Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation.
Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation.
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DOI：
10.1038/cddis.2015.249
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发表时间：
2015-09-10
影响因子：
9
通讯作者：
Alonzi T
中科院分区：
文献类型：
--
作者：
Grassi G;Di Caprio G;Santangelo L;Fimia GM;Cozzolino AM;Komatsu M;Ippolito G;Tripodi M;Alonzi T
上皮-间充质转化（EMT）和间充质-上皮转化（MET）是涉及发育、伤口愈合和干细胞行为的事件，并在病理上促进癌症进展。确定肝细胞中这些表型转化的分子机制是设计旨在优化肝修复的特定治疗策略的基础。在肝脏特异性自噬缺陷小鼠（Alb-Cre;ATG7fl/fl）和非致瘤性永生化肝细胞系MMH中，研究了自噬在肝细胞EMT/MET过程中的作用。体内自噬不足会降低上皮标志物的表达，增加间充质标志物的水平。这些改变与EMT主调控因子Snail蛋白水平的升高有关，没有转录诱导。有趣的是，我们发现自噬以p62/SQSTM1 （Sequestosome-1）依赖的方式降解Snail。此外，根据促上皮功能，我们观察到自噬刺激强烈影响EMT的进展，而这对于MET是必要的。最后，我们发现TGFβ诱导的EMT影响自噬通量，表明这些过程相互调节。总的来说，我们发现自噬调节肝细胞的表型可塑性，通过抑制间充质程序促进其上皮特性。
Epithelial-to-mesenchymal transition (EMT) and the reverse process mesenchymal-to-epithelial transition (MET) are events involved in development, wound healing and stem cell behaviour and contribute pathologically to cancer progression. The identification of the molecular mechanisms underlying these phenotypic conversions in hepatocytes are fundamental to design specific therapeutic strategies aimed at optimising liver repair. The role of autophagy in EMT/MET processes of hepatocytes was investigated in liver-specific autophagy-deficient mice (Alb-Cre;ATG7fl/fl) and using the nontumorigenic immortalised hepatocytes cell line MMH. Autophagy deficiency in vivo reduces epithelial markers' expression and increases the levels of mesenchymal markers. These alterations are associated with an increased protein level of the EMT master regulator Snail, without transcriptional induction. Interestingly, we found that autophagy degrades Snail in a p62/SQSTM1 (Sequestosome-1)-dependent manner. Moreover, accordingly to a pro-epithelial function, we observed that autophagy stimulation strongly affects EMT progression, whereas it is necessary for MET. Finally, we found that the EMT induced by TGFβ affects the autophagy flux, indicating that these processes regulate each other. Overall, we found that autophagy regulates the phenotype plasticity of hepatocytes promoting their epithelial identity through the inhibition of the mesenchymal programme.