YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors

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...

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Vydáno v:Hepatology (Baltimore, Md.) Ročník 62; číslo 5; s. 1497 - 1510
Hlavní autoři: Marti, Patricia, Stein, Claudia, Blumer, Tanja, Abraham, Yann, Dill, Michael T., Pikiolek, Monika, Orsini, Vanessa, Jurisic, Giorgia, Megel, Philippe, Makowska, Zuzanna, Agarinis, Claudia, Tornillo, Luigi, Bouwmeester, Tewis, Ruffner, Heinz, Bauer, Andreas, Parker, Christian N., Schmelzle, Tobias, Terracciano, Luigi M., Heim, Markus H., Tchorz, Jan S.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Wolters Kluwer Health, Inc 01.11.2015
Témata:
Angiogenesis
Animals
Apoptosis
Bile Duct Neoplasms - blood supply
Bile Duct Neoplasms - drug therapy
Bile Duct Neoplasms - pathology
Bile Ducts, Intrahepatic
Cell Cycle Proteins
Cell Proliferation
Cholangiocarcinoma - blood supply
Cholangiocarcinoma - drug therapy
Cholangiocarcinoma - pathology
Contractile Proteins - genetics
DNA-Binding Proteins - physiology
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Genes
Glycoproteins - genetics
Humans
Intercellular Signaling Peptides and Proteins
Mice
Neovascularization, Pathologic - etiology
Nuclear Proteins - physiology
Oncogenes
Transcription factors
Transcription Factors - physiology
ISSN:0270-9139, 1527-3350, 1527-3350
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Shrnutí: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. (Hepatology 2015;62:1497–1510)
Bibliografie:Supported by ONCOSUISSE grant KLS‐2867‐08‐2011 (to L.M.T.) and Swiss National Science Foundation grant 310030B_147089/1 and European Research Commission Synergy grant 609883 (MERiC) (to M.H.H.).
Potential conflict of interest: Patricia Marti, Claudia Stein, Yann Abraham, Monika Pikiolek, Vanessa Orsini, Giorgia Jurisic, Philippe Megel, Claudia Agarinis, Tewis Bouwmeester, Heinz Ruffner, Andreas Bauer, Christian N. Parker, Tobias Schmelzle and Jan S. Tchorz are employed by and/or own stock in Novartis.
All microarray data were uploaded to the Gene Expression Omnibus repository (GSE61767, GSE69655).
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ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.27992