title: Deregulation of Hippo kinase signalling in human hepatic malignancies.
abstract: OBJECTIVE
  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 signalling in human hepatic malignancies, especially CC and HB, is lacking.
  
  
  METHODS
  We investigated Hippo kinase signalling 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 tumour 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Andy
authors.initials: A
authors.lastname: Wolfe
authors.forename: Seth
authors.initials: S
authors.lastname: Septer
authors.forename: Genea
authors.initials: G
authors.lastname: Edwards
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhong
authors.forename: Ahmad Bashar
authors.initials: AB
authors.lastname: Abdulkarim
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002450:Cell Communication; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D018197:Hepatoblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
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