Hepatocyte Growth Factor Promotes Cell Survival From Fas-Mediated Cell Death in Hepatocellular Carcinoma Cells via Akt Activation and Fas-Death–Inducing Signaling Complex Suppression

Suzuki, Atsushi

doi:10.1053/jhep.2000.17738

Cited by 117 publications

(79 citation statements)

References 45 publications

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“…23 Both PI-3Kinase/Akt and JAK/STAT signaling are activated by these growth factors in a number of cell types. 24 Consistent to results using other cell types, we have shown that these pathways are induced after EGF/HGF treatment in primary human hepatocytes isolated from several donors. These results are supported by recent work showing induction of STAT3 after HGF treatment in primary human hepatocytes contributes to reduced response to CD95 stimulation.…”

Section: Discussionsupporting

confidence: 90%

“…These results are supported by recent work showing induction of STAT3 after HGF treatment in primary human hepatocytes contributes to reduced response to CD95 stimulation. 24 The physiological relevance of our findings are supported by the fact that the levels of HGF we found in some of the patients approached the dose of HGF used in vitro on isolated human hepatocytes for achieving protection against apoptosis signaling induction.…”

Section: Discussionsupporting

confidence: 63%

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EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus-infected liver cells to apoptosis may play a role in the failure to remove virus-infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV-infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95-mediated apoptosis and cytotoxic T-cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3-K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF-dependent upregulation of b 1 -integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside-in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95-mediated apoptosis and the action of cytotoxic T-cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 63%

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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“…26,39 Activation of PI3-kinase and Akt also inhibits Fas receptor-mediated cell death in hepatocytes. 40,41 Therefore, under the context of a constitutive Fas receptor expression in HSC/ MFB, 35 Gas6 could protect these cells and macrophages against apoptosis in vivo during tissue repair. It may favor a transient accumulation of these cytokine-and matrixproducing cells, which are necessary to the reorganization of liver architecture and hepatocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

et al. 2006

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The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins. We investigated the expression and the role of Gas6 and its receptor Axl in liver repair. Three days after CCl 4 -induced liver injury in the rat, we detected the expression of Gas6 in ED1-positive macrophages as well as in desmin-positive HSC, which accumulated in injured areas. Axl, the high-affinity receptor for Gas6, was detected in macrophages, HSC, and HSC/MFB. In vitro, expression of ␥-carboxylated Gas6 was strongly induced in HSC along with their transformation into myofibroblasts, and it exerted an anti-apoptotic effect on both HSC and HSC/MFB mediated by the Axl/PI3-kinase/Akt pathway. In conclusion, Gas6 is a survival factor for these cells and we suggest

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“…This receptor tyrosine kinase (RTK) is predominantly expressed on epithelial and endothelial cells and regulates proliferation (Efimova et al, 2004), migration (Monvoisin et al, 1999), cell survival (Suzuki et al, 2000), morphogenesis , angiogenesis (Schmidt et al, 1995), as well as tissue regeneration (Borowiak et al, 2004). Hepatocyte growth factor binding and MET multimerization results in receptor auto-and paraphosphorylation of adaptor proteins (e.g.…”

Section: Transforming Growth Factor B Signaling Axismentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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Hepatocyte Growth Factor Promotes Cell Survival From Fas-Mediated Cell Death in Hepatocellular Carcinoma Cells via Akt Activation and Fas-Death–Inducing Signaling Complex Suppression

Abstract: The Akt/PI-3 kinase pathway is a system essential for cell survival. In the current study, we showed that hepatocyte growth factor (HGF) activates the Akt/PI-3 kinase pathway to suppress Fas-mediated cell death in human hepatocellular carcinoma (

Cited by 117 publications

References 45 publications

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

Dysregulation of growth factor signaling in human hepatocellular carcinoma

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Hepatocyte Growth Factor Promotes Cell Survival From Fas-Mediated Cell Death in Hepatocellular Carcinoma Cells via Akt Activation and Fas-Death–Inducing Signaling Complex Suppression

Abstract: The Akt/PI-3 kinase pathway is a system essential for cell survival. In the current study, we showed that hepatocyte growth factor (HGF) activates the Akt/PI-3 kinase pathway to suppress Fas-mediated cell death in human hepatocellular carcinoma (

Cited by 117 publications

References 45 publications

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

Dysregulation of growth factor signaling in human hepatocellular carcinoma

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Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells