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

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

doi:10.1186/s13046-018-0781-8

Cited by 45 publications

(55 citation statements)

References 52 publications

(54 reference statements)

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“…Mechanically, it has been discovered that FGF19 increases the phosphorylation of GSK‐3β, resulting in the inactivation of GSK‐3β, and thus leading to the accumulation and activation of β‐catenin . Increasing evidence has shown that FGF19‐mediated Wnt/GSK‐3β/β‐catenin signalling contributes to the promotion of cell proliferation during tumour progression . Therefore, we speculated that FGF19 might regulate keratinocyte proliferation through Wnt/β‐catenin signalling.…”

Section: Discussionmentioning

confidence: 99%

“…14 Increasing evidence has shown that FGF19-mediated Wnt/GSK-3β/β-catenin signalling contributes to the promotion of cell proliferation during tumour progression. [30][31][32] Therefore, we speculated that FGF19 might regulate keratinocyte proliferation through Wnt/β-catenin signalling. As expected, we found that FGF19 overexpression increased the phosphorylation of 19,20,33,34 In addition, the Wnt signalling inhibitor Dickkopf-1 is decreased in psoriatic lesional skin.…”

Section: Discussionmentioning

confidence: 99%

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FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

Yan

et al. 2019

Clin Exp Pharma Physio

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Accumulating evidence has shown that fibroblast growth factor 19 (FGF19) plays an important role in regulating cell proliferation. Psoriasis is characterized by the hyperproliferation of keratinocytes in skin lesions. However, whether FGF19 regulates the proliferation of keratinocytes in psoriasis remains unknown. In this study, we aimed to explore the potential relevance of FGF19 in psoriasis. We found that FGF19 was highly expressed in psoriatic skin from psoriasis patients, as well as keratinocytes that were stimulated with a cocktail of cytokines (M5), which is an in vitro model of psoriasis. Functional experiments demonstrated that FGF19 overexpression promoted the growth and proliferation of keratinocytes, while FGF19 knockdown showed opposite effect. Moreover, we found that FGF19 increased the phosphorylation of glycogen synthase kinase (GSK)‐3β and promoted the expression of β‐catenin and the activation of T cell factor 4 (TCF4) transcriptional activity. Notably, blocking Wnt/β‐catenin signalling by silencing β‐catenin partially reversed FGF19‐mediated promotional effects on keratinocyte proliferation. In addition, FGFR4 inhibition significantly blocked the promotional effect of FGF19 on keratinocyte proliferation and GSK‐3β/β‐catenin/TCF4 signalling. Taken together, our results demonstrated that FGF19 contributes to sustaining the high proliferative ability of keratinocytes through promoting Wnt/GSK‐3β/β‐catenin signalling via FGFR4, highlighting the importance of FGF19 in the pathogenesis of psoriasis. Our study suggests that FGF19 may serve as a novel and potential therapeutic target for psoriasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

Yan

et al. 2019

Clin Exp Pharma Physio

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“…Activation of FXR by BA triggers the secretion of FGF15/ FGF19 in humans (39), and the beneficial effects of FGF expression on the obese metabolic profile has been well characterized (40). However, the clinical use of FGF has been debated due to the potential for increasing liver tumor development (41,42).…”

Section: Discussionmentioning

confidence: 99%

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Manieri

Folgueira

Rodríguez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

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“…Epithelial-mesenchymal transition (EMT) is known to be associated with tumor aggressiveness and poor survival, and Zhao et al found that FGF19 induces EMT via the FGFR4/GSK3β/β-catenin axis in HCC cells [34]. In addition, Cui et al reported that FGF15 binds to FGFR4 and promotes the development of HCC by activating EMT and Wnt/β-catenin signaling in a microenvironment in which lipid metabolism is disordered [35].…”

Section: Mechanisms Of the Effects Of Fgf19 On Glucose Metabolism Andmentioning

confidence: 99%

Serum Fibroblast Growth Factor 19 and Total Bile Acid Concentrations Are Potential Biomarkers of Hepatocellular Carcinoma in Patients with Type 2 Diabetes Mellitus

Sun

Zhu

Zhao

et al. 2020

BioMed Research International

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Purpose. Type 2 diabetes mellitus (T2DM) carries a high risk of hepatocellular carcinoma (HCC). Both serum fibroblast growth factor 19 (FGF19) and bile acid concentrations are associated with T2DM and HCC. We aimed at evaluating the relationships between FGF19 and bile acid concentrations and HCC in patients with T2DM. Methods. Twenty-seven healthy volunteers (control group), 27 patients with T2DM (T2DM group), 16 patients with newly diagnosed HCC (HCC group), and 10 T2DM patients with newly diagnosed HCC (T2DM-HCC group) were studied at the Affiliated Hospital of Nantong University between June 2016 and June 2017. The serum concentrations of serum FGF19 and total bile acids (TBA) were measured in all the participants. Correlation analysis and multiple stepwise regression analysis of the FGF19 and TBA concentrations were performed in all the participants and in the four groups. Results. The concentrations of FGF19 were 220.5 pg/ml, 185.1 pg/ml, 115.8 pg/ml, and 70.4 pg/ml in the HCC, T2DM-HCC, control, and T2DM groups, respectively (p<0.001), and the TBA concentrations were 21.75 μmol/l, 14.25 μmol/l, 3.6 μmol/l, and 3.1 μmol/l (p<0.001). There were positive correlations between the FGF19 and TBA concentrations across all the participants (r = 0.777; p<0.001), and in the control (r = 0.400; p=0.039), T2DM (r = 0.477; p=0.012), HCC (r = 0.684; p=0.003), and T2DM-HCC (r = 0.673; p=0.033) groups. Conclusions. Simultaneous increase of serum FGF19 and TBA levels may be used as indicators of HCC screening at early stage in patients with T2DM.

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

Cited by 45 publications

References 52 publications

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Serum Fibroblast Growth Factor 19 and Total Bile Acid Concentrations Are Potential Biomarkers of Hepatocellular Carcinoma in Patients with Type 2 Diabetes Mellitus

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