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

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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.