Deregulation of Hippo kinase signalling in Human hepatic malignancies

Abstract

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 Hippo Kinase pathway in cancer development but detailed analysis of Hippo Kinase signaling in human hepatic malignancies, especially CC and HB, is lacking. Methods: We investigated Hippo Kinase signaling in HCC, CC and HB using cells and patient samples. Results: Increased expression of yes-associated protein (Yap), the downstream effector of the Hippo Kinase pathway, was observed in HCC cells and siRNA-mediated knockdown of Yap 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 Yap in HCC, CC and HB tissues indicated extensive nuclear localization of Yap in majority of tissues. Western blot analysis performed using total cell extracts from patient samples and normal livers showed extensive activation of Yap. Marked induction of glypican-3, CTGF and Survivin, the three Yap target genes was observed in the tumor samples. Further analysis revealed significant decrease in expression and activity of Lats kinase, the main upstream regulator of Yap. However, no change in activation of Mst-2 kinase, the upstream regulator of Lats kinase was observed. Conclusions: These data show that Yap induction mediated by inactivation of Lats is observed in hepatic malignancies. These studies highlight Hippo Kinase pathway as a novel therapeutic target for hepatic malignancies.

YAP activation is an early event and a potential therapeutic target in liver cancer development

“…Consistent with these findings, the comprehensive survey of the most common solid cancer types revealed elevated YAP protein levels and nuclear localization in multiple human cancers, including HCC, cholangiocarcinoma (CC) and hepatoblastoma (HB) [5,13]. Furthermore, clinical studies showed that YAP was an independent prognostic marker for overall survival and disease-free survival for HCC patients and that it was associated with tumor differentiation [14].…”

“…On the contrary, uninhibited YAP localizes in the nucleus where it serves as a co-activator for the TEAdomain family member (TEAD) group of DNA-binding transcription factors. The YAP/TEAD complex promotes proliferative and survival programs by inducing the expression of target genes [4][5][6]. Notably, both the transgenic overexpression of YAP in mice [3,7] and the liver-specific knockout of Mst1/2 or Sav1 [8][9][10][11] expanded the liver size and ultimately induced HCC, revealing a significant role for the Hippo pathway in regulating organ size and tumorigenesis in mammals.…”

“…Recently, landmark studies have implicated the Hippo signaling pathway in the pathogenesis of HCC [3][4][5]. First identified in Drosophila, this pathway has emerged as an evolutionarily conserved mechanism that restricts organ size in different species.…”

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

“…Hippo, a highly conserved growth control pathway, is deregulated in several human malignancies (5-7) including human CCA (8,9). Recently, we reported that direct transfection of the biliary tree with a constitutively active mediator of the Hippo pathway, YAPS127A, along with mouse myr-Akt as a permissive factor, induces CCA in mice (10).…”

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

“…Furthermore, in these studies YAP1 has been implicated as an oncogene which has been altered in different kinds of human digestive system cancers, especially HCC [64]. For instance, a study aimed at evaluating the expression of YAP1 in 115 cases of human HCC samples has identified significant difference in YAP1 protein levels between normal and cancerous tissues [65].…”