Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3

Riehle, K. J., et al. 2008. J. Exp. Med. 205, 91-103

Speaker: Yi Wang (王壹)                          Time: 14:10~15:00, Feb. 20, 2008

Commentator: Dr. Hsiao-Sheng Liu (劉校生博士)     Place: Room 601

Abstract

After partial hepatectomy (PH), interleukin 6 (IL-6) is up-regulated (1) and leads to expression of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of IL-6-activated signal transducer and activator of transcription 3 (STAT3) signaling during liver regeneration (2). The role of SOCS3 on PH-induced liver regeneration remains unclear. In the present study, the authors develop SOCS3 hepatocye-specific knockout (SOCS3 h-KO) mice to investigate its potential actions during liver regeneration. SOCS3 h-KO mice show the increased expression of cell cycle proteins, enhanced DNA replication, and rapider liver weight restoration. SOCS3 h-KO mice have the similar change on serum IL-6 level in comparison with littermate controls. However, they have prolonged STAT3 and the mitogenic extracellular signal-regulated kinase 1/2 (ERK1/2) (3) activation and the stronger expression of STAT3 target genes. Additionally, absence of SOCS3 promotes epidermal growth factor-induced phosphorylation of STAT3 and ERK1/2 and cell proliferation in vitro. However, inhibition of JAK (upstream of STAT3) and MEK (upstream of ERK1/2) pathways suppresses these phenomena, suggesting that SOCS3 may modulate liver regeneration through JAK/STAT3- and MEK/ERK1/2-mediated pathways. In addition, SOCS3 deficiency also increases IL-6-induced STAT3, ERK1/2, and S6 protein activation in vitro. Microarray and transcriptional regulatory network analysis show profound changes in proliferation-associated gene expression after PH in SOCS3 h-KO mice. Treating SOCS3 h-KO mice with N-nitrosodiethylamine show an accelerated development of hepatocellular carcinoma (HCC) and an increase in serum IL-6 level. In conclusion, SOCS3 regulates PH-initiated liver regeneration and chemical-induced HCC by regulating on cytokine signaling and multiple proliferative pathways.

References

1.          Fausto, N., et al. 2006. Liver regeneration. Hepatology. 43, S45-S53.

2.          Campbell, J. S., et al. 2001. Expression of suppressors of cytokine signaling during liver regeneration. J. Clin. Invest. 107, 1285-1292.

3.          Talamin, H., et al. 1999. The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signaling pathway involved in the regulation of G1 phase progression in proliferating hepatocyte. Mol. Cell. Biol. 19, 6003-6011.

*Presentation in English