Snail controls differentiation of hepatocytes by repressing HNF4alpha expression.
Epithelial-to-mesenchymal transition (EMT) is a coordinated process, occurring both during morphogenesis and tumor progression, that allows epithelial cells to dissociate from initial contacts and migrate to secondary sites. The transcriptional repressors of the Snail family induce EMT in different epithelial cell lines and their expression is strictly correlated with EMT during the development and progression of carcinomas. We have previously shown that EMT in hepatocytes correlates with the downregulation of hepatic differentiation key factors HNFs (hepatocyte nuclear factors), and in particular of HNF4alpha. Here, we demonstrate that Snail overexpression is sufficient (i) to induce EMT in hepatocytes with conversion of morphology, downregulation of several epithelial adhesion molecules, reduction of proliferation and induction of matrix metalloproteinase 2 expression and, (ii) most relevantly, to repress the transcription of the HNF4alpha gene through a direct binding to its promoter. These finding demonstrate that Snail is at the crossroads of the regulation of EMT in hepatocytes by a dual control of epithelial morphogenesis and differentiation.
Cicchini
Carla
C
Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
Filippini
Daniela
D
Coen
Sabrina
S
Marchetti
Alessandra
A
Cavallari
Claudio
C
Laudadio
Ilaria
I
Spagnoli
Francesca M
FM
Alonzi
Tonino
T
Tripodi
Marco
M
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004848:Epithelium / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology*; D051379:Mice; D011401:Promoter Regions, Genetic; D040081:Protein Array Analysis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014162:Transfection
D051557:Hepatocyte Nuclear Factor 4; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors