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

Li, Yan; Zhang, Weizhong; Doughtie, Anne; Cui, Guozhen; Li, Xuanyi; Pandit, Harshul; Yang, Yanwen; Li, Suping; Martin, Robert C.G.

doi:10.18632/oncotarget.10750

Cited by 39 publications

(51 citation statements)

References 37 publications

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“…FGFR4 is highly expressed in embryonic tissues and overexpressed in many tumor tissues, such as prostate, breast, and pancreatic cancers, and HCC [22-25]. Data show that FGFR4 has an oncogenic role in HCC and chemotherapeutic resistance, and tumor invasion is related to high expression of FGFR4 [26-27]. However, high expression of FGFR4 contributes to apoptosis and better prognoses [25].…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang¹,

Qiu²,

Wan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: TGF-β1 is beneficial during early liver disease but is tumor-progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-β1 in HCC. Methods: Western blot and real-time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-β1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-β1 induction on FGFR4 expression with various inhibitors. Results: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-β1 in vitro and in vivo. Moreover, TGF-β1 induced FGFR4 expression through the ERK pathway. Conclusion: Promoting FGFR4 expression via the ERK pathway, TGF-β1 contributes to HCC invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang¹,

Qiu²,

Wan³

et al. 2018

Cell Physiol Biochem

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“…However, FGF19 overexpression can be found in a proportion of liver tumors that may exceed 25%, suggesting the existence of additional mechanisms leading to FGF19 upregulation [50][51][52] . Most interestingly, increased hepatocellular FGF19 expression has also been detected in cirrhotic and steatotic livers [30,73] , and it was later described that FGF19 gene amplification was associated with the presence of cirrhosis, which is a preneoplastic condition [53] . Very recently, a study performed in patients with primary biliary cirrhosis showed that hepatic and circulating levels of FGF19 protein were upregulated, with serum FGF19 concentrations correlating with worse liver biochemistry [54] .…”

Section: Defining a Role For The Fgf19-fgfr4/klb Signaling System Inmentioning

confidence: 99%

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis

Álvarez‐Sola

Uriarte²,

Latasa³

et al. 2017

Dig Dis

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Background: Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The fibroblast growth factor 15/19 (FGF15/19), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/19-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/19-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF19-FGFR4/KLB expression. Conclusions: Interference with FGF19-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF19-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.

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“…FGF-19 is FXR activation dependently produced in the liver, gallbladder, and the distal small intestine and may despite its short half-life potentially stimulate cell proliferation in the liver and gut [30][31][32][33][34]. Synthetic FGF-19 derivatives may provide a prolonged inhibition of bile acid synthesis via the FGFR4/βklotho signalling axis, which might be beneficial in cholestatic liver disease, but may also have less cell proliferative activity.…”

Section: Ngm282mentioning

confidence: 99%

Future Medical Treatment of PSC

Krones

Marschall

Fickert

2019

Curr Hepatology Rep

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Purpose of Review Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by inflammation of intrahepatic and/or extrahepatic bile ducts leading to stricturing, biliary fibrosis, cirrhosis, and liver failure. PSC is highly associated with inflammatory bowel diseases (IBD) and bears significant risk for cholangiocellular and colorectal cancer. To date, no medical treatment has been proven in randomized controlled trials to improve transplant-free and overall patient survival. However, numerous innovative therapeutic concepts are currently tested in phase 2 to phase 3 clinical trials. Based on currently suggested pathogenetic mechanisms of PSC, such drugs target its immunopathogenesis and nuclear and membrane receptors regulating bile acid transport and metabolism, gut microbiota, and liver fibrosis. The purpose of this review is to discuss recent advances in targeted medical treatment options for PSC. Recent Findings While a large carefully designed phase 2b trial targeting fibrosis development in PSC failed (simtuzumab), another compound was promoted from phase 2a to phase 3 trial based on significant improvements of alkaline phosphatase (AP) and excellent safety profile (norursodeoxycholic acid, norUDCA). Summary Ongoing trials evaluate numerous different targets considered to be involved in PSC pathogenesis, with so far, no clear advantage of either compound. This must be attributed to the still unknown cause of PSC. It may turn out that only combination therapy may reach a breakthrough. The fact that numerous studies isochronally test the same drug or therapeutic concept like in the case of vancomycin or faecal microbiota transplantation (FMT) demands improved and coordinated international strategies for study design to develop more effective drug pipelines, which is one major target of the International PSC Study Group (IPSCSG).

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

Cited by 39 publications

References 37 publications

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis

Future Medical Treatment of PSC

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