Hypomethylation of DNA and the insulin-like growth factor-II gene in dichloroacetic and trichloroacetic acid-promoted mouse liver tumors.
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.
Tao
Lianhui
L
Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA. tao.31@osu.edu
Li
Yingzhe
Y
Kramer
Paula M
PM
Wang
Wei
W
Pereira
Michael A
MA
D044503:5-Methylcytosine / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation / Q000187:drug effects*; D003999:Dichloroacetic Acid / Q000633:toxicity*; D005260:Female; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014238:Trichloroacetic Acid / Q000633:toxicity*
D002273:Carcinogens; D012333:RNA, Messenger; D014238:Trichloroacetic Acid; D007335:Insulin-Like Growth Factor II; D008770:Methylnitrosourea; D044503:5-Methylcytosine; D004247:DNA; D003999:Dichloroacetic Acid