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.

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 and non-tumorous tissue, respectively, as assessed by quantitative PCR, Western blotting and immunohistochemistry. Fat1 expression was further increased in HCC cells under hypoxia, and this induction was strongly repressed by pharmaceutical inhibition of HIF-1 activity with YC-1 or echinomycin. Interestingly, immunofluorescence analysis and Western blotting of cell fractions revealed Fat1 localization in the cytoplasm in addition to the membrane, and the half life of Fat1 protein in HCC cell lines was determined to be more than 7 days. Suppression of Fat1 expression by siRNA impaired the migratory potential and invasiveness of HCC cells. Further, Fat1 suppression resulted in decreased expression of the anti-apoptotic Bcl-xL gene and increased apoptosis of HCC cells in vitro.

Conclusion: Fat1 expression is increased in HCC and hypoxia further enhances its expression, which functionally promotes tumorigenicity. Thus, we propose this atypical cadherin as a potential prognostic marker and novel therapeutic target of this highly aggressive tumor.