Instituto de Neurociencias (CSIC-UMH), 03550 San Juan de Alicante, Spain.
J Cell Sci. 2010 Oct 15;123(Pt 20):3467-77. doi: 10.1242/jcs.068692.
Although TGF-β suppresses early stages of tumour development, it later contributes to tumour progression when cells become resistant to its suppressive effects. In addition to circumventing TGF-β-induced growth arrest and apoptosis, malignant tumour cells become capable of undergoing epithelial-to-mesenchymal transition (EMT), favouring invasion and metastasis. Therefore, defining the mechanisms that allow cancer cells to escape from the suppressive effects of TGF-β is fundamental to understand tumour progression and to design specific therapies. Here, we have examined the role of Snail1 as a suppressor of TGF-β-induced apoptosis in murine non-transformed hepatocytes, rat and human hepatocarcinoma cell lines and transgenic mice. We show that Snail1 confers resistance to TGF-β-induced cell death and that it is sufficient to induce EMT in adult hepatocytes, cells otherwise refractory to this transition upon exposure to TGF-β. Furthermore, we show that Snail1 silencing prevents EMT and restores the cell death response induced by TGF-β. As Snail1 is a known target of TGF-β signalling, our data indicate that Snail1 might transduce the tumour-promoting effects of TGF-β, namely the EMT concomitant with the resistance to cell death.
虽然 TGF-β 抑制肿瘤发展的早期阶段，但当细胞对其抑制作用产生抗性时，它后来会促进肿瘤的进展。除了规避 TGF-β 诱导的生长停滞和细胞凋亡外，恶性肿瘤细胞还能够经历上皮间质转化（EMT），有利于侵袭和转移。因此，定义允许癌细胞逃避 TGF-β抑制作用的机制对于理解肿瘤进展和设计特定治疗方法至关重要。在这里，我们研究了 Snail1 作为一种抑制物在鼠未转化肝细胞、大鼠和人肝癌细胞系以及转基因小鼠中 TGF-β 诱导的细胞凋亡的作用。我们表明 Snail1 赋予 TGF-β 诱导的细胞死亡抗性，并且足以诱导成年肝细胞发生 EMT，否则这些细胞在接触 TGF-β 时会抵抗这种转化。此外，我们表明 Snail1 的沉默可防止 EMT 并恢复 TGF-β 诱导的细胞死亡反应。由于 Snail1 是 TGF-β 信号通路的已知靶标，我们的数据表明 Snail1 可能传递 TGF-β 的促肿瘤作用，即 EMT 伴随着对细胞死亡的抗性。
