Deregulation of Hippo kinase signalling in Human hepatic malignancies

Background/Aims Hepatocellular carcinoma ( HCC ), cholangiocarcinoma ( CC ) and hepatoblastoma ( HB ) are the main hepatic malignancies with limited treatment options and high mortality. Recent studies have implicated H ippo kinase pathway in cancer development, but detailed analysis of H ippo kinase signalling in human hepatic malignancies, especially CC and HB , is lacking. Methods We investigated H ippo kinase signalling in HCC , CC and HB using cells and patient samples. Results Increased expression of yes‐associated protein ( Y ap), the downstream effector of the H ippo kinase pathway, was observed in HCC cells, and si RNA ‐mediated knockdown of Y ap resulted in decreased survival of HCC cells. The density‐dependent activation of Hippo kinase pathway characteristic of normal cells was not observed in HCC cells and CCLP cells, a cholangiocarcinoma cell line. Immunohistochemistry of Y ap in HCC , CC and HB tissues indicated extensive nuclear localization of Y ap in majority of tissues. Western blot analysis performed using total cell extracts from patient samples and normal livers showed extensive activation of Y ap. Marked induction of G lypican‐3, CTGF and S urvivin, the three Y ap target genes was observed in the tumour samples. Further analysis revealed significant decrease in expression and activity of Lats kinase, the main upstream regulator of Y ap. However, no change in activation of Mst ‐2 kinase, the upstream regulator of Lats kinase was observed. Conclusions These data show that Y ap induction mediated by inactivation of L ats is observed in hepatic malignancies. These studies highlight H ippo kinase pathway as a novel therapeutic target for hepatic malignancies.