Extracellular matrix induced signaling and TGF-β regulate Caveolin–1 expression in hepatocytes

A major obstacle for the use of primary hepatocytes in research and drug testing is their tendency to dedifferentiate towards a mesenchymal phenotype during culture. This process is driven by integrin/FAK/Src signaling cascades, which leads to the upregulation of fibroblastoid markers, such as vimentin and N-Cadherin. Caveolin–1 is involved in endocytic processes as well as in the regulation of diverse signaling cascades and has been linked to cancer invasiveness. Culture driven hepatocyte dedifferentiation culminates in a significant increase in Caveolin–1 expression. This is driven by a Src dependent signaling initiation involving ERK and AKT pathways. In sharp contrast, the profibrogenic cytokine TGF-β is also inducing features of an epithelial to mesenchymal transition (EMT), but prevents upregulation of Caveolin–1. Although Caveolin–1 itself has been proposed to be an EMT marker, TGF-β is not linked to Caveolin–1 expression in untransformed hepatocytes. This is underscored by the observation that Snail, an essential EMT promoting transcription factor is dispensable for culture induced Caveolin–1 upregulation but not for TGF-β mediated EMT. Besides primary hepatocytes, HCC cell lines were subjected to TGF-β treatment. Intrinsic Caveolin–1 expression differed strongly with a correlation to the HCC differentiation status. Only the differentiated HCC cell lines with a relative low Caveolin–1 expression respond to TGF-β treatment with a strong upregulation of Caveolin–1 expression. This indicates that TGF-β can induce Caveolin–1 expression during an EMT process in transformed epithelial cells, which subsequently might influence migration and invasion of tumor cells.

EMT - HCC