Intricate role of yes-associated protein1 in human liver cirrhosis: TGF-β1 still is a giant player.

Abstract

Numerous investigations have been performed on the role of the transforming growth factor-β1 (TGF-β1) pathway in the development of chronic liver diseases (CLDs); however, they failed to explain the underlying mechanism of its pathogenesis, suggesting that other alternative pathways might have been overlooked. The involvement of yes-associated protein1 (YAP1) has been attributed to liver fibrosis; yet, the precise function of this protein has not been fully understood. Therefore, this study aimed to investigate the activity of the YAP1 pathway in human liver cirrhosis (regardless of its causality) and its correlation with the TGF-β1 and sonic hedgehog (SHH) pathways. In this case-control study, the immunohistochemical and quantitative real-time polymerase chain reaction analyses were carried out to determine the activation of the YAP1 pathway in patients with liver cirrhosis (n = 38) and control 1 individuals (n = 10). The western blot analysis and ELISA method were also performed to assess the SHH and TGF-β1 pathways. Although significantly increased expression of cytoplasmic YAP1 was found in patients with liver cirrhosis (P < 0.045), the rate of the nuclear YAP1 expression was similar to that of the control 1 subjects. Moreover, the hepatic expression of amphiregulin (AREG), known as the YAP1 target, along with proteins involved in the TGF-β1 pathway was significantly elevated in all cirrhotic patients, compared with the control subjects. Our results showed that the increased activity of the TGF-β1 pathway is strongly associated with the expression of AREG, denoting a direct and positive relationship between the TGF-β1 and YAP1 pathways. It seems that, unlike the TGF-β1 and SHH pathways, the YAP1 pathway does not play a significant role in the development of liver cirrhosis.