Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice.
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1 and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4 . In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer.
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC.
Grace
G
Chappell
Kristy
K
Kutanzi
Takeki
T
Uehara
Volodymyr
V
Tryndyak
Hue-Hua
HH
Hong
Mark
M
Hoenerhoff
Frederick A
FA
Beland
Ivan
I
Rusyn
Igor P
IP
Pogribny
D000818:Animals; D002251:Carbon Tetrachloride; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D042822:Genomic Instability / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020086:Short Interspersed Nucleotide Elements / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis; D051176:beta Catenin / Q000235:genetics
C495267:CTNNB1 protein, mouse; D002843:Chromatin; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones; C496488:Hnf1a protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D004052:Diethylnitrosamine; D002251:Carbon Tetrachloride; D011495:Histone-Lysine N-Methyltransferase; C489242:Prdm2 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
DNA methylation; epigenetics; genetics; histone lysine methylation; liver carcinogenesis; mouse