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首页> 外文期刊>Cell and Tissue Research >Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells.
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Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells.

机译：急性和慢性肝损伤中的Smad磷酸亚型信号：上皮和间充质细胞之间的相似性和差异。

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摘要

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.
机译：肝细胞癌（HCC）通常源于慢性炎症引起的肝纤维化。在慢性肝损伤中，肝星状细胞会逐渐激活成肌纤维细胞（MFB），这是重要的细胞外生成间充质细胞。同时，肝脏上皮细胞（肝细胞）中促炎性细胞因子对转化生长因子（TGF）-β信号的干扰促进了纤维化和癌变（纤维癌变）。最近对TGF-β信号转导过程进行了详细分析，从而发现了对慢性受损肝细胞的纤维致癌作用。从TGF-β受体传递信号到细胞核的Smad蛋白在保守的Mad同源（MH）1和MH2结构域之间具有中间连接区。 TGF-βI型受体和促炎性细胞因子激活的激酶差异磷酸化Smad2和Smad3，从而在COOH末端，接头或两个（L / C）区域产生磷酸化的磷酸同工型。急性肝损伤后，TGF-β介导的pSmad3C信号传导终止由促炎性细胞因子介导的有丝分裂性pSmad3L途径诱导的肝细胞增殖。 TGF-β和促炎细胞因子通过激活的肝星状细胞通过pSmad2L / C和pSmad3L / C途径协同增强胶原蛋白的合成。在慢性肝脏疾病的进展过程中，持续受到TGF-β影响的肿瘤前肝细胞与促炎性细胞因子一起显示出与MFB相同的致癌（促有丝分裂）pSmad3L和纤维化pSmad2L / C信号，从而加速了肝纤维化，同时增加了肝纤维化的风险肝癌这篇有关Smad磷酸同工型介导信号的综述检查了急性和慢性肝损伤中上皮细胞与间充质细胞之间的异同，并认为Smad接头磷酸化是化学预防纤维癌变的潜在靶标。

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