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

Abstract

SummaryAlthough 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.

HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

“…Reports have shown that Snail plays an important role in the initiation of EMT 49, 50. Some studies have demonstrated that β‐catenin may be involved in the formation of pulmonary fibrosis by driving A549 cells to fibroblasts 51, 52.…”

Mixed-effects model of epithelial–mesenchymal transition reveals rewiring of signaling networks

“…We note that this lack of HSP27 induction does not result in higher levels of apoptosis, as EMT-hSAECs are resistant to apoptosis. The transcription factor SNAI, which is involved in EMT progression, down-regulates many pro-apoptotic genes [38]. …”

FBXL5 Inhibits Metastasis of Gastric Cancer Through Suppressing Snail1

“…Transcription factors that repress E-cadherin are considered as EMT-promoting factors, including Snail1, Slug1, ZEB1, ZEB2, E47 and Kruppel-like factor 8 (KLF8) that directly bind to E-cadherin promoter and repress its transcription, and including Twist, TCF4, SIX1 and FOXC2 that repress E-cadherin indirectly [5,6,7]. Snail1 is a member of the Snail superfamily of zinc-finger transcription factors [20,21]. Snail1 is composed of 264 amino acids and usually acts as a transcriptional repressor.…”

“…Snail1 is composed of 264 amino acids and usually acts as a transcriptional repressor. Phosphorylation and nuclear localization of Snail1, governed by PI3K and Wnt signaling pathways crosstalk, are critical in Snail1's regulation [20,21]. Snail1 has a pivotal role in the regulation of EMT, involving the loss of E-cadherin and claudins with concomitant upregulation of vimentin and fibronectin, among other biomarkers [20,21].…”

“…Phosphorylation and nuclear localization of Snail1, governed by PI3K and Wnt signaling pathways crosstalk, are critical in Snail1's regulation [20,21]. Snail1 has a pivotal role in the regulation of EMT, involving the loss of E-cadherin and claudins with concomitant upregulation of vimentin and fibronectin, among other biomarkers [20,21]. Recently, it is found that Snail1 degradation by FBXO11 is dependent on Ser-11 phosphorylation of Snail by protein kinase D1 (PKD1), and FBXO11 blocks Snail-induced EMT, tumor initiation, and metastasis in multiple breast cancer models [22].…”