FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation

Huakan Zhao, Fenglin Lv, Guizhao Liang, Xiaobin Huang, Gang Wu, Wenfa Zhang, Le Yu, Lei Shi, Yong Teng

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3β inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3β/β-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.

Original languageEnglish (US)
Pages (from-to)13575-13586
Number of pages12
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - Mar 22 2016
Externally publishedYes

Fingerprint

Catenins
Epithelial-Mesenchymal Transition
Hepatocellular Carcinoma
Cadherins
Cholangiocarcinoma
Colorectal Neoplasms
Neoplasms
Neoplasm Metastasis
Cell Line

Keywords

  • E-cadherin
  • EMT
  • FGF19
  • FGFR4
  • GSK3β/β-catenin

ASJC Scopus subject areas

  • Oncology

Cite this

FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation. / Zhao, Huakan; Lv, Fenglin; Liang, Guizhao; Huang, Xiaobin; Wu, Gang; Zhang, Wenfa; Yu, Le; Shi, Lei; Teng, Yong.

In: Oncotarget, Vol. 7, No. 12, 22.03.2016, p. 13575-13586.

Research output: Contribution to journalArticle

Zhao, Huakan ; Lv, Fenglin ; Liang, Guizhao ; Huang, Xiaobin ; Wu, Gang ; Zhang, Wenfa ; Yu, Le ; Shi, Lei ; Teng, Yong. / FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation. In: Oncotarget. 2016 ; Vol. 7, No. 12. pp. 13575-13586.
@article{7d740fb18e654d25a1d0c32a19481dd3,
title = "FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation",
abstract = "Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3β inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3β/β-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.",
keywords = "E-cadherin, EMT, FGF19, FGFR4, GSK3β/β-catenin",
author = "Huakan Zhao and Fenglin Lv and Guizhao Liang and Xiaobin Huang and Gang Wu and Wenfa Zhang and Le Yu and Lei Shi and Yong Teng",
year = "2016",
month = "3",
day = "22",
doi = "10.18632/oncotarget.6185",
language = "English (US)",
volume = "7",
pages = "13575--13586",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "12",

}

TY - JOUR

T1 - FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation

AU - Zhao, Huakan

AU - Lv, Fenglin

AU - Liang, Guizhao

AU - Huang, Xiaobin

AU - Wu, Gang

AU - Zhang, Wenfa

AU - Yu, Le

AU - Shi, Lei

AU - Teng, Yong

PY - 2016/3/22

Y1 - 2016/3/22

N2 - Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3β inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3β/β-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.

AB - Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3β inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3β/β-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.

KW - E-cadherin

KW - EMT

KW - FGF19

KW - FGFR4

KW - GSK3β/β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84971667932&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971667932&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.6185

DO - 10.18632/oncotarget.6185

M3 - Article

VL - 7

SP - 13575

EP - 13586

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 12

ER -