Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver

Guozhen Cui,Robert C Martin,Lu Cai,Ping Zhang,Hang Jin,Hengjun Zhao,Wei Li,Xingkai Liu,Yan Li,Harshul Pandit

doi:10.1186/s13046-018-0781-8

Abstract

BackgroundUpregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC.MethodsA steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high-fat diet (HFD). A mouse HCC cell line (Hepa1–6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor β-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis.ResultsHCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/β-klotho, aberrant epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/β-catenin signaling.ConclusionsUp-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/β-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients.

Highlights

Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis
Novelty and impact FGF15/19 is well studied in Nonalcoholic steatohepatitis (NASH) and HCC, but it is unknown if FGF15/19 can bridge NASH-associated HCC, which has not been addressed yet
The gross anatomy confirmed the ultrasound findings in which there was no HCC nodule found on the livers of DEN+high-fat diet (HFD) and DEN+control diet (CD) treated mice from month 2, but HCC nodules were found in those two groups from 6 and 10 months (Additional file 2: Figure S1)

Summary

Introduction

Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC. Upregulated FGF19 expression in human HCC specimens was found to be associated with tumor progression and poor prognosis [1]. We found that FGF19 was significantly increased in both serum and tumor tissue of HCC patients. Up-regulated FGF19 signaling significantly correlated with epithelial cell adhesion molecule (EpCAM), one of biomarkers of EMT and stemness, following the steatosis-steatohepatitis-cirrhosis-HCC sequence [2]. Recent evidence indicates that FGF19 gene amplification is shown to act as a driver for adult HCC [6].

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