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

Kimberly J Riehle,Nelson Fausto,Jean S Campbell,Richard P Beyer,Ryan S Mcmahan,Melissa M Johnson,Theo K Bammler

doi:10.1084/jem.20070820

Kimberly J Riehle, Nelson Fausto + Show 5 more

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https://doi.org/10.1084/jem.20070820

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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.

Highlights

Cytokines are secreted proteins that regulate multiple processes, including growth and differentiation, cell survival, hematopoiesis, and immunological functions
We demonstrate that in the absence of SOCS3, (a) hepatocyte DNA replication and progression through the cell cycle are markedly enhanced after partial hepatectomy (PH), leading to an acceleration of liver regeneration; (b) hepatocytes isolated from Socs3 hepatocyte-specific knockout (h-KO) mice have an increased replication capacity; and (c) Socs3-deficient mice develop hepatocellular carcinoma (HCC) at an accelerated rate
Liver regeneration is enhanced in Socs3 h-KO mice Socs3 is robustly induced during the first few hours after PH [9], suggesting that SOCS3 might act as a negative regulator of liver regeneration

Summary

Introduction

Cytokines are secreted proteins that regulate multiple processes, including growth and differentiation, cell survival, hematopoiesis, and immunological functions. We demonstrate that in the absence of SOCS3, (a) hepatocyte DNA replication and progression through the cell cycle are markedly enhanced after PH, leading to an acceleration of liver regeneration; (b) hepatocytes isolated from Socs h-KO mice have an increased replication capacity; and (c) Socs3-deficient mice develop hepatocellular carcinoma (HCC) at an accelerated rate These data suggest that, in addition to its role in the control of cytokine expression in the regenerating liver, SOCS3 coordinates the responses of innate immune system components with that of proliferative pathways. Coordination between these systems may be required for the precise regulation and synchronization of hepatocyte proliferation during liver regeneration and for the prevention of tumorigenesis in such a highly proliferative environment

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