转录因子c-Jun的/ AP-1促进小鼠HBV相关的肝癌发生

StephenW

Cell Death & Differentiation , (16 October 2015) | doi:10.1038/cdd.2015.121

   
The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice

C Trierweiler, B Hockenjos, K Zatloukal, R Thimme, H E Blum, E F Wagner and P Hasselblatt
Abstract

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV+), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV+ mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV+ mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV+ livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.

StephenW

细胞死亡和分化，（2015年10月16日）| DOI：10.1038 / cdd.2015.121

   
转录因子c-Jun的/ AP-1促进小鼠HBV相关的肝癌发生

ÇTrierweiler，B Hockenjos，K Zatloukal，R Thimme，何百隆，EF瓦格纳和P Hasselblatt
抽象的

肝细胞癌（HCC）发展为慢性炎症肝病如慢性乙型肝炎病毒（HBV）感染的结果。转录因子的c-Jun /激活蛋白-1（AP-1）的强表达响应于炎症刺激，促进肝细胞存活期间急性肝炎和充当期间小鼠化学诱导肝癌癌基因。在这里，我们的目的，因此在HBV相关的肝癌发生表征的c-Jun的功能。为此，表达所有的HBV包膜蛋白（HBV +），建立HBV相关HCC的模型的转基因小鼠，杂交用基因敲除小鼠缺乏c-Jun的特别是在肝细胞和肿瘤发生进行分析。的c-Jun的肝表达肿瘤发生中的HBV +小鼠期间强烈诱导在几个时间点，而其它的AP-1的组件的表达保持不变。重要的是，形成癌前病灶和肿瘤是在HBV +缺乏c-Jun的小鼠大大减少。这种表型相关受损肝细胞增殖和增加的细胞周期抑制剂p21基因表达，而肝细胞存活并没有受到影响。进展HBV相关HCC的预后相关联地细胞因子骨桥蛋白（OPN），已建立的AP-1的靶基因的表达。 OPN表达强烈减少HBV +肝脏和原代小鼠肝细胞缺乏c-Jun的，这表明c-Jun的调节肝OPN在细胞自主的方式表达。这些结果表明，c-Jun的乙肝相关肿瘤的发生，促进肝细胞增殖和发育不良的发展过程中具有重要的作用。因此，针对c-Jun的可能是一个有用的策略，以防止肝炎相关肿瘤的发生。