An important phenotypic change in cadherin switching is the loss of ECAD expression. The loss of ECAD causes cells to dissociate from their neighbors and results in a loss of cell polarity. This, in turn, leads to the activation of cell signaling pathways that regulate the mesenchymal transition. On the contrary, an increase in ECAD expression inhibits cell transformation and tumor cell invasion in an adhesion-independent manner.3, 4 Myofibroblasts play a key role in wound healing and pathological organ remodeling.5 The most accepted myofibroblast progenitors in the liver are hepatic stellate cells (HSCs),5, 6 although various

other resident cells are recognized as sources of liver myofibroblasts.5 PF-02341066 chemical structure As HSCs activate, the level of ECAD expression decreases.7 Activated HSCs then promote the synthesis and deposition of the extracellular matrix (ECM) component and the induction of α-smooth muscle actin (αSMA). In addition, multiple signaling cascades accelerate the growth of activated HSCs6 and contribute to the development of liver fibrosis. Although the link between cadherin switching and the EMT process in HSCs has been studied,7, 8 it is yet unclear whether ECAD affects the activation of HSCs. Moreover, the potential

signaling Selleck PS341 and molecular regulatory mechanism by which ECAD antagonizes profibrogenic gene expression in quiescent HSCs has not been explored. Several lines of evidence indicate Suplatast tosilate that transforming growth factor β1 (TGFβ1) from autocrine or paracrine sources plays a role in activating HSCs and increasing the synthesis of ECM proteins and cellular receptors for various matrix proteins.6

TGFβ1 is regulated transcriptionally by transcription factors and posttranslationally by the maturation of the precursors.6 In response to TGFβ1, type I and II TGFβ1 receptors form a complex and induce receptor autophosphorylation. TGFβ1 is also known as a cytokine that induces EMT, which inhibits ECAD expression by up-regulating transcriptional repressors such as Snail, Zeb, and Twist.9 Activated TGFβ1 receptors transmit the signal by which regulatory Smad molecules (Smad3/2) are phosphorylated and form an active complex with co-Smad (Smad4). The transcription factor complex then moves to the nucleus, in which it promotes the transcription of target genes through interactions with specific Smad binding elements (SBEs; also called the CAGA box).10 It has been reported that single or multiple copies of SBEs are located in the upstream regions of TGFβ1′s target genes, such as plasminogen activator inhibitor 1 (PAI-1), matrix metalloproteinases (MMPs), and collagen type I.11, 12 Despite the finding that TGFβ1 leads to HSC activation with a phenotypic change of ECAD loss and causes hepatic ECM accumulation, it has not yet been determined whether ECAD overexpression inhibits the expression of TGFβ1 and its downstream target genes.