Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation.
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;ATG7(fl/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.
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.
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Grassi
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.|Department of Cellular Biotechnologies and Hematology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
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Di Caprio
Department of Cellular Biotechnologies and Hematology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
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Santangelo
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.|Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy.
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Fimia
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.|Department of Cellular Biotechnologies and Hematology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
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Cozzolino
Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan.
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Komatsu
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.
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Ippolito
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.|Department of Cellular Biotechnologies and Hematology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
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Tripodi
National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.
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Alonzi
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors