The combination of epidermal growth factor and transforming growth factor-β induces novel phenotypic changes in mouse liver stem cell lines

Isfort, Robert J.; Cody, David B.; Stuard, Sharon B.; Randall, Catherine J.; Miller, C. M.; Ridder, Gregg M.; Doersen, Claus-Jens; Richards, William G.; Yoder, Bradley K.; Wilkinson, John E.; Woychik, Richard P.

doi:10.1242/jcs.110.24.3117

Cited by 25 publications

References 30 publications

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c‐Fos accelerates hepatocyte conversion to a fibroblastoid phenotype through ERK‐mediated upregulation of paxillin‐Serine178 phosphorylation

Güller

André

Legrand

et al. 2008

Molecular Carcinogenesis

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Transforming growth factor beta (TGF-beta) exerts an important role in the late steps of carcinogenesis by cooperating with Ras to induce cell motility and tumor invasion. The transcription complex AP-1 has been implicated in the regulation of genes involved in motility and invasion, by mechanisms not yet delineated. We utilized a model of immortalized human hepatocytes (IHH) overexpressing c-Fos (IHH-Fos) or not (IHH-C) to investigate the role of c-Fos on cell motility in response to a prolonged treatment with TGF-beta, EGF or a combination of both. Cotreatment with EGF and TGF-beta, but neither cytokine alone, induced the conversion of hepatocytes to a fibroblastoid phenotype and increased their motility in Boyden chambers. EGF/TGF-beta cotreatment induced a higher effect on ERK phosphorylation compared to TGF-beta treatment alone. It also induced an increase in total and phosphorylated Ser(178) paxillin, a protein previously implicated in cell motility. This response was inhibited by two specific MEK inhibitors, indicating the involvement of the ERK pathway in paxillin activation. Overexpression of c-Fos correlated with increased cell scattering and motility, higher levels of ERK activation and phospho Ser(178) paxillin, increased levels of EGF receptor (EGF-R) mRNA and higher EGF-R phosphorylation levels following EGF/TGF-beta cotreatment. Conversely, siRNA-mediated invalidation of c-Fos delayed the appearance of fibroblastoid cells, decreased EGF-R mRNA and downregulated ERK and Ser(178) paxillin phosphorylations, indicating that c-Fos activates hepatocyte motility through an EGF-R/ERK/paxillin pathway. Since c-Fos is frequently overexpressed in hepatocarcinomas, this newly identified mechanism might be involved in the progression of hepatic tumors in vivo.

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c‐Fos accelerates hepatocyte conversion to a fibroblastoid phenotype through ERK‐mediated upregulation of paxillin‐Serine178 phosphorylation

Güller

André

Legrand

et al. 2008

Molecular Carcinogenesis

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Hepatic tissue engineering: applications in disease treatment and liver support

Abu-Absi¹,

Narayanan²,

2003

Frontiers in Biomedical Engineering

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Activation of stem cells in hepatic diseases

2007

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The liver has enormous regenerative capacity. Following acute liver injury, hepatocyte division regenerates the parenchyma but, if this capacity is overwhelmed during massive or chronic liver injury, the intrinsic hepatic progenitor cells (HPCs) termed oval cells are activated. These HPCs are bipotential and can regenerate both biliary epithelia and hepatocytes. Multiple signalling pathways contribute to the complex mechanism controlling the behaviour of the HPCs. These signals are delivered primarily by the surrounding microenvironment. During liver disease, stem cells extrinsic to the liver are activated and bone-marrow-derived cells play a role in the generation of fibrosis during liver injury and its resolution. Here, we review our current understanding of the role of stem cells during liver disease and their mechanisms of activation.

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The combination of epidermal growth factor and transforming growth factor-β induces novel phenotypic changes in mouse liver stem cell lines

Cited by 25 publications

References 30 publications

c‐Fos accelerates hepatocyte conversion to a fibroblastoid phenotype through ERK‐mediated upregulation of paxillin‐Serine178 phosphorylation

c‐Fos accelerates hepatocyte conversion to a fibroblastoid phenotype through ERK‐mediated upregulation of paxillin‐Serine178 phosphorylation

Hepatic tissue engineering: applications in disease treatment and liver support

Activation of stem cells in hepatic diseases

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