EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

Martínez-Palacián, Adoración; Castillo, Gaelle del; Herrera, Blanca; Fernández, Margarita; Roncero, César; Fabregat, Isabel; Sánchez, Aránzazu

doi:10.1016/j.cellsig.2011.09.031

Cited by 15 publications

(14 citation statements)

References 44 publications

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“…That being said, our results are not inconsistent with reports of the lack of crosstalk between EGFR and c-Met in mouse adult liver oval cells. 24 In our experimental conditions, a c-Met inhibitor decreased c-Met phosphorylation, but interestingly, c-Met phosphorylation was not affected by an HGF blocking antibody (previously optimized for blocking efficiency 20 ) in EPC-hTERT-p53 R175H ± EGFR cells ( Fig. 1B and C).…”

Section: Mutant P53 R175h Expression Leads To C-met Activation In a Hmentioning

confidence: 58%

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

Grugan

Vega

Wong

et al. 2013

Cancer Biology & Therapy

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Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of human cancer with poor prognosis due to late diagnosis and metastasis. Common genomic alterations in ESCC include p53 mutation, p120ctn inactivation, and overexpression of oncogenes such as cyclin D1, EGFR, and c-Met. Using esophageal epithelial cells transformed by the overexpression of EGFR and p53(R175H), we find novel evidence of a functional link between p53(R175H) and the c-Met receptor tyrosine kinase to mediate tumor cell invasion. Increased c-Met receptor activation was observed upon p53(R175H) expression and enhanced further upon subsequent EGFR overexpression. We inhibited c-Met phosphorylation, resulting in diminished invasion of the genetically transformed primary esophageal epithelial cells (EPC-hTERT-EGFR-p53(R175H)), suggesting that the mechanism of increased invasiveness upon EGFR and p53(R175H) expression may be the result of increased c-Met activation. These results suggest that the use of therapeutics directed at c-Met in ESCC and other squamous cell cancers.

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Section: Mutant P53 R175h Expression Leads To C-met Activation In a Hmentioning

confidence: 58%

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

Grugan

Vega

Wong

et al. 2013

Cancer Biology & Therapy

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“…Additionally, we show that either LY294002 or siRNA-mediated PI3K silencing by themselves decrease cell viability and increase apoptosis in the absence of serum or any exogenously added growth factor, indicating that PI3K is also mediating autocrine survival signals. We and others have shown that oval cells have an autocrine production of a number of growth factors, including PDGF, EGF and HGF [24], [27], [68], all of them being putative PI3K activators. We have also demonstrated that autocrine signaling through Met and EGFR promotes oval cell survival [24], [27].…”

Section: Discussionmentioning

confidence: 90%

“…We and others have shown that oval cells have an autocrine production of a number of growth factors, including PDGF, EGF and HGF [24], [27], [68], all of them being putative PI3K activators. We have also demonstrated that autocrine signaling through Met and EGFR promotes oval cell survival [24], [27]. The fact that PI3K inhibition or silencing only increased apoptosis in Met flx/flx but not in Met −/− oval cells strongly evidences a Met-dependent PI3K autocrine survival signaling.…”

Section: Discussionmentioning

confidence: 90%

“…Furthermore, some of these pathways have been involved in HGF-mediated proliferative effect on these cells [25], [27], [40], [41], [42]. However, their potential implication in the protective effect of Met revealed in oval cells is not yet known.…”

Section: Resultsmentioning

confidence: 99%

“…siRNA knockdown assays were performed as previously described [27]. For transient siRNA transfection, cells were seeded at 50–60% confluence.…”

Section: Methodsmentioning

confidence: 99%

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Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis

et al. 2013

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We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met−/− oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Metflx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Metflx/flx and Met−/− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met−/− oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met−/− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Metflx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met−/− oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Metflx/flx oval cells, whereas no effect was observed in Met−/− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

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In vitro differentiated hepatic oval‐like cells enhance hepatic regeneration in CCl₄‐induced hepatic injury

Awan

Baig

Yaqub

et al. 2016

Cell Biology International

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Hepatic oval cells are likely to be activated during advanced stage of liver fibrosis to reconstruct damaged hepatic tissue. However, their scarcity, difficulties in isolation, and in vitro expansion hampered their transplantation in fibrotic liver. This study was aimed to investigate the repair potential of in vitro differentiated hepatic oval-like cells in CCl -induced liver fibrosis. BMSCs and oval cells were isolated and characterized from C57BL/6 GFP mice. BMSCs were differentiated into oval cells by preconditioning with HGF, EGF, SCF, and LIF and analyzed for the oval cells-specific genes. Efficiency of oval cells to reduce hepatocyte injury was studied by determining cell viability, release of LDH, and biochemical tests in a co-culture system. Further, in vivo repair potential of differentiated oval cells was determined in CCl -induced fibrotic model by gene expression analysis, biochemical tests, mason trichrome, and Sirius red staining. Differentiated oval cells expressed hepatic oval cells-specific markers AFP, ALB, CK8, CK18, CK19. These differentiated cells when co-cultured with injured hepatocytes showed significant hepato-protection as measured by reduction in apoptosis, LDH release, and improvement in liver functions. Transplantation of differentiated oval cells like cells in fibrotic livers exhibited enhanced homing, reduced liver fibrosis, and improved liver functions by augmenting hepatic microenvironment by improved liver functions. This preconditioning strategy to differentiate BMSCs into oval cell leads to improved survival and homing of transplanted cells. In addition, reduction in fibrosis and functional improvement in mice with CCl -induced liver fibrosis was achieved.

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EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

Cited by 15 publications

References 44 publications

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis

In vitro differentiated hepatic oval‐like cells enhance hepatic regeneration in CCl₄‐induced hepatic injury

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EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

Cited by 15 publications

References 44 publications

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion

Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis

In vitro differentiated hepatic oval‐like cells enhance hepatic regeneration in CCl4‐induced hepatic injury

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In vitro differentiated hepatic oval‐like cells enhance hepatic regeneration in CCl₄‐induced hepatic injury