Aflatoxin-B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock-in) mice.
Hepatocellular carcinoma (HCC) is a common human malignancy that is often associated with risk factors such as aflatoxin-B1 (AFB1) exposure and Hepatitis-B virus infection in developing countries. There is a strong correlation between these risk factors and mutation of the tumor-suppressor gene p53 at codon 249. In vitro experiments have also shown that treatment of human liver cells with AFB1 results in p53 mutations. A tumor-promoting role for mutant p53 was demonstrated using transgenic mice models, in which HCC development was accelerated upon AFB1-exposure. However, wild-type mice in which AFB1 alone was used to induce liver cancers have failed to recapitulate p53 mutations, raising the possibility that mouse DNA context may not be appropriate for the generation of AFB1-induced p53 mutations. We have now tested this hypothesis using the Hupki mice (human p53 knock-in) in which the mouse DNA-binding domain has been replaced by the homologous human p53 segment. Mice were followed for 80 weeks after AFB1 injection for survival and HCC formation. Hupki mice were found to be more susceptible to AFB1 than wild-type mice. Moreover, only 19% of wild-type mice developed HCCs compared to 44% in Hupki mice. However, none of the liver tumors and normal tissues from Hupki mice contained any mutations in the DNA-binding domain of p53. These findings suggest that the human DNA context of the p53 gene alone may not be the sole determinant of AFB1-induced mutagenesis. Furthermore, humanized p53 appears not to be as effective as murine p53 in the mouse cellular environment in preventing malignant transformation.
International Agency for Research on Cancer, 69008 Lyon, France.
Wei-Min
WM
Tong
Ming-Kei
MK
Lee
Dominique
D
Galendo
Zhao-Qi
ZQ
Wang
Kanaga
K
Sabapathy
D016604:Aflatoxin B1 / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D018076:DNA, Complementary; D016159:Tumor Suppressor Protein p53; D016604:Aflatoxin B1