c-Myc-driven Hepatocarcinogenesis

Background/Aim: Dysregulation of the c-Myc gene is frequently found in human hepatocellular carcinoma (HCC), often accompanied by genetic and epigenetic alterations in other cancer-related genes. Here, we investigated the tumorigenic potential of c-Myc in diverse genetic environments in which the Ras, Wnt/β-catenin, Sonic hedgehog, or P53 pathways were either activated or inactivated. Materials and Methods: Hydrodynamic tail vein injection was employed to administer expression transposons and generate transgenic livers expressing c-Myc together with a constitutively active form of RAS (HRAS^G12V), β-catenin (β-catenin^S33Y), Smo (SmoM2), or short hairpin RNA targeting P53 (shp53). Results: c-Myc was most tumorigenic when the RAS signaling pathway was activated, whereas no tumors were found in mice when either β-catenin^S33Y or SmoM2 was co-expressed with c-Myc. Approximately 40% of mice had HCC when c-Myc was over-expressed under P53 inactivation. Furthermore, we investigated the effect of mutation in c-Myc on hepatocarcinogenesis. Conclusion: No significant differences in tumorigenic potential were found between wild type c-Myc and c-Myc^T58A, minimizing the role of the mutation in hepatocarcinogenesis.