Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury.
Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury.
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DOI：
10.1038/s41388-018-0181-8
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发表时间：
2018-06
期刊：
影响因子：
8
通讯作者：
Trautwein C
中科院分区：
文献类型：
--
作者：
Ehedego H;Mohs A;Jansen B;Hiththetiya K;Sicinski P;Liedtke C;Trautwein C
慢性肝损伤引发肝纤维化和肝细胞癌（HCC），这是癌症相关死亡的第三大原因。细胞周期蛋白E1（CcnE 1，以前称为细胞周期蛋白E）是细胞周期蛋白依赖性激酶2（CDK 2）的调节亚基。它在约70%的人HCC中过表达，与不良预后相关，而其直向同源物细胞周期蛋白E2（CcnE 2）的相关性尚不清楚。肝细胞特异性缺失NF-κ-B必需调节因子（NEMO）导致慢性肝炎、肝纤维化和HCC以及CcnE上调。为此，我们产生了NEMO cohepa/CcnE 1 −/−和NEMO cohepa/CcnE 2 −/−双敲除小鼠，并研究了这些动物的年龄依赖性肝病进展。NEMO Hepa小鼠中CcnE 1的缺失降低了基础肝损伤，并减少了年轻小鼠的自发性肝脏炎症。相比之下，CcnE 2的丢失并不影响NEMO Hepa肝脏的肝损伤，这表明CcnE 1在慢性肝炎中具有独特的非冗余功能。因此，NEMO肝癌小鼠的基础代偿性肝细胞增殖减少伴随消融CcnE 1，但不是在损失CcnE 2。在老年NEMO肝癌小鼠中，CcnE 1的缺失导致肝肿瘤发生的显著减少，而CcnE 2的缺失对HCC形成没有影响。CcnE 1，而不是其直向同源物CcnE 2实质上有助于NEMO肝癌小鼠的肝脏炎症反应，肝脏疾病进展和肝癌发生。
Chronic liver injury triggers liver fibrosis and hepatocellular carcinoma (HCC) the third leading cause of cancer-related mortality. Cyclin E1 (CcnE1, formerly designated Cyclin E) is a regulatory subunit of the Cyclin-dependent kinase 2 (CDK2). It is overexpressed in approximately 70 % of human HCCs correlating with poor prognosis, while the relevance of its orthologue Cyclin E2 (CcnE2) is unclear. Hepatocyte-specific deletion of NF-kappa-B essential modulator (NEMO∆hepa) leads to chronic hepatitis, liver fibrosis and HCC as well as CcnE up-regulation. To this end, we generated NEMO∆hepa/CcnE1−/− and NEMO∆hepa/CcnE2−/− double knockout mice and investigated age-dependent liver disease progression in these animals. Deletion of CcnE1 in NEMO∆hepa mice decreased basal liver damage and reduced spontaneous liver inflammation in young mice. In contrast, loss of CcnE2 did not affect liver injury in NEMO∆hepa livers pointing to a unique, non-redundant function of CcnE1 in chronic hepatitis. Accordingly, basal compensatory hepatocyte proliferation in NEMO∆hepa mice was reduced by concomitant ablation of CcnE1, but not after loss of CcnE2. In aged NEMO∆hepa mice, loss of CcnE1 resulted in significant reduction of liver tumor-igenesis, while deletion of CcnE2 had no effect on HCC formation. CcnE1, but not its orthologue CcnE2 substantially contributes to hepatic inflammatory response, liver disease progression and hepatocarcinogenesis in NEMO∆hepa mice.
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Cyclin E1控制肝星状细胞的增殖，对于小鼠的肝纤维发生至关重要。
影响因子：
13.5
作者：
Nevzorova, Yulia A.;Bangen, Joerg-Martin;Hu, Wei;Haas, Ute;Weiskirchen, Ralf;Gassler, Nikolaus;Huss, Sebastian;Tacke, Frank;Sicinski, Piotr;Trautwein, Christian;Liedtke, Christian
通讯作者：
Liedtke, Christian
DOI：
10.1084/jem.20082152
发表时间：
2009-08-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Beraza N;Malato Y;Sander LE;Al-Masaoudi M;Freimuth J;Riethmacher D;Gores GJ;Roskams T;Liedtke C;Trautwein C
通讯作者：
Trautwein C
影响因子：
4.1
作者：
Pok, Sharon;Wen, Victoria;Teoh, Narci C.
通讯作者：
Teoh, Narci C.
影响因子：
10.5
作者：
Clurman, BE;Sheaff, RJ;Roberts, JM
通讯作者：
Roberts, JM
影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis