Marti, Patricia, blumer, tanja, dill, michael, Abraham, Yann, Stein, Claudia, Megel, Philippe, Jurisic, Giorgia, Makowska, Zuzanna, Pikiolek, Monika, Orsini, Vanessa, Agarinis, Claudia, Tornillo, Luigi, Bouwmeester, Antonius, Ruffner, Heinz, Bauer, Andreas, Schmelzle, Tobias, Parker, Christian, Terracciano, Luigi, Heim, Markus and Tchorz, Jan (2015) YAP promotes proliferation, chemoresistance and angiogenesis in human cholangiocarcinoma. Hepatology, 62 (5). pp. 1497-1510.

Abstract

Cholangiocarcinoma (CC) is the second most prevalent liver tumor with resistance to chemotherapy and high mortality. The underlying molecular mechanisms that propagate CC are poorly understood. The YAP/Hippo pathway has been implicated in tumorigenesis, however, its role in CC is not established. We show that YAP activation is a common feature in CC patient biopsies and human CC cell lines. Proliferation and colony formation of CC cells are increased upon YAP activation and impaired upon YAP downregulation. Likewise, CC xenografts show increased tumor size and growth when YAP is overexpressed in vivo. Moreover, YAP activation prevents apoptosis induced by cytotoxic drugs, whereas YAP knockdown sensitizes CC cells to drug-induced apoptosis. Using microarray expression profiling of CC cells with overexpressed or downregulated YAP, respectively, we establish a CC YAP target gene signature demonstrating that YAP regulates genes involved in proliferation, anti-apoptotic mechanisms and angiogenesis. We show that MFAP5 is a direct transcriptional target in CC cells and that secreted MFAP5 protein promotes tube formation of human microvasculature endothelial cells. The expression of YAP target genes and TEADs, transcription factors mediating YAP signaling, correlates with MFAP5 expression in 176 cell lines derived from different tumors, suggesting that this mechanism is not restricted to CC. Moreover, we show that YAP promotes CC cell proliferation, resistance to apoptosis and angiogenesis via functionally interacting with TEAD transcription factors. Together, our data establish YAP as a key regulator of proliferation and anti-apoptotic mechanisms in CC. Additionally, this report provides first evidence that the YAP/Hippo regulates MFAP5 expression which in turn promotes angiogenesis.

Item Type:	Article
Keywords:	YAP Hippo, liver cancer, biliary epithelial cells, cholangioma, tumor angiogenesis
Date Deposited:	28 Apr 2016 23:45
Last Modified:	28 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/23069