Impact of the transcription factor c-Jun/AP-1 and related signaling pathways on the progression from non-alcoholic fatty liver disease to steatohepatitis and hepatocellular carcinoma

肝细胞癌（HCC）是一种常见且通常致命的癌症，通常是慢性炎症性肝脏疾病（如病毒性肝炎）的结果。然而，连接肝炎和癌症的分子途径还没有很好地定义。我们的初步研究结果表明，转录因子c-Jun/AP-1是肝炎中肝细胞存活和增殖的重要调节因子。此外，由肝病毒蛋白在内质网（ER）积累、DNA氧化损伤或致癌Wnt/-Catenin信号激活引起的肝脏应激反应是肝炎相关性HCC发病机制中的常见事件，都可能诱导c-Jun表达。因此，我们将使用肝细胞特异性敲除小鼠来解剖c-Jun及其靶基因在遗传性小鼠HCC模型中对细胞存活、增殖和肿瘤发生的作用。肝脏肿瘤可通过肝病毒蛋白的转基因表达、随后的内质网应激、氧化损伤和慢性炎症或-Catenin的遗传激活诱导。这些项目将提供对连接慢性肝炎和癌症的分子途径的见解，并可能有助于确定预防或治疗这种毁灭性恶性肿瘤的新方法。

Hepatocellular carcinoma (HCC) is a common and often fatal cancer that frequently develops as a consequence of chronic inflammatory liver diseases such as viral hepatitis. However, the molecular pathways that link hepatitis and cancer are not well defined. Our preliminary findings indicate that the transcription factor c-Jun/AP-1 is an important regulator of hepatocyte survival and proliferation in hepatitis. Moreover, hepatic stress responses induced by accumulation of hepatoviral proteins in the endoplasmic reticulum (ER), oxidative DNA damage or activation of oncogenic Wnt/-Catenin signaling are frequent events in the pathogenesis of hepatitis-associated HCC and may all induce c-Jun expression. Therefore, we will use hepatocyte-specific knock-out mice to dissect the functions of c-Jun and its target genes on cell survival, proliferation and tumorigenesis in genetic mouse HCC models. Liver tumors will be induced either by transgenic expression of hepatoviral proteins, subsequent ER stress, oxidative damage and chronic inflammation or by genetic activation of -Catenin. These projects should provide insights into the molecular pathways linking chronic hepatitis and cancer and may be helpful for identifying novel approaches to prevent or treat this devastating malignancy.