Snail: in the cross-roads among EMT and apoptosis

Although Transforming Growth Factor-beta (TGF-β) suppresses early stages of tumour development, it later contributes to tumour progression when cells become resistant to its suppressive effects. 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. TGF-β plays a dual role in the control of apoptosis in fetal hepatocytes and hepatoma cells. On one side, it mediates cell death by a mitochondrial-dependent mechanism [1]. On another side, it induces anti-apoptotic signals through activation of the EGF receptor pathway [2, 3]. Cells that survive to the apoptotic effects of TGF-β undergo Epithelial-Mesenchymal transition (EMT), which mediates acquisition of motility and scattering properties and, additionally, confer cell resistance to apoptosis [4]. Snail is a well-known EMT inducer, which can also block cell proliferation and confer resistance to cell death [5]. In recent works from our labs 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 [6]. We have shown 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 found that Snail1 silencing prevents EMT and restores the cell death response induced by TGF-β. Together, our work points to a role of Snail1 in overcoming TGF-β tumour-suppressor effects in hepatocytes, and particularly in liver cancer cells, switching the response from tumour suppression to tumour progression, making them resistant to cell death and prone to undergo EMT and acquire invasive properties. Acknowledgements This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2008-01042, CONSOLIDER-INGENIO 2010 CSD2007-00017 and CSD2007-00023 to M.A.N.; BFU2006-01036, BFU2009-07219 and ISCIII-RTICC RD06/0020 to I.F.), the Generalitat Valenciana (Prometeo 2008/049) to M.A.N. and AGAUR-Generalitat de Catalunya (2009SGR312) to I.F.