The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma

The occurrence of chronic diarrhea after cholecystectomy (CCY) has been described by many researchers. However, the main mechanisms of the development of this diarrhea are not fully understood. Supposed that dysregulation of the bile acids (ВA) absorption in the ileum is played a significant role in the development of diarrhea syndrome. Aim. To determine the role of the fibroblast growth factor 19 (FGF19) level in the serum and BA concentration in feces in pathogenesis of bile acid diarrhea (ВАD) in patients after CCY. Materials and methods. Sixty-one patients were examined at various times after CCY: 30 patients with chronic diarrhea that appeared after CCY (group 1) and 31 patients with normal stools (group 2). In all patients, the level of FGF19 in the blood serum, and the daily excretion of BA in the feces were studied. The control group consisted of 28 healthy individuals. Results. In the 1st group we found lower concentrations of FGF19 in the blood serum 86.2 ng/ml (67.8; 117.8) compared with concentrations in the 2nd group 259 ng/ml (170.6; 318.8), p0.001. The daily excretion of bile acids with feces in the 1st group was 657.4 mg/day (524.6; 830.1), which was twice more than in the 2nd group and the control group. It was established an inverse correlation between serum concentration of the FGF19 and the BA excretion in the feces in all examined patients. It indicates a possible relationship between the low concentration of FGF19 in blood serum and malabsorption of the BA. Conclusion. Low level of FGF19 in the blood serum and a high excretion of BA in the feces may be one of the causes of BAD in patients undergoing cholecystectomy. Our results indicate the important role of FGF19 in the development of chronic diarrhea, which can be considered as one of the variants of postcholecystectomy syndrome.

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Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma

BMC Cancer ◽

10.1186/s12885-019-6322-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Takahiro Maeda ◽

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Junjie Ao ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Serum Levels ◽

Diagnostic Value ◽

Enzyme Linked Immunosorbent Assay ◽

Fibroblast Growth ◽

Ablation Therapy ◽

Receiver Operating Characteristic Curves ◽

Fibroblast Growth Factor 19

Abstract Background Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA). Methods The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined. Results The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called “double negative HCC”) exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment. Conclusion Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.

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Role of the fibroblast growth factor 19 in the skeletal system

Life Sciences ◽

10.1016/j.lfs.2020.118804 ◽

2021 ◽

Vol 265 ◽

pp. 118804

Author(s):

Hao Chen ◽

Jiazhou Li ◽

Demao Zhang ◽

Xuedong Zhou ◽

Jing Xie

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth ◽

Skeletal System ◽

Fibroblast Growth Factor 19

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Src is essential for the endosomal delivery of the FGFR4 signaling complex in hepatocellular carcinoma

Journal of Translational Medicine ◽

10.1186/s12967-021-02807-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ji-Yon Shin ◽

Sung-Min Ahn

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Cell Lines ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Regulatory Relationship ◽

Signaling Complex ◽

Fibroblast Growth Factor 19 ◽

Migration Pathways

Abstract Background Hepatocytes usually express fibroblast growth factor receptor 4 (FGFR4), but not its ligand, fibroblast growth factor 19 (FGF19). A subtype of hepatocellular carcinoma (HCC) expresses FGF19, which activates the FGFR4 signaling pathway that induces cell proliferation. FGFR4 inhibitors that target this mechanism are under clinical development for the treatment of HCCs with FGF19 amplification or FGFR4 overexpression. Src plays an essential role in the FGFR1 and FGFR2 signaling pathways. However, it is yet to be understood whether Src has any role in the FGF19-FGFR4 pathway in HCCs. In this study, we aimed to elucidate the role of Src in the FGF19-FGFR4 axis in HCC. Methods 3 HCC cell lines expressing both FGF19 and FGFR4 were selected. The expression of each protein was suppressed by siRNA treatment, and the activity-regulating relationship between FGFR4 and Src was investigated by westernblot. Co-immunoprecipitation was performed using the FGFR4 antibody to identify the endosomal complex formation and receptor endocytosis. The intracellular migration pathways of the endosomal complex were observed by immuno-fluorescence and nuclear co-immunoprecipitation. Dasatinib and BLU9931 were used for cytotoxicity comparison. Results FGFR4 modulates the activity of Src and Src modulates the expression of FGFR4, showing a mutual regulatory relationship. FGFR4 activated by FGF19 formed an endosomal complex with Src and STAT3 and moved to the nucleus. However, when Src was suppressed, the formation of the endosomal complex was not observed. FGFR4 was released from the complex transferred into the nucleus and the binding of Src and STAT3 was maintained. Dasatinib showed cytotoxic results comparable to BLU9931. The results of our study demonstrated that Src is essential for the nuclear transport of STAT3, as it induces the endosomal delivery of FGFR4 in FGF19-expressing HCC cell lines. Conclusions We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.

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