title: Snail controls differentiation of hepatocytes by repressing HNF4alpha expression.
abstract: 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.
authors.affiliation: Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Cicchini
authors.forename: Daniela
authors.initials: D
authors.lastname: Filippini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Coen
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marchetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Cavallari
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laudadio
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Spagnoli
authors.forename: Tonino
authors.initials: T
authors.lastname: Alonzi
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
mesh_terms: 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
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors