可塑性的改变，包括Ras转化上皮细胞中细胞-细胞接触的丧失，促进了侵袭力。为了研究TGF-β 1在Ras诱导的反应中的作用，在本研究中使用了表达条件活化的Ha-Ras（Val 12）的肠上皮细胞（RIE-iRas细胞）。激活的Ha-Ras（Val 12）的诱导表达引起RIE-iRas细胞的形态转化，其中波形蛋白表达增加和E-钙粘蛋白水平降低。在Ras诱导后，β-catenin也从细胞质重新分布到细胞核，TGF-β 1处理增强了E-cadherin水平的降低和β-catenin的重新分布。有趣的是，Ras的激活显著降低了RIE-iRas细胞中TGF-β受体II型（T β RII）的水平。然而，纤溶酶原激活物抑制剂-1的表达，这是已知的转录诱导TGF-β 1，强烈诱导TGF-β 1，尽管显着下调的T β RII。Ha-Ras（Val 12）的诱导显著增加了RIE-iRas细胞的侵袭性，如通过I型胶原包被的Boyden室测定所评估的，并且Ras介导的侵袭性通过TGF-β 1处理显著增强。在RIE-iRas细胞中表达显性阴性形式的T β RII消除了对TGF-β 1的生长抑制和侵袭反应。总的来说，这些结果表明，TGF-β 1和致癌Ras合作，促进肠上皮细胞的细胞侵袭。侵袭性的增强与E-钙粘蛋白水平的降低和β-连环蛋白的亚细胞分布相关。TGF-β 1通过T β RII增强致癌Ras介导的细胞转化。(C)北京：科学出版社.
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.