Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-β during the process of epithelial to mesenchymal transition in rat proximal epithelial cells

Abstract

Epithelial to mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis and the initial step is disruption of cell junction and cell polarity. TGF-β has been demonstrated as the most important mediator of EMT which is sufficient to initiate and complete the whole course of EMT, however, the detailed mechanism of TGF-β in modulating the disruption of cell junction still remains unclear. Par-3 is a component of Par complex which plays a crucial role in the establishment and maintenance of epithelial polarity. In this study, we found that TGF-β treatment resulted in a dose- and time-dependent downregulation of Par-3 protein together with the suppression of E-cadherin expression and induction of α-SMA. The decreased Par-3 subsequently resulted in the redistribution of Par-6–aPKC complex from cell membrane to cytoplasm. Forced expression of exogenous Par-3 into rat proximal epithelial cells (NRK52E) led to a drastic blockage of TGF-β1-induced E-cadherin suppression and α-SMA induction. In contrast, knockdown Par-3 expression by siRNA significantly enhanced TGF-β1-induced E-cadherin suppression and α-SMA induction. These data indicate that downregulation of Par-3 and subsequent disruption of Par complex integrity might be one mechanism that TGF-β destroys cell polarity during EMT.