Research Papers:

Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma

Yan Li, Weizhong Zhang, Anne Doughtie, Guozhen Cui, Xuanyi Li, Harshul Pandit, Yingbin Yang, Suping Li and Robert Martin _

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Oncotarget. 2016; 7:52329-52339. https://doi.org/10.18632/oncotarget.10750

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Yan Li1,*, Weizhong Zhang2,*, Anne Doughtie1, Guozhen Cui3, Xuanyi Li1, Harshul Pandit1, Yingbin Yang1, Suping Li1, Robert Martin1

1Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

2Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, 130022, China

3Department of Hepatology, Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China

*These authors contributed equally to this work

Correspondence to:

Yan Li, email: [email protected]

Robert Martin, email: [email protected]

Keywords: hepatocellular carcinoma, FGF19, FGFR4, cancer stem cell

Received: February 08, 2016     Accepted: June 12, 2016     Published: July 21, 2016


Background: Human fibroblast growth factor 19 (FGF19), its receptor (FGFR4) and EpCAM play an important role in cell proliferation, differentiation, motility, and overexpression have been linked to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the FGF19 signals responsible for the progression of HCC arising from fatty liver.

Results: FGF19 level was significantly increased in the HCC patients’ serum compared to non-HCC controls. The IHC results demonstrated significant increases of protein expressions of FGF19, FGFR4 and EpCAM in specimens with fatty liver, NASH, cirrhosis, and HCC compared to healthy liver tissue. There was a significant positive correlation between the protein expressions (FGF19, FGFR4, and EpCAM) and histopathologic changes from FL to HCC. Furthermore, FGF19 was positively correlated with FGFR4 and with EpCAM.

Materials and Methods: FGF19 protein levels in serum and tissues were determined by ELISA assay. The FGFR4, and EpCAM expression and tissue distribution were further evaluated by immunohistochemical staining in tissue array samples. FGF19, FGFR4 and EpCAM expressions between the different histologic stages of fatty liver steatohepatitis-cirrhosis-HCC carcinogenesis sequence were compared to healthy hepatic tissue.

Conclusions: Overexpression of FGF19/FGFR4 significantly correlated with EpCAM as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence.

Impact: This is the first study to elucidate FGF19/FGFR4 signaling in favor of HCC cells developing as indicated by increased EpCAM within the carcinogenesis sequence from fatty liver to hepatocellular carcinoma. Our study has the potential to yield novel and cost effective screening strategies for HCC patients.

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