Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells |
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Authors: | Koichi Matsuzaki |
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Institution: | (1) Department of Gastroenterology and Hepatology, Kansai Medical University, 10–15 Fumizonocho, Moriguchi, Osaka 570–8506, Japan |
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Abstract: | 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. |
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