Hypomethylation of DNA and the insulin-like growth factor-II gene in dichloroacetic and trichloroacetic acid-promoted mouse liver tumors

• Published in: Toxicology (Amsterdam) 2004-03, Vol.196 (1), p.127-136
• Main Authors: Tao, Lianhui, Li, Yingzhe, Kramer, Paula M, Wang, Wei, Pereira, Michael A
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - chemistry; 5-Methylcytosine - metabolism; Animals; Biological and medical sciences; Carcinogens - toxicity; CpG Islands - drug effects; CpG Islands - genetics; Dichloroacetic acid; Dichloroacetic Acid - toxicity; DNA - chemistry; DNA hypomethylation; DNA Methylation - drug effects; Female; Immunohistochemistry; Insulin-Like Growth Factor II - genetics; Insulin-like growth factor-II gene; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Medical sciences; Methylnitrosourea - toxicity; Mice; Mice, Inbred Strains; Mouse liver tumors; mRNA expression; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Toxicology; Trichloroacetic acid; Trichloroacetic Acid - toxicity
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2003.11.011

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver carcinogens. DNA hypomethylation is a common molecular event in cancer that is induced by DCA and TCA. Hypomethylation of DNA and the insulin-like growth factor-II (IGF-II) gene was determined in DCA- and TCA-promoted liver tumors. Mouse liver tumors were initiated by N-methyl- N-nitrosourea and promoted by either DCA or TCA. By dot–blot analysis using an antibody for 5-methylcytosine, the DNA in DCA- and TCA-promoted tumors was demonstrated to be hypomethylated. The methylation status of 28 CpG sites in the differentially methylated region-2 (DMR-2) of mouse IGF-II gene was determined. In liver, 79.3±1.7% of the sites were methylated, while in DCA- and TCA-treated mice, only 46.4±2.1% and 58.0±1.7% of them were methylated and 8.7±2.6% and 10.7±7.4% were methylated in tumors. The decreased methylation found in liver from mice exposed to DCA or TCA occurred only in the upstream region of DMR-2, while in tumors it occurred throughout the probed region. mRNA expression of the IGF-II gene was increased in DCA- and TCA-promoted liver tumors but not in non-involved liver from DCA- and TCA-exposed mice. The results support the hypothesis that DNA hypomethylation is involved in the mechanism for the tumorigenicity of DCA and TCA.