The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice
The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice
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DOI：
10.1038/cdd.2015.121
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发表时间：
2015-10
影响因子：
12.4
通讯作者：
C. Trierweiler;B. Hockenjos;K. Zatloukal;R. Thimme;H. Blum;E. Wagner;P. Hasselblatt
中科院分区：
文献类型：
--
作者：
C. Trierweiler;B. Hockenjos;K. Zatloukal;R. Thimme;H. Blum;E. Wagner;P. Hasselblatt
肝细胞癌是慢性炎症性肝病的结果，如慢性乙肝病毒感染。转录因子c-jun/激活蛋白1(AP-1)在炎症刺激下高表达，在急性肝炎时促进肝细胞存活，在化学诱导的小鼠肝癌变中起癌基因的作用。因此，我们的目标是研究c-jun在乙肝相关肝肿瘤发生中的作用。为此，将已建立的乙肝相关肝细胞癌模型--表达全部乙肝病毒包膜蛋白(HBV+)的转基因小鼠与在肝细胞中缺乏c-jun的基因敲除小鼠杂交，分析肿瘤的发生。在乙肝病毒阳性小鼠的肿瘤形成过程中，肝脏c-jun的表达在多个时间点被强烈诱导，而其他AP-1成分的表达保持不变。重要的是，在缺乏c-jun的乙肝病毒阳性小鼠中，癌前病变和肿瘤的形成明显减少。这种表型与肝细胞增殖受损和细胞周期抑制因子p21表达增加有关，而肝细胞存活率不受影响。乙肝病毒相关性肝癌的进展和预后与细胞因子骨桥蛋白(OPN)的表达有关，OPN是AP-1的靶基因。C-jun基因在乙肝病毒阳性小鼠肝脏和缺乏c-jun基因的原代小鼠肝细胞中的表达显著降低，表明c-jun基因以一种细胞自主的方式调节肝组织中opn基因的表达。这些发现表明，c-jun通过促进肝细胞的增殖和异型增生的进展，在乙肝相关肿瘤的发生发展过程中起着重要作用。因此，靶向c-jun可能是预防肝炎相关肿瘤发生的有效策略。
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.