Comparison of liver oncogenic potential among human RAS isoforms

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.