FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation.
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.
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Huakan
H
Zhao
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Fenglin
F
Lv
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Guizhao
G
Liang
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Xiaobin
X
Huang
Third Affiliated Hospital, Third Military Medical University, Chongqing, PR China.
Gang
G
Wu
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Wenfa
W
Zhang
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Le
L
Yu
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Lei
L
Shi
School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China.
Yong
Y
Teng
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C117476:FGF19 protein, human; D051176:beta Catenin; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000071679:Glycogen Synthase Kinase 3 beta
E-cadherin; EMT; FGF19; FGFR4; GSK3β/β-catenin