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

Abstract

Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration (Campbell, J.S., L. Prichard, F. Schaper, J. Schmitz, A. Stephenson-Famy, M.E. Rosenfeld, G.M. Argast, P.C. Heinrich, and N. Fausto. 2001.J. Clin. Invest. 107:1285–1292). We developed Socs3 hepatocyte-specific knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after a two-thirds partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor or interleukin 6 stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes, which fall into diverse physiological categories, after PH. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiological and neoplastic proliferative processes in the liver and may act as a tumor suppressor.

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…The TNAP-AID mouse model exhibits several characteristics of human HCC, in that the mice develop HCC spontaneously and the HCC tissue expresses a-fetoprotein and that it has the p53 gene mutations, some of which cause the same amino acid replacements as those seen in human tumours. Earlier HCC mouse models include mice with genetic modifications of Lkb1, Mdr2, Aox and Pten genes (Fan et al, 1998;Nakau et al, 2002;Horie et al, 2004;Katzenellenbogen et al, 2006), transgenic mice overexpressing c-myc, transforming growth factor-a, transforming growth factor-b1, HBx of hepatitis B virus and HCV core (Sandgren et al, 1989;Kim et al, 1991;Murakami et al, 1993;Koike et al, 1994Koike et al, , 2002Factor et al, 1997;Riehle et al, 2008) and chemical-or diet-induced HCC (Sell, 2001;Maeda et al, 2005;Ma et al, 2006;Sakurai et al, 2006). In contrast to these models, our TNAP-AID model is unique because it does not arbitrarily target specific oncogenes, tumour suppressors or stability genes.…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Equally important is what actually governs the magnitude of the regenerative response; TGFβ produced by the stellate cells certainly inhibits hepatocyte replication, and the IL-6 response mediated by STAT3 homodimers (Figure 2) is negatively regulated through transcriptional up-regulation of Socs3 (suppressor of cytokine signalling 3), a molecule that prevents further interaction of JAKs with STAT3, thus blocking further JAK-mediated phosphorylation (activation) of STAT3. Nevertheless, SOCS is not essential for termination of the regenerative response; Socs3 knock-out mice do have higher levels of hepatocyte proliferation after PH than their wild-type counterparts and do restore their liver weight 2 days earlier, but proliferation still ceases after 4 days and there is no inexorable rise in liver weight [15]. On the other hand, over-expression of the Yes-associated protein (YAP) in a conditional YAP transgenic mouse led to a phenomenal liver weight increase through hyperplasia, reaching 25% of body weight -normal liver weight is ∼5% of body weight [16].…”

“…Numerous growth factors and cytokines have been implicated in the initiation and control of this regenerative response [1,[10][11][12][13][14][15][16], with the activation of seemingly critical transcription factors, such as AP-1, NFκB and STAT-3. Liver injury can be associated with a defective intestinal barrier, leading to exposure to bacterial products such as lipopolysaccharides and components of the innate immune system (complement fragments), and their activation of the NFκB pathway in Kupffer cells, leading to the production and secretion Figure 1.…”

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

“…13,33 In addition, it was determined that inhibition of STAT3 using chemical inhibitors or small-interfering RNA induced liver cancer cell apoptosis and cell cycle arrest in vitro and inhibited growth of transplanted liver cancer cells in vivo. 33 Other evidence suggesting a role of STAT3 in tumorigenesis included findings that deletion of hepatic SOCS3, an inhibitor of STAT3, elevated STAT3 activation in the liver and accelerated DEN-induced liver tumorigenesis, 34 whereas overexpression of SOCS3 inhibited HCC cell growth. 35 Moreover, several cytokines (IL-6, IL-6 family cytokines, IL-22, leptin, etc) that activate STAT3 in hepatocytes have also been shown to promote HCC cell growth in vitro and in vivo.…”