<i>Klotho‐beta</i> and <i>fibroblast growth factor 19</i> expression correlates with early recurrence of resectable hepatocellular carcinoma

Lin, Zhong‐Zhe; Hsu, Chiun; Jeng, Yung‐Ming; Hu, Fu‐Chang; Pan, Hung‐Wei; Wu, Yao‐Ming; Hsu, Hey‐Chi; Cheng, Ann‐Lii

doi:10.1111/liv.14055

Cited by 22 publications

(21 citation statements)

References 37 publications

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“…Since these findings imply the possibility that a combination therapy of ATRA and some LSD1-specific inhibitors such as Iadademstat might be effective for HCC, we plan to study effects of combined treatment of ATRA and Iadademstat or other LSD1-specific inhibitors on HCC cells. Furthermore, a number of papers have already been published relevant to the involvement of the FGFR and/or Klotho-mediated ligand binding pathway, and the MST1-mediated signaling pathway in HCC [54][55][56][57][58][59]. Taken together, our results imply that LSD1 seems to contribute to hepatocarcinogenesis through regulation of the signaling pathways we identified.…”

Section: Discussionsupporting

confidence: 62%

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

Kim

Bolatkan²,

Kaneko³

et al. 2019

Biomolecules

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. In order to tackle this issue, we conducted functional analysis of the histone lysine-specific demethylase (LSD1) to explore the possibility that this enzyme acts as a therapeutic target in HCC. According to immunohistochemical analysis, 232 of 303 (77%) HCC cases showed positive staining of LSD1 protein, and its expression was correlated with several clinicopathological characteristics, such as female gender, AFP (alpha-fetoprotein) levels, and HCV (hepatitis C virus) infectious. The survival curves for HCC using the Kaplan-Meier method and the log-rank test indicate that positive LSD1 protein expression was significantly associated with decreased rates of overall survival (OS) and disease-free survival (DFS); the multivariate analysis indicates that LSD1 expression was an independent prognostic factor for both OS and DFS in patients with HCC. In addition, knockout of LSD1 using the CRISPR/Cas9 system showed a significantly lower number of colony formation units (CFUs) and growth rate in both SNU-423 and SNU-475 HCC cell lines compared to the corresponding control cells. Moreover, LSD1 knockout decreased cells in S phase of SNU-423 and SNU-475 cells with increased levels of H3K4me1/2 and H3K9me1/2. Finally, we identified the signaling pathways regulated by LSD1 in HCC, including the retinoic acid (RA) pathway. Our findings imply that deregulation of LSD1 can be involved in HCC; further studies may explore the usefulness of LSD1 as a therapeutic target of HCC.

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Section: Discussionsupporting

confidence: 62%

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

Kim

Bolatkan²,

Kaneko³

et al. 2019

Biomolecules

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“…154 Indeed, blockade of FGFR4 has been investigated in specific forms of hepatocellular carcinoma in humans. 155 Nevertheless, if histological effects reported from an open label study are confirmed, an FGF19 mimetic could offer an attractive therapy for NASH.…”

Section: Pharmacological Modulation Of Gut Peptidesmentioning

confidence: 99%

The gut-liver axis in liver disease: Pathophysiological basis for therapy

Albillos

Gottardi

Rescigno

2020

Journal of Hepatology

1,192

881

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The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.

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“…Previous studies have shown that the expression of FGF19 is significantly higher in patients with liver cirrhosis and liver cancer and is significantly associated with the pathologic stage of liver cancer [8,13]. Furthermore, Kang et al demonstrated that a unique molecular subtype of FGF19 is associated with poor prognosis in liver cancer [28].…”

Section: Relationships Between Fgf19 Glucose Metabolism Andmentioning

confidence: 99%

“…In addition, high FGF19 concentrations have been reported to be present in HCC patients and are associated with a poor prognosis [8]. Furthermore, the FGF19-FGFR4 pathway may be a key contributor to the pathogenesis of HCC [13]. Because of its apparently contrasting role in these two diseases, a genetically modified FGF19 (M70) has been developed that retains its beneficial metabolic activity but lacks the deleterious mitogenic activity and is currently undergoing clinical trials [14,15].…”

Section: Introductionmentioning

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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Klotho‐beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma

Cited by 22 publications

References 37 publications

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

The gut-liver axis in liver disease: Pathophysiological basis for therapy

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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