Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and
mesenchymal-to-epithelial transitions promoting Snail degradation
#MMPMID26355343
Grassi G
; Di Caprio G
; Santangelo L
; Fimia GM
; Cozzolino AM
; Komatsu M
; Ippolito G
; Tripodi M
; Alonzi T
Cell Death Dis
2015[Sep]; 6
(9
): e1880
PMID26355343
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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 TGF? 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.
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