Abstract
Hepatocellular Carcinoma (HCC) is the most common malignancy of the liver associated with high mortality. We are interested in understanding the role of pathways involved in organ size regulation in pathogenesis of HCC. Specifically, we are investigating the role of Hippo Kinase pathway and yes‐associated protein (Yap), the downstream effector of the pathway. Three HCC cell lines investigated, Hep3B, HepG2 and Huh7, demonstrated increase in Yap as compared to normal human hepatocytes. The expression levels and cellular localization of Yap was responsive to cell density. High cell confluency resulted in decreased Yap expression and nuclear export. siRNA‐mediated knockdown of Yap resulted in decreased cell proliferation of Hep3B cells. Immunohistochemical analysis of Yap in phenobarbital+diethylnitrosamine‐induced liver tumors in C57BL/6 mice, spontaneous tumors in Farnesoid X Receptor knockout mice and human HCC biopsies revealed extensive nuclear staining on Yap in highly proliferative tumors. These data indicate that Yap helps the hepatoma cells overcome the cell adhesion‐mediated growth inhibition and plays a critical role in pathogenesis of HCC.
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