title: Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes.
abstract: BACKGROUND
  Dedifferentiation and loss of hepatocyte polarity during primary culture of hepatocytes are major drawbacks for metabolic analyses. As a prominent profibrotic cytokine and potent inducer of epithelial mesenchymal transition (EMT), TGF-β contributes to these processes in liver epithelial cells. Yet, a distinction between culture dependent and TGF-β driven hepatocyte dedifferentiation has not been shown to date.
  
  
  RESULTS
  Here, we show that in both settings, mesenchymal markers are induced. However, upregulation of Snai1 and downregulation of E-Cadherin are restricted to TGF-β effects, neglecting a full EMT of culture dependent hepatocyte dedifferentiation. Mechanistically, the latter is mediated via FAK/Src/ERK/AKT pathways leading to the induction of the oncogene caveolin-1 (Cav1). Cav1 was recently proposed as a new EMT marker, but our results demonstrate Cav1 is not up-regulated in TGF-β mediated hepatocyte EMT, thus limiting validity of its use for this purpose. Importantly, marking differences on Cav1 expression exist in HCC cell lines. Whereas well differentiated HCC cell lines exhibit low and inducible Cav1 protein levels - by TGF-β in a FAK/Src dependent manner, poorly differentiated cell lines display high Cav1 expression levels which are not further modulated by TGF-β.
  
  
  CONCLUSIONS
  This study draws a detailed distinction between intrinsic and TGF-β mediated hepatocyte dedifferentiation and elucidates cellular pathways involved. Additionally, by evaluating the regulation of the oncogene Cav1, we provide evidence to argue against Cav1 as a reliable EMT marker.
authors: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. steven.dooley@medma.uni-heidelberg.de.
authors: Christoph
authors: C
authors: Meyer
authors: Johanna
authors: J
authors: Dzieran
authors: Yan
authors: Y
authors: Liu
authors: Felizitas
authors: F
authors: Schindler
authors: Stefan
authors: S
authors: Munker
authors: Alexandra
authors: A
authors: Müller
authors: Cédric
authors: C
authors: Coulouarn
authors: Steven
authors: S
authors: Dooley