Fat1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis

Fat1 is an atypical cadherin and in vitro studies indicate that it plays a role in cell polarity and migration. In some tumors as breast cancer FAT1 is over-expressed while FAT1 expression is reduced or deleted in others as astrocytic tumors or cholangiocarcinoma.The aim of this study was to analyze the expression and function of Fat1 in hepatocellular carcinoma (HCC).

Methods and Results: Fat1 mRNA and protein are increased in human HCC cell lines and tissues compared to normal primary human hepatocytes (PHH) and non-tumorous tissue as assessed by quantitative PCR, Western blotting and immunohistochemistry. Fat1 expression was further increased in HCC cells under hypoxia and by free reactive oxygen (ROS) formation, while ROS-scavengers inhibited both basal as well as hypoxia induced FAT1 expression in HCC cells. HCC cells stably transfected with FAT1 siRNA revealed an impaired migratory and invasive potential, and increased apoptosis compared to mock-transfected controls in vitro. Upon injection into nude mice FAT1 suppression caused a delayed tumor onset. Tumors of HCC cells with suppressed FAT1 expression revealed significantly reduced Bcl-xL expression, as well as reduced snail–1 expression and increased E-Cad expression indicative for cellular differentiation.

Conclusion: Fat1 expression in HCC functionally promotes tumorigenicity. Thus, this atypical cadherin appears as a potential prognostic marker and novel therapeutic target of this highly aggressive tumor.