Comparison of liver oncogenic potential among human RAS isoforms
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Sook In Chung1, Hyuk Moon1, Hye-Lim Ju2, Dae Yeong Kim1, Kyung Joo Cho1, Silvia Ribback3, Frank Dombrowski3, Diego F. Calvisi3, Simon Weonsang Ro1,2
1Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
2Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, Korea
3Institute of Pathology, University Medicine Greifswald, Greifswald, Germany
Simon Weonsang Ro, e-mail: [email protected]
Keywords: RAS isoform, liver cancer, hydrodynamic transfection, KRAS splicing variant, P16-INK4A
Received: July 07, 2015 Accepted: January 07, 2016 Published: January 18, 2016
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.
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