Journal
ONCOTARGET
Volume 8, Issue 11, Pages 18213-18226Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15313
Keywords
aflatoxin B1; hepatocellular carcinoma; p53 codon 249 mutations; AFB1-8,9-epoxide-deoxyguanosine; cyclic alpha-methyl-gamma-hydroxy-1,N-2-propano-dG
Categories
Funding
- National Institutes of Health [R01CA190678, 1P01CA165980, ES00260]
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Aflatoxin B1 (AFB1) contamination in the food chain is a major cause of hepatocellular carcinoma (HCC). More than 60% of AFB1 related HCC carry p53 codon 249 mutations but the causal mechanism remains unclear. We found that 1) AFB1 induces two types of DNA adducts in human hepatocytes, AFB1-8,9-epoxide-deoxyguanosine (AFB1-E-dG) induced by AFB1-E and cyclic alpha-methyl-.-hydroxy-1, N-2-propano-dG (meth-OH-PdG) induced by lipid peroxidation generated acetaldehyde (Acet) and crotonaldehyde (Cro); 2) the level of meth-OH-PdG is > 30 fold higher than the level of AFB1-E-dG; 3) AFB1, Acet, and Cro, but not AFB1-E, preferentially induce DNA damage at codon 249; 4) methylation at -CpG-sites enhances meth-OH-PdG formation at codon 249; and 5) repair of meth-OH-PdG at codon 249 is poor. AFB1, Acet, and Cro can also inhibit DNA repair and enhance hepatocyte mutational sensitivity. We propose that AFB1-induced lipid peroxidation generated aldehydes contribute greatly to hepatocarcinogenesis and that sequence specificity of meth-OHPdG formation and repair shape the codon 249 mutational hotspot.
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