title: YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors.
abstract: The Yes-associated protein (YAP)/Hippo pathway has been implicated in tissue development, regeneration, and tumorigenesis. However, its role in cholangiocarcinoma (CC) is not established. We show that YAP activation is a common feature in CC patient biopsies and human CC cell lines. Using microarray expression profiling of CC cells with overexpressed or down-regulated YAP, we show that YAP regulates genes involved in proliferation, apoptosis, and angiogenesis. YAP activity promotes CC growth in vitro and in vivo by functionally interacting with TEAD transcription factors (TEADs). YAP activity together with TEADs prevents apoptosis induced by cytotoxic drugs, whereas YAP knockdown sensitizes CC cells to drug-induced apoptosis. We further show that the proangiogenic microfibrillar-associated protein 5 (MFAP5) is a direct transcriptional target of YAP/TEAD in CC cells and that secreted MFAP5 promotes tube formation of human microvascular endothelial cells. High YAP activity in human CC xenografts and clinical samples correlates with increased MFAP5 expression and CD31(+) vasculature.
  
  
  CONCLUSIONS
  These findings establish YAP as a key regulator of proliferation and antiapoptotic mechanisms in CC and provide first evidence that YAP promotes angiogenesis by regulating the expression of secreted proangiogenic proteins.
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marti
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stein
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Blumer
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Abraham
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Pikiolek
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Orsini
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Jurisic
authors.affiliation: Novartis Institutes for Biomedical Research, Oncology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Megel
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Agarinis
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ruffner
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Christian N
authors.initials: CN
authors.lastname: Parker
authors.affiliation: Novartis Institutes for Biomedical Research, Oncology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmelzle
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Tchorz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D003285:Contractile Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D009687:Nuclear Proteins / Q000502:physiology*; D009857:Oncogenes; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D003285:Contractile Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C115627:MFAP5 protein, human; D009687:Nuclear Proteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; C456659:YY1AP1 protein, human