Increased expression of Fat1 in hepatocellular carcinoma promotes tumorigenicity

Fat1 is an atypical cadherin, and the Fat1-Hippo signaling pathway plays an important role in the regulation of normal organ growth during development and in pathological growth during cancer. However, expression pattern and function vary in different types of cancer, and so far there are no data regarding Fat1 expression in hepatocellular carcinoma (HCC).

Method 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. Suppression of Fat1 by siRNA revealed high stability of Fat1 protein in HCC cells with a half-life of more than 7 days. Significant abrogation of FAT1 protein impaired the migratory potential and invasiveness of HCC cells (as assessed by Boyden-chamber assays and matrigel invasion assays) and their attachment to the matrix proteins fibronectin and laminin. Further, Fat1 suppression resulted in decreased expression of the anti-apoptotic Bcl-xL gene and increased (basal as well as induced) apoptosis of HCC cells in vitro.

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