Snail1 suppresses TGF-β-induced apoptosis and is sufficient to trigger EMT in hepatocytes

Abstract

Although TGF- 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--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- is fundamental to understand tumour progression and to design specific therapies. Here, we have examined the role of Snail1 as a suppressor of TGF--induced apoptosis in murine non-transformed hepatocytes, rat and human hepatocarcinoma cell lines and transgenic mice. We show that Snail1 confers resistance to TGF--induced cell death and that it is sufficient to induce EMT in adult hepatocytes, cells otherwise refractory to this transition upon exposure to TGF-. Furthermore, we show that Snail1 silencing prevents EMT and restores the cell death response induced by TGF-. As Snail1 is a known target of TGF- signalling, our data indicate that Snail1 might transduce the tumour-promoting effects of TGF-, namely the EMT concomitant with the resistance to cell death.

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

“…As such, it remains possible that the role of Snail1 in fibrosis may be limited to the formation of "metastable" hepatocytes displaying a combination of epithelial and mesenchymal properties that exert a more complex effect on disease progression than was appreciated previously. Consistent with this premise, we and others have documented the ability of hepatocytes to undergo an incomplete EMT characterized by a partial repression of E-cadherin with maintenance of an overall epithelial-like phenotype in vitro and in vivo (9,10,13,15,16,24,57). Nevertheless, these data fall short of proving that Snail1-expressing hepatocytes contribute directly to scar formation during liver fibrosis by depositing substantive quantities of type I/III collagens in vivo, an untested hypothesis that can be clarified only by conditionally deleting the type I collagen gene in hepatocytes alone.…”

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

“…Indeed, we have described that TGF-␤ can induce not only proapoptotic but also prosurvival signals in hepatocytes. Interestingly, these signals are dependent on NF-B activity (20,37). In our model, results obtained with p65-targeted knockdown confirm the inhibitory effect of NF-B on TGF-␤ signaling in both PTP1B ϩ/ϩ and PTP1B Ϫ/Ϫ hepatocytes (Figs.…”

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

“…[30][31][32][33][34] Reduced proliferation may increase the resistance to apoptosis of cancer cells undergoing invasion and metastasis. 32 Antiapoptotic activity is another common feature of the genes induced by EMT, such as Snail1, 30,34,66 ZEB2/SIP1, 31,39,67 YB-1 32,64 and miR-19 (the present study). Therefore, resistance to apoptosis conferred by miR-19 provides a selective Figure S10, overexpression of miR-19 led to the loss of epithelial markers, the expression of mesenchymal markers, changes of cell shape, and the acquisition of motility and invasive properties, and apoptosis resistance of lung cancer cells.…”