title: 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 HRASQ61L, KRAS4BG12V and NRASQ61K. However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4AG12V mice was significantly lower than in KRAS4BG12V mice (p < 0.001), and KRAS4AG12V mice lived significantly longer than KRRAS4BG12V mice (p < 0.0001). Notably, tumors from KRAS4AG12V mice displayed higher expression of the p16INK4A tumor suppressor when compared with KRAS4BG12V tumors. Forced overexpression of p16INK4A significantly reduced tumor growth in KRAS4BG12V mice, suggesting that upregulation of p16INK4A by KRAS4AG12V presumably delays tumor development driven by the latter oncogene.
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sook In
authors.initials: SI
authors.lastname: Chung
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Moon
authors.affiliation: Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Ju
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dae Yeong
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung Joo
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Simon Weonsang
authors.initials: SW
authors.lastname: Ro
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D020033:Protein Isoforms; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D008565:Membrane Proteins; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS splicing variant; P16-INK4A; RAS isoform; hydrodynamic transfection; liver cancer