Protumorigenic role of MDM4 in human hepatocarcinogenesis.

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The tumor suppressor p53 encodes a transcription factor that is mutated in about 50% of all human tumors. Whereas the frequency of p53 mutations in HCCs is high in developing countries (>50%) due to exposure to exotoxins, it is low (<10-25%) in Western countries. We have previously demonstrated that the p53-interacting factor MDM4 is frequently upregulated in human HCCs. Thus, MDM4 dysregulation may complement for mutational inactivation of p53. On the other hand we observed a p53-independent MDM4 function, which might significantly affect the translation of targeting MDM4 into the treatment of human HCC patients. It is the aim of the project to characterize the p53-dependency of the protumorigenic MDM4 function using CRISPR/Cas9-mediated, specific knockout in vivo. Recently, the small molecule inhibitor XI-006 was described to suppress MDM4 transcription through a yet undefined mechanism. Therefore, we will focus on mechanisms resulting in upregulation of MDM4-mRNA expression in HCC by aberrant transcriptional activation and by microRNA-dependent mechanisms. Finally, we will generate a novel transposon-based chimeric MDM4 mouse model to evaluate the protumorigenic function of MDM4 in an orthotopic context and the efficacy of SJ-172550 treatment (inhibiting the p53-MDM4 interaction) in vivo. In addition, the MDM4 chimeric mice will serve as a valuable tool for in vivo analyses of p53 dysregulation in liver tumor development and its cross-talk to other protumorigenic signaling cascades frequently altered in human HCC. Our analyses may unravel relevant mechanisms underlying MDM4 dysregulation in HCC, evaluate new therapeutic approaches and their p53-dependency, which will be the basis for the further translational development of this project and may identify new predictive marker for efficiently targeting the p53 network in tumor therapy.