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Cell and Tissue Research

, Volume 347, Issue 1, pp 225–243

First Online: 31 May 2011Received: 07 March 2011Accepted: 15 April 2011


Hepatocellular carcinoma HCC usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts MFB, which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor TGF-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver hepatocytes promotes both fibrogenesis and carcinogenesis fibro-carcinogenesis. Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology MH 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both L-C regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L-C and pSmad3L-C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic mitogenic pSmad3L and fibrogenic pSmad2L-C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis.

KeywordsTGF-β Smad JNK Liver fibrosis Hepatic carcinogenesis AbbreviationsActRIActivin type I receptor

CDKCyclin-dependent kinase

CTGFConnective tissue growth factor

ECMExtracellular matrix

EMTEpithelial-to-mesenchymal transition

ERKExtracellular signal-regulated kinase

HBVHepatitis B virus

HCVHepatitis C virus

HCCHepatocellular carcinoma

HSCHepatic stellate cells

JNKc-Jun N-terminal kinase


MAPKMitogen-activated protein kinase



MKKMitogen-activated kinase kinase

PAIPlasminogen activator inhibitor

PDGFPlatelet-derived growth factor

pSmadCC-terminally phosphorylated Smad

pSmadLLinker phosphorylated Smad

pSmadL-CDually phosphorylated Smad

SMASmooth muscle actin

TGFTransforming growth factor

TβRITGF-β type I receptor

TNFTumor necrosis factor

The author’s work is supported financially by the Ministry of Education, Science and Culture of Japan.

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Autor: Koichi Matsuzaki


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