A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma

Sumera Rizvi, Daisaku Yamada, Petra Hirsova, Steven F. Bronk, Nathan W. Werneburg, Anuradha Krishnan, Warda Salim, Liang Zhang, Eugenia D Trushina, Mark Truty, Gregory James Gores

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8031-8047
Number of pages17
JournalJournal of Biological Chemistry
Volume291
Issue number15
DOIs
StatePublished - Apr 8 2016

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Fibroblast Growth Factor Receptors
Cholangiocarcinoma
Proteins
Nuclear Proteins
Cells
Cell Line
Heterografts
Chemical activation
Receptor, Fibroblast Growth Factor, Type 4
Receptor, Fibroblast Growth Factor, Type 2
Receptor, Fibroblast Growth Factor, Type 1
Tumors
Therapeutics
Small Interfering RNA
Biomarkers
Cell death
Neoplasms
Cell Death
Up-Regulation
Ligands

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. / Rizvi, Sumera; Yamada, Daisaku; Hirsova, Petra; Bronk, Steven F.; Werneburg, Nathan W.; Krishnan, Anuradha; Salim, Warda; Zhang, Liang; Trushina, Eugenia D; Truty, Mark; Gores, Gregory James.

In: Journal of Biological Chemistry, Vol. 291, No. 15, 08.04.2016, p. 8031-8047.

Research output: Contribution to journalArticle

Rizvi, Sumera ; Yamada, Daisaku ; Hirsova, Petra ; Bronk, Steven F. ; Werneburg, Nathan W. ; Krishnan, Anuradha ; Salim, Warda ; Zhang, Liang ; Trushina, Eugenia D ; Truty, Mark ; Gores, Gregory James. / A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 15. pp. 8031-8047.
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