Details

Autor(en) / Beteiligte

• Nevzorova, Yulia A.
• Hu, Wei
• Cubero, Francisco J.
• Haas, Ute
• Freimuth, Julia
• Tacke, Frank
• Trautwein, Christian
• Liedtke, Christian

Titel

Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis

Ist Teil von

• Biochimica et biophysica acta, 2013-10, Vol.1832 (10), p.1765-1775

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Liver fibrosis is a consequence of chronic liver injury and can further progress to hepatocellular carcinoma (HCC). Fibrogenesis involves activation of hepatic stellate cells (HSC) and proliferation of hepatocytes upon liver injury. HCC is frequently associated with overexpression of the proto-oncogene c-myc. However, the impact of c-myc for initiating pathological precursor stages such as liver fibrosis is poorly characterized. In the present study we thus investigated the impact of c-myc for liver fibrogenesis. Expression of c-myc was measured in biopsies of patients with liver fibrosis of different etiologies by quantitative real-time PCR (qPCR). Primary HSC were isolated from mice with transgenic overexpression of c-myc in hepatocytes (alb-myctg) and wildtype (WT) controls and investigated for markers of cell cycle progression and fibrosis by qPCR and immunofluorescence microscopy. Liver fibrosis in WT and alb-myctg mice was induced by repetitive CCl4 treatment. We detected strong up-regulation of hepatic c-myc in patients with advanced liver fibrosis. In return, overexpression of c-myc in alb-myctg mice resulted in increased liver collagen deposition and induction of α-smooth-muscle-actin indicating HSC activation. Primary HSC derived from alb-myctg mice showed enhanced proliferation and accelerated transdifferentiation into myofibroblasts in vitro. Accordingly, fibrosis initiation in vivo after chronic CCl4 treatment was accelerated in alb-myctg mice compared to controls. Overexpression of c-myc is a novel marker of liver fibrosis in man and mice. We conclude that chronic induction of c-myc especially in hepatocytes has the potential to prime resident HSC for activation, proliferation and myofibroblast differentiation. •Constitutive expression of the proto-oncogene c-myc triggers enhanced hepatic cell proliferation.•Liver fibrosis in human patients is associated with induction of c-myc.•Hepatocyte-specific over-expression of c-myc activates hepatic stellate cells in vivo.•Hepatic c-myc expression facilitates liver fibrogenesis.