Transforming growth factor-β induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes


Takashi Kojima, PhD, Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo 060-8556, Japan
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Background/Aims: Transforming growth factor-β (TGF-β) initiates and maintains epithelial–mesenchymal transition (EMT), which causes disassembly of tight junctions and loss of epithelial cell polarity. In mature hepatocytes during EMT induced by TGF-β, changes in the expression of tight junction proteins and the fence function indicated that epithelial cell polarity remains unclear.

Methods: In the present study, using primary cultures of adult rat hepatocytes at day 10 after plating, in which epithelial cell polarity is well maintained by tight junctions, we examined the effects of 0.01–20 ng/ml TGF-β on the expression of the integral tight junction proteins, claudin-1, -2 and occludin, as well as the fence function.

Results: In adult rat hepatocytes, TGF-β induced EMT, which was indicated as upregulation of Smad-interacting protein-1 (SIP1) and Snail and down-regulation of E-cadherin. Down-regulation of claudin-1 and upregulation of occludin were observed beginning from a low dose of TGF-β, whereas upregulation of claudin-2 was observed at a high dose of TGF-β. Furthermore, treatment with TGF-β caused disruption of the fence function, which was closely associated with the expression of claudin-1 via p38 mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase and protein kinase C but not MAPK signalling pathways.

Conclusion: These results suggest that in mature hepatocytes in vitro, TGF-β induces EMT by down-regulation of claudin-1 and the fence function via distinct signalling pathways.