Yi-Jen Liao, Shih-Ping Liu and Cheng-Ming Lee contributed equally to this work.
Cancer Cell Biology
Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility
Article first published online: 9 SEP 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 4, pages 816–826, 15 February 2009
How to Cite
Liao, Y.-J., Liu, S.-P., Lee, C.-M., Yen, C.-H., Chuang, P.-C., Chen, C.-Y., Tsai, T.-F., Huang, S.-F., Lee, Y.-H. W. and Chen, Y.-M. A. (2009), Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility. Int. J. Cancer, 124: 816–826. doi: 10.1002/ijc.23979
- Issue published online: 11 DEC 2008
- Article first published online: 9 SEP 2008
- Accepted manuscript online: 9 SEP 2008 12:00AM EST
- Manuscript Accepted: 19 AUG 2008
- Manuscript Received: 22 MAY 2008
- National Science Council of the Republic of China [National Research Program on Genomic Medicine (NRPGM)]. Grant Number: NSC96-3112-B-010-003
- Ministry of Education of the Republic of China [Genomic Research Center of the National Yang-Ming University, Top University and Center Grant]
- National Research Program for Genomic Medicine
- National Science Council, Taiwan, ROC
- National Mouse Mutagenesis Program Core in National Yang-Ming University, Taiwan, ROC
- hepatocellular carcinoma;
- Wnt signaling;
- MAPK pathway;
- gender difference
Hepatocellular carcinoma (HCC) is the fifth common cancer in the world and it mainly occurs in men. Glycine N-methyltransferase (GNMT) participates in one-carbon metabolism and affects DNA methylation by regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine. Previously, we described that the expression of GNMT was diminished in human HCC. Here, we showed that 50% (3/6) male and 100% (7/7) female Gnmt−/− mice developed HCC, and their mean ages of HCC development were 17 and 16.5 months, respectively. In addition, 42.9% (3/7) of female Gnmt−/− mice had hemangioma. Wnt reporter assay demonstrated that Gnmt is a negative regulator for canonical Wnt signaling pathway. Beta-catenin, cyclin D1 and c-Myc, genes related to Wnt pathway, were upregulated in the liver tissues from both 11 weeks and HCC stage of Gnmt−/− mice. Furthermore, global DNA hypomethylation and aberrant expression of DNA methyltransferases 1 and 3b were found in the early and late stages of HCC development. Hierarchical cluster analysis of 6,023 transcripts from microarray data found that gene expression patterns of HCC tumors from male and female Gnmt−/− mice were distinctively different. Real-time PCR confirmed that Gadd45a, Pak1, Mapk3 and Dsup3 genes of mitogen-activated protein kinase (MAPK) pathway were activated in Gnmt−/− mice, especially in the female mice. Therefore, GNMT is a tumor suppressor gene for liver cancer, and it is associated with gender disparity in liver cancer susceptibility. © 2008 Wiley-Liss, Inc.