title: Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma.
abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P=0.002) and PHCC (P=0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P=0.045) and PHCC (P=0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial-mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Department of Pathology, Shandong University, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Yang
authors.affiliation: Department of Gastrointestinal Surgery, Jinan Central Hospital, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Shang-Lei
authors.initials: SL
authors.lastname: Ning
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Anatomy, Shandong University, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Suo
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, China. Electronic address: yxu8@bidmc.harvard.edu.
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Chen
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011724:Pyridazines / Q000494:pharmacology; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011724:Pyridazines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C545373:ponatinib; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: Cholangiocarcinoma; Fibroblast growth factor receptor 4; Inhibitor; Prognosis; Progression