Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

Liu, Yanan; Cao, Meng; Cai, Yuepiao; Li, Xiaokun; Zhao, Chengguang; Cui, Ri

doi:10.3389/fcell.2020.00095

Cited by 57 publications

(48 citation statements)

References 79 publications

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“…Overexpressions of FGFR4 and β-klotho in the liver of FGF21KO-HFMCD mice with advanced NASH were con rmed by IHC and qPCR (Figure S3). Taken together, continuously up-regulated FGFR4 expression in advanced NASH should call attention because hyperactivation of FGFR4 by FGF19 was reported in colon cancer and HCC [37]. However, FGF15/19 was also reported to down-regulate FGFR4 and β-klotho [27].…”

Section: Nash Progression Is Associated To the Up-regulated Fgfr4 Levmentioning

confidence: 94%

Aberrant FGF15/FGFR4 Signaling Worsens Nonalcoholic Steatohepatitis Severity in FGF21KO Mice

Yu¹,

Shi²,

Zheng³

et al. 2021

Preprint

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BackgroundPharmacological application of the endocrine fibroblast growth factor15/19 (FGF15/19) and FGF21 holds great promise to be effective therapeutic agents for treating nonalcoholic steatohepatitis (NASH), which is the most severe form of non-alcoholic fatty liver disease (NAFLD) and accepted as a potential precursor of hepatocellular carcinoma (HCC). In our previous studies, we found that FGF21 played a key role in preventing the development of NASH, however, the FGF15/19 mediated-FGFR4 signaling worsened NASH and even contributed to the NASH-HCC transition. MethodsNASH models were established in FGF21KO mice fed with high fat methionine-choline deficient (HFMCD) diet to investigate FGF15/FGFR4 signaling during NASH development. We sought to determine whether FGF15/FGFR4 signaling could alleviate or aggravate NASH in the FGF21KO mice challenged with HFMCD. ResultsSignificant increase of FGF15 production was found in the liver of the NASH-FGF21KO mice, however the increased FGF15 protein was unable to alleviate hepatic lipid accumulation. In contrast, the up-regulated hepatic FGFR4–β‑klotho was found during NASH progression, as evident by hepatocyte injury/repair, fibrosis and potential malignant events, in the NASH-FGF21KO mice. ConclusionThe increased FGF15 production in NASH-FGF21KO mice could not substitute for FGF21 to compensate its lipid metabolic benefits thereby to prevent NASH development. The up-regulated FGFR4/β-klotho was coupled to cellular and molecular events which might associate to carcinogenic transformation.

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Section: Nash Progression Is Associated To the Up-regulated Fgfr4 Levmentioning

confidence: 94%

Aberrant FGF15/FGFR4 Signaling Worsens Nonalcoholic Steatohepatitis Severity in FGF21KO Mice

Yu¹,

Shi²,

Zheng³

et al. 2021

Preprint

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“…In other words, there is an urgent need to discover predictive biomarkers for identifying those NSCLC patients who can most benefit from complete resection and to identify biomarkers that can predict treatment efficacy. The family of fibroblast growth factors (FGFs), which regulate a series of biological functions and multiple developmental processes, consists of 22 members divided into 7 subfamilies (4)(5)(6). The canonical FGFs account for the majority of FGF's known functions in paracrine protein and autocrine protein.…”

Section: Original Articlementioning

confidence: 99%

Enhanced expression of FGF19 predicts poor prognosis in patients with non-small cell lung cancer

et al. 2021

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Background: Lung cancer is one of the most common cancers and a leading cause of cancer-related death worldwide. Although many treatment options exist for lung cancer, some patients still suffer postoperative recurrence, and a consequent reduction of overall survival (OS). Our study aimed to investigate the correlation of FGF19 expression with the clinicopathological features and survival outcomes of non-small cell lung cancer (NSCLC) patients.Methods: Bioinformatics analysis was conducted using the data from The Cancer Genome Atlas (TCGA) database to distinguish between the FGF19 levels of tumor and normal tissue and to determine their correlation with the OS. A total of 187 NSCLC patients who underwent radical resection of lung cancer were enrolled, and tissues were collected to determine FGF19 expression by immunohistochemistry (IHC) assay. Clinicopathological features including the survival date were collected for detailed research. Results: According to the analysis based on the TCGA database, we found that the NSCLC tissues exhibited enhanced FGF19 messenger RNA (mRNA) expression and that the FGF19 mRNA levels correlated with shorter OS in NSCLC patients. IHC staining indicated that 88 (47.1%) patients had high FGF19 expression and 99 (52.9%) patients had low FGF19 expression. Meanwhile, survival data showed that high FGF19 expression was correlated with reduced OS (P<0.001). Moreover, both the univariate analysis and the forward stepwise multivariate Cox regression revealed that high FGF19 expression was an independent prognostic factor for decreased OS (P=0.001). Conclusions:The expression of FGF19 is significantly upregulated in NSCLC, and the overexpression of FGF19 is correlated with poor OS, especially in lung adenocarcinoma (LUAD) cases. FGF19 might serve as a potential biomarker for predicting poor OS in NSCLC patients.

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“…is phosphorylated at tyrosine residue 705 (Tyr705), leading to its dimerization followed by nuclear entry, where it binds to specific elements in the genomic DNA and activates gene transcription. 4,11,12 Therefore, STAT3 is an attractive target for the development of novel antitumour drugs. Various STAT3 inhibitors have been identified in the past 15 years.…”

Section: Introductionmentioning

confidence: 99%

“…Mounting evidence shows that constitutively activated STAT3 contributes to tumour development and progression in most cancers, including breast, prostate, gastric, pancreas, colorectum, cervix, ovary, lung, melanoma and blood cancers 6‐10 . Stimulated by cytokines and growth factors, STAT3 is phosphorylated at tyrosine residue 705 (Tyr705), leading to its dimerization followed by nuclear entry, where it binds to specific elements in the genomic DNA and activates gene transcription 4,11,12 . Therefore, STAT3 is an attractive target for the development of novel antitumour drugs.…”

Section: Introductionmentioning

confidence: 99%

Gracillin shows potent efficacy against colorectal cancer through inhibiting the STAT3 pathway

Yang

Zhu

et al. 2020

J Cellular Molecular Medi

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Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

Cited by 57 publications

References 79 publications

Aberrant FGF15/FGFR4 Signaling Worsens Nonalcoholic Steatohepatitis Severity in FGF21KO Mice

Aberrant FGF15/FGFR4 Signaling Worsens Nonalcoholic Steatohepatitis Severity in FGF21KO Mice

Enhanced expression of FGF19 predicts poor prognosis in patients with non-small cell lung cancer

Gracillin shows potent efficacy against colorectal cancer through inhibiting the STAT3 pathway

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