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

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• 作者：Yulia A. Nevzorova ; Wei Hu ; Francisco J. Cubero ; Ute Haas ; Julia Freimuth ; Frank Tacke ; Christian Trautwein ; Christian Liedtke
• 关键词：¦Á-SMA ; alpha-smooth-muscle-actin ; CCl4 ; carbon tetrachloride ; HCC ; hepatocellular carcinoma ; HSC ; hepatic stellate cells ; NPC ; non-parenchymal cells ; PCNA ; proliferating cell nuclear antigen ; qPCR ; quantitative real-time polymerase chain reaction ; WT ; wi
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：1832
• 期：10
• 页码：1765-1775
• 全文大小：2176 K

文摘

Background

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-myc^tg) 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-myc^tg 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-myc^tg mice resulted in increased liver collagen deposition and induction of ¦Á-smooth-muscle-actin indicating HSC activation. Primary HSC derived from alb-myc^tg mice showed enhanced proliferation and accelerated transdifferentiation into myofibroblasts in vitro. Accordingly, fibrosis initiation in vivo after chronic CCl₄ treatment was accelerated in alb-myc^tg 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.