A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

被引:80
作者
Ilyas, Sumera I. [1 ]
Yamada, Daisaku [1 ]
Hirsova, Petra [1 ]
Bronk, Steven F. [1 ]
Werneburg, Nathan W. [1 ]
Krishnan, Anuradha [1 ]
Salim, Warda [1 ]
Zhang, Liang [2 ]
Trushina, Eugenia [2 ,3 ]
Truty, Mark J. [4 ]
Gores, Gregory J. [1 ]
机构
[1] Mayo Clin, Div Gastroenterol & Hepatol, 200 First St S-W, Rochester, MN 55905 USA
[2] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA
[3] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA
[4] Mayo Clin, Dept Surg, Rochester, MN 55905 USA
基金
美国国家卫生研究院;
关键词
animal model; cancer biology; fibroblast growth factor receptor (FGFR); Hippo pathway; Yes-associated protein (YAP); BGJ398; mcl-1; YAP; LIVER; EXPRESSION; PHOSPHORYLATION; IDENTIFICATION; HOMEOSTASIS; ACTIVATION; GENERATION; DIAGNOSIS; ONCOGENE;
D O I
10.1074/jbc.M115.698472
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.
引用
收藏
页码:8031 / 8047
页数:17
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