Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer mortality. Despite continuing development of new therapies, prognosis for patients with HCC remains extremely poor. In recent years, control of organ size becomes a hot topic in HCC development. The Hippo signaling pathway has been delineated and shown to be critical in controlling organ size in both Drosophila and mammals. The Hippo kinase cascade, a singling pathway that antagonizes the transcriptional coactivator Yes-associated protein (YAP), plays an important role in animal organ size control by regulating cell proliferation and apoptosis rates. During HCC development, this pathway is likely inactivated in tumor initiated cells that escape suppressive constrain exerted by the surrounding normal tissue, thus allowing clonal expansion and tumor development. We have reviewed evolutionary changes in YAP as well as other components of the Hippo pathway and described the relationships between YAP genes and HCC. We also discuss regulation of transcription factors that are up- and downstream of YAP in liver cancer development. 1. Introduction Human hepatocellular carcinoma (HCC) is one of the most common cancers, with nearly 600,000 deaths each year worldwide. In addition, its incidence increases every year. HCC usually develops in patients with chronic inflammatory liver disease such as viral infection and/or exposure to chemical carcinogens. Surgical reaction and liver transplantation are currently the best curative options to treat HCC. However, recurrence or metastasis is quite common in patients who have had a resection [1]. Hepatocarcinogenesis is a complex process associated with accumulation of genetic and epigenetic changes that occur during initiation, promotion, and progression of the disease. The role of hepatitis B virus (HBV) infection in causing HCC is well established. The risk of developing HCC was 200 times higher among employees who had chronic HBV as compared to employees without chronic HBV. Hepatitis B virus X protein (HBx) plays critical roles in the development of HCC. Zhang et al. found that the expression of YAP was dramatically elevated in clinical HCC samples, HBV infected hepatic cell line, and liver cancer tissues of HBx transgenic mice. Overexpression of HBx resulted in the upregulation of YAP, while HBx-RNA interference reduced YAP expression. YAP short interfering RNA was able to remarkably block the HBx-enhanced growth of hepatoma cells in vivo and in vitro. Hepatitis C virus (HCV) infection is also
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