Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility.
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.
Liao
Yi-Jen
YJ
Molecular Medicine Program, Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Liu
Shih-Ping
SP
Lee
Cheng-Ming
CM
Yen
Chia-Hung
CH
Chuang
Pei-Chun
PC
Chen
Chia-Yen
CY
Tsai
Ting-Fen
TF
Huang
Shiu-Feng
SF
Lee
Yan-Hwa Wu
YH
Chen
Yi-Ming Arthur
YM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics; D019175:DNA Methylation; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D050938:Glycine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D012737:Sex Factors; D051153:Wnt Proteins / Q000378:metabolism
D051153:Wnt Proteins; D050938:Glycine N-Methyltransferase