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Comparison of liver oncogenic potential among human RAS isoforms.

Authors
 Sook In Chung  ;  Hyuk Moon  ;  Hye-Lim Ju  ;  Dae Yeong Kim  ;  Kyung Joo Cho  ;  Silvia Ribback  ;  Frank Dombrowski  ;  Diego F. Calvisi  ;  Simon Weonsang Ro 
Citation
 Oncotarget, Vol.7(6) : 7354-7366, 2016 
Journal Title
 Oncotarget 
Issue Date
2016
MeSH
Animals ; Apoptosis ; Blotting, Western ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology* ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology* ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; GTP Phosphohydrolases/genetics* ; GTP Phosphohydrolases/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoenzyme Techniques ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology* ; Membrane Proteins/genetics* ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mutation/genetics* ; Protein Isoforms ; Proto-Oncogene Proteins p21(ras)/genetics* ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Keywords
KRAS splicing variant ; P16-INK4A ; RAS isoform ; hydrodynamic transfection ; liver cancer
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.
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DOI
10.18632/oncotarget.6931
Appears in Collections:
5. Research Institutes (연구소) > Liver Cirrhosis Clinical Research Center (간경변증임상연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
노원상(Ro, Simon Weonsang) ORCID logo https://orcid.org/0000-0003-2187-3698
정숙인(Chung, Sook In) ORCID logo https://orcid.org/0000-0002-7915-9203
조경주(Cho, Kyuong Joo)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146919
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