Higher susceptibility to aflatoxin B1-related hepatocellular carcinoma in glycine N-methyltransferase knockout mice

Shih Ping Liu, Ying Shiuan Li, Cheng Ming Lee, Chia Hung Yen, Yi Jen Liao, Shiu Feng Huang, Chau Heng Chien, Yi Ming Arthur Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B1 (AFB 1) and reduces both AFB1-DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt-/-) mice developed HCC, with first dysplastic hepatocellular nodules detected at mean ages of 17 and 16.5 months, respectively. In our study, we tested our hypothesis that male and female Gnmt-/- mice are susceptible to AFB1 carcinogenesis, and that the absence of Gnmt expression may accelerate AFB1-induced liver tumorigenesis. We inoculated Gnmt-/- and wild-type mice intraperitoneally with AFB1 at 7 days and 9 weeks of age and periodically examined them using ultrasound. Dysplastic hepatocellular nodules were detected in six of eight males and five of five females at 12.7 and 12 months of ages, respectively. Dysplastic hepatocellular nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt-/- mice were diagnosed as having HCC, ∼6 months earlier than AFB1-treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were downregulated in AFB1-treated Gnmt-/- mice: Cyp1a2, Cyp3a44, Cyp2d22, Gsta4 and Abca8a. In summary, we observed overall higher susceptibility to AFB1-related HCC in Gnmt-/- mice, further evidence that GNMT overexpression is an important contributing factor to liver cancer resistance.

Original languageEnglish
Pages (from-to)511-523
Number of pages13
JournalInternational Journal of Cancer
Volume128
Issue number3
DOIs
Publication statusPublished - Feb 1 2011
Externally publishedYes

Keywords

  • aflatoxin B
  • detoxification
  • gender disparity
  • gene knockout mice
  • GNMT
  • hepatocarcinogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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