Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway
Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway
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Gankyrin 通过 Rac1/JNK 通路驱动慢性肝损伤介导的纤维化恶性转化
DOI：
10.1038/cddis.2015.120
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发表时间：
2015-05
影响因子：
9
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhao X;Fu J;Xu A;Yu L;Zhu J;Dai R;Su B;Luo T;Li N;Qin W;Wang B;Jiang J;Li S;Chen Y;Wang H
肝癌发生是一个复杂的过程，涉及慢性肝损伤，炎症，不受调节的伤口愈合，随后的纤维化和癌变。为了解释从慢性肝损伤到异型增生转变的分子机制，我们在转基因小鼠模型中研究了Gankyrin（PSMD 10或p28 GANK）在恶性转化过程中的致癌作用。在这里，我们发现肝硬化患者中Gankyrin增加。除了DEN加CCl 4治疗后更严重的肝纤维化和肿瘤发生外，肝细胞特异性gankyrin过表达小鼠（gankyrin hep）甚至在单次CCl 4给药下也表现出从肝纤维化到肿瘤的恶性转化，而野生型小鼠仅经历纤维化。CCl 4处理后肝细胞损伤加重，炎症反应加重，代偿性增生增强.这与细胞周期相关基因的表达增强和Rac 1/c-jun N-末端激酶（JNK）的异常激活有关。药理学抑制Rac 1/JNK通路可减轻肝纤维化并防止CCl 4诱导的Gankyrin hep小鼠的癌变。总之，这些发现表明，Gankyrin促进肝纤维化/肝硬化进展为肝癌，依赖于持续的肝损伤和炎症微环境。阻断Rac 1/JNK的激活可阻止Gankyrin介导的肝细胞恶性转化，表明Gankyrin和Rac 1/JNK的联合抑制是肝硬化转化的潜在预防机制。
Hepatocarcinogenesis is a complex process involving chronic liver injury, inflammation, unregulated wound healing, subsequent fibrosis and carcinogenesis. To decipher the molecular mechanism underlying transition from chronic liver injury to dysplasia, we investigated the oncogenic role of gankyrin (PSMD10 or p28 GANK) during malignant transformation in a transgenic mouse model. Here, we find that gankyrin increased in patients with cirrhosis. In addition to more severe liver fibrosis and tumorigenesis after DEN plus CCl 4 treatment, hepatocyte-specific gankyrin-overexpressing mice (gankyrin hep) exhibited malignant transformation from liver fibrosis to tumors even under single CCl 4 administration, whereas wild-type mice merely experienced fibrosis. Consistently, enhanced hepatic injury, severe inflammation and strengthened compensatory proliferation occurred in gankyrin hep mice during CCl 4 performance. This correlated with augmented expressions of cell cycle-related genes and abnormal activation of Rac1/c-jun N-terminal kinase (JNK). Pharmacological inhibition of the Rac1/JNK pathway attenuated hepatic fibrosis and prevented CCl 4-induced carcinogenesis in gankyrin hep mice. Together, these findings suggest that gankyrin promotes liver fibrosis/cirrhosis progression into hepatocarcinoma relying on a persistent liver injury and inflammatory microenvironment. Blockade of Rac1/JNK activation impeded gankyrin-mediated hepatocytic malignant transformation, indicating the combined inhibition of gankyrin and Rac1/JNK as a potential prevention mechanism for cirrhosis transition.
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影响因子：
4.8
作者：
Subauste, MC;Von Herrath, M;Hahn, KM
通讯作者：
Hahn, KM
DOI：
10.1016/s0021-9258(17)43327-8
发表时间：
1984-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
P. McCay;E. Lai;J. Poyer;C. M. Dubose;E. Janzen
通讯作者：
P. McCay;E. Lai;J. Poyer;C. M. Dubose;E. Janzen
影响因子：
44.1
作者：
Yao Chen;H. Li;Jing Fu;Xue Feng Wang;Y. Ren;Liwei Dong;Shanhua Tang;S. Liu;Meng-chao Wu;H. Y. Wang
通讯作者：
Yao Chen;H. Li;Jing Fu;Xue Feng Wang;Y. Ren;Liwei Dong;Shanhua Tang;S. Liu;Meng-chao Wu;H. Y. Wang
影响因子：
64.8
作者：
E. Pikarsky;R. Porat;I. Stein;R. Abramovitch;S. Amit;Shafika Kasem;Elena Gutkovich-Pyest;S. Urieli-Sh
通讯作者：
E. Pikarsky;R. Porat;I. Stein;R. Abramovitch;S. Amit;Shafika Kasem;Elena Gutkovich-Pyest;S. Urieli-Sh
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi