Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes

Here, we show that in both settings, mesenchymal markers are induced. However, upregulation of Snai1 and downregulation of E-Cadherin are restricted to TGF-beta 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-beta 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-beta in a FAK/Src dependent manner, poorly differentiated cell lines display high Cav1 expression levels which are not further modulated by TGF-beta.This study draws a detailed distinction between intrinsic and TGF-beta 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.