Modulation of TGF-beta signaling during progression of chronic liver diseases
Modulation of TGF-beta signaling during progression of chronic liver diseases
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DOI：
10.2741/3423
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发表时间：
2009-01-01
影响因子：
3.1
通讯作者：
Matsuzaki, Koichi
中科院分区：
文献类型：
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作者：
Matsuzaki, Koichi
大量的工作已经确立了上皮细胞作为进行性纤维化和癌发生的重要介质的作用。转化生长因子-β（TGF-β）和促炎细胞因子是纤维癌发生的重要诱导物。TGF-β信号传导涉及Smad 3在中间接头和/或C-末端区域的磷酸化。在过度活跃的Ras表达上皮细胞中，Smad 3依赖性信号传导在肿瘤抑制和肿瘤发生之间的可逆转换表明，在C端区域磷酸化的Smad 3（pSmad 3C）传递肿瘤抑制性TGF-β信号，而在连接区磷酸化的Smad 3（pSmad 3L）促进肿瘤活性，如细胞增殖和侵袭。值得注意的是，pSmad 3L介导的信号传导通过活化的间充质细胞促进细胞外基质沉积。在慢性肝病的进展过程中，肝上皮肝细胞经历从肿瘤抑制性pSmad 3C途径到致纤维化/致癌性pSmad 3L途径的转变，加速肝纤维化并增加肝细胞癌的风险。由促炎细胞因子激活的c-Jun N-末端激酶介导这种扰动的肝细胞TGF-β信号传导。因此，受慢性炎症影响的肝细胞的TGF-β信号传导为理解慢性肝病进展过程中人类纤维癌发生的分子机制提供了一个总体框架。
A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF- beta signaling. Thus, TGF- beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases.