STAT3 aggravates TGF-β1-induced hepatic epithelial-to-mesenchymal transition and migration - 04/02/18
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Abstract |
Signal transducer and activator of transcription 3 (STAT3) has been shown to affect epithelial-to-mesenchymal transition (EMT) in cancers. We investigated the underlying molecular mechanisms of STAT3 crosstalk with Snail-Smad3/transforming growth factor (TGF)-β1 signaling pathways during the EMT in hepatocellular carcinoma (HCC). STAT3 and TGF-β1 expressions are examined in liver tissues of HCC patients and rats. The effect of IL-6/ STAT3 crosstalk with Snail-Smad3/TGF-β1 on EMT, carcinogenesis, migration and invasion are tested in vitro and in vivo. Phosphorylation of STAT3 and TGF-β1 proteins are universally high and positively co-expressed in HCC tissues from human and rats. Hepatic lower p-STAT3 proteins are related to earlier tumor stages in HCC patients. AG490 (a JAK2-specific inhibitor) treatment could reduce tumor numbers and sizes depending on suppression of STAT3 signaling in HCC rats. TGF-β1 could induce EMT along with an E-cadherin decrease, while vimentin, Snail, p-Smad2/3, and p-STAT3/STAT3 increase in HepG2. SIS3 (a specific inhibitor of Smad3) could markedly inhibit Snail, Vim and p-STAT3 along with blocking phosphorylation of Smad3, but E-cadherin could be activated in HepG2. IL-6 activates STAT3 signaling and then has cascading consequences for activating Snail-Smad3/TGF-β1 and vimentin as well as migration and invasion in liver cancer cells. In contrast, AG490 has an effect that inhibits phosphorylation of STAT3, lowers Snail-p-Smad3 protein levels, decreases TGF-β1-related PAI-1 promoter activation and then reduces migration or invasion of liver cancer cells. STAT3 functions as a positive regulator to activate TGF-β1-induced EMT and metastasis of HCC. STAT3 and the Snail-Smad3/TGF-β1 signaling pathways synergistically augment EMT and migration in HCC.
Le texte complet de cet article est disponible en PDF.Keywords : Hepatocellular carcinoma (HCC), Epithelial-to-mesenchymal transition (EMT), Signal transducer and activator of transcription 3 (STAT3), Transforming growth factor-β1 (TGF-β1), Migration
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Vol 98
P. 214-221 - février 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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