TY - JOUR
T1 - Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis
AU - Nevzorova, Yulia A.
AU - Hu, Wei
AU - Cubero, Francisco J.
AU - Haas, Ute
AU - Freimuth, Julia
AU - Tacke, Frank
AU - Trautwein, Christian
AU - Liedtke, Christian
N1 - Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) , SFB/TRR57 , project P04 (to C.L. and C.T) and by the START program of the Faculty of Medicine, RWTH Aachen to Y.A.N. We are grateful for the excellent assistance of Sibille Sauer-Lehnen, Carmen C. Tag and the Core Unit “Q3-Cell Isolation” of the SFB/TRR57 with the isolation of primary HSCs. We also would like to thank Snorri S. Thorgeirsson for providing alb-myc tg mice.
PY - 2013/10
Y1 - 2013/10
N2 - 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. Methods: 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. Results: 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. Conclusion: 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.
AB - 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. Methods: 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. Results: 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. Conclusion: 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.
KW - Cell cycle
KW - Hepatic stellate cell activation
KW - Hepatocellular carcinoma
KW - Liver fibrosis
KW - Myofibroblast
UR - http://www.scopus.com/inward/record.url?scp=84879808762&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2013.06.001
DO - 10.1016/j.bbadis.2013.06.001
M3 - Article
C2 - 23770341
AN - SCOPUS:84879808762
SN - 0925-4439
VL - 1832
SP - 1765
EP - 1775
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 10
ER -