Comparison of liver oncogenic potential among human RAS isoforms

Abstract

Mutation in one of three RAS genes (i.e., HRAS, KRAS, and NRAS) leading to constitutive activation of RAS signaling pathways is considered a key oncogenic event in human carcinogenesis. Whether activated RAS isoforms possess different oncogenic potentials remains an unresolved question. Here, we compared oncogenic properties among RAS isoforms using liver-specific transgenesis in mice. Hydrodynamic transfection was performed using transposons expressing short hairpin RNA downregulating p53 and an activated RAS isoform, and livers were harvested at 23 days after gene delivery. No differences were found in the hepatocarcinogenic potential among RAS isoforms, as determined by both gross examination of livers and liver weight per body weight ratio (LW/BW) of mice expressing HRAS^Q61L, KRAS4B^G12V and NRAS^Q61K. However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4A^G12V mice was significantly lower than in KRAS4B^G12V mice (p < 0.001), and KRAS4A^G12V mice lived significantly longer than KRRAS4B^G12V mice (p < 0.0001). Notably, tumors from KRAS4A^G12V mice displayed higher expression of the p16^INK4A tumor suppressor when compared with KRAS4B^G12V tumors. Forced overexpression of p16^INK4A significantly reduced tumor growth in KRAS4B^G12V mice, suggesting that upregulation of p16^INK4A by KRAS4A^G12V presumably delays tumor development driven by the latter oncogene.