Objective To establish a real-time monitoring mouse model for primary liver cancer (HCC) research. Methods We applied an approach for stable gene expression in mouse hepatocytes by hydrodynamic injection in combination with PiggyBac transposon system-mediated somatic gene integration. We fused an oncogene with a luciferase reporter gene for live imaging of mouse hepatocytes. Results Mouse hepatocytes integrated with a YAP1 mutant gene (YAP5SA) were used to form liver tumors with characteristics similar to the Hippo signaling pathway-inactivated HCC subclass. Live imaging of the liver showed strong a fluorescence signal from hepatocytes integrated with the oncogene and luciferase. The peak fluorescence signal decreased rapidly in the early stage after hydrodynamic injection because of hepatocyte apoptosis. The fluorescence signal was significantly increased after tumor initiation and progression. We applied this real-time monitoring model to confirm that PTEN was a HCC tumor suppressor gene by an additionally fused oncogene with shRNA expression elements. We also validated small molecular targeted drug sorafenib by oral administration. Conclusions A real-time monitoring mouse HCC model was successfully established. This method can be applied to molecular characterization of HCC subtypes and targeted drug screening.