Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells
Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells
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DOI：
10.1038/sj.onc.1205766
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发表时间：
2002-09-05
期刊：
影响因子：
8
通讯作者：
Schwarte-Waldhoff, I
中科院分区：
文献类型：
--
作者：
Müller, N;Reinacher-Schick, A;Schwarte-Waldhoff, I
Smad4 是 TGF-β 信号的细胞内递质，其肿瘤抑制功能据推测在于其介导 TGF-β 诱导的生长抑制的能力。然而，越来越多的证据表明这个假设可能过于简单。 TGF-β在癌发生中的作用是复杂的，并且还包括肿瘤促进功能，特别是在晚期癌发生中。重要的是，结肠癌中 Smad4 的功能失活经常发生在肿瘤获得侵袭和转移能力的晚期。我们之前曾报道，Smad4在SW480人结肠癌细胞中的稳定重新表达足以抑制裸鼠中的肿瘤生长。然而，它不会影响体外细胞生长，也不会恢复 TGF-β 反应性。在这里，我们报告 Smad4 转录诱导经典钙粘蛋白，包括侵袭抑制因子 E-钙粘蛋白，可能重建上皮形态。 Smad4 诱导的钙粘蛋白能够将连环蛋白募集到质膜上，并且在细胞间粘附中具有功能活性。这些结果表明 Smad4 介导的肿瘤抑制的新途径，并表明结肠细胞中的 Smad4 可能参与上皮性状的维持。
Smad4 is an intracellular transmitter of TGF-beta signals and its tumor suppressor function is presumed to reside in its capacity to mediate TGF-beta-induced growth inhibition. However, there is accumulating evidence that this hypothesis may be too simple. The roles of TGF-beta in carcinogenesis are complex and also comprise tumor promoting functions particularly in late stage carcinogenesis. Importantly, functional inactivation of Smad4 in colon carcinomas frequently occurs at late stages when tumors acquire invasive and metastatic capabilities. We have previously reported that stable re-expression of Smad4 in SW480 human colon carcinoma cells was adequate to suppress tumor growth in nude mice. However, it did not affect cell growth in vitro nor did it restore TGF-beta responsiveness. Here, we report that Smad4 transcriptionally induced classical cadherins including the invasion suppressor E-cadherin, presumably re-establishing epithelial morphology. Smad4-induced cadherins were able to recruit catenins to the plasma membrane and were functionally active in cell-cell adhesion. These results indicate a novel pathway of Smad4-mediated tumor suppression and suggest that Smad4 in colon cells may be involved in the maintenance of epithelial traits.