Basic, Research : The Difference of Ras Isoform in Liver Cancer

Background/Aims: Activation of Ras proteins is a key oncogenic event in human carcinogenesis. Mutations affecting the three prototype Ras oncoproteins, Hras, Nras and Kras, show a high degree of tumor-type specificity. Kras and Nras are mutated in liver cancer, but mutations in Hras are rare. In this study, we have used the different Ras isoforms to determine whether they have different tumorigenic potentials in the liver. Methods: Transgenic liver cancer mouse models expressing different Ras isoforms were developed using a hydrodynamic injection method and the Sleeping Beauty Transposon System. Transposon vectors, each encoding an oncogene (HrasG12V, KrasG12V, NrasG12V) or downregulating a tumor suppressor gene (shp53), were constructed. To induce liver cancer, 40 μg of the three plasmids, encoding the sleeping beauty transposase and two transposons, was diluted in 2.5 mL of 0.9% saline and injected into the lateral tail veins of 6week-old C57BL/6 mice. Mice were observed at 23 days post-hydrodynamic injection or near to death. Results: Coexpression of H-, K-, N-RasG12V and shp53 resulted in a massive abdomen enlargement within 4 weeks after injection. Several nodular lesions emerged from the liver parenchyma, finally occupying most of the liver surface in 23 days after injection. The ratio of liver/ body weight in Kras- G12V group increased significantly compared to the Hras- G12V (P=0.0005) or NrasG12V group(p=0.0181) individually. Although the ratio of NrasG12V group showed a mild increase compared to the HrasG12V group, but statistically it was not significant (P=0.3819). Survival curve of these groups corresponded to the ratio of liver/body weight. All mice became moribund by 36 days. Conclusion: Coexpression of RasG12V and shp53 in the mouse liver promotes rapid hepatocarcinogenesis. In particular, we found that Kras was the most oncogenic in the liver among the Ras isoforms when co-expressed with shp53.