Activating β‐catenin Mutations And AKT Synergize To Promote Lipogenic Liver Tumors In Mice

Abstract

AKT/mTOR and Wnt/β‐catenin cascades are frequently deregulated in human tumors. Here, we establish a novel mouse model by co‐expression of active form of AKT (myr‐AKT) and β‐catenin mutants (S33Y, S45Y) in mouse liver using the sleeping beauty transposon/transposase delivered via hydrodynamic tail vein injection. The mice showed large liver tumors at 14‐15 weeks post injection for the AKT/S45Y‐β‐catenin group, and 16 weeks for the AKT/S33Y‐β‐catenin group. All tumors displayed notable lipid accumulation in hepatocytes. Activation of downstream target genes of Akt and β‐catenin were found in both models and included Raptor, Rictor, mitochondrial related genes PKM2 and Myc, Hippo/Yap/TAZ and Glutamine synthetase. To demonstrate their relative contribution in the HCC model, we sub‐cloned shRNA against various downstream targets and co‐delivered with AKT and β‐catenin mutants by hydrodynamic tail vein injection. Suppression of key target genes notably affected tumorigenesis in this model revealing their unique and specific biological functions. Thus, while differences in β‐catenin mutations can lead to differing extents of β‐catenin activation, b‐catenin does cooperate with AKT to induce HCC with lipogenic phenotype. Also several downstream targets of AKT/mTOR and β‐catenin pathways play key roles in HCC development.