Dietary methyl deficiency, microRNA expression and susceptibility to liver carcinogenesis.
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BACKGROUND/AIMS: Altered expression of microRNAs is frequently detected during tumor development; however, it has not been established if variations in the expression of specific microRNAs are associated with differences in the susceptibility to tumorigenesis. METHODS: Inbred male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet, which causes liver injury that progresses to liver tumors. Differentially expressed microRNAs were identified by Paraflo microRNA microarray analysis and validated by quantitative reverse transcription PCR. RESULTS: We identified 74 significantly up- or down-regulated microRNAs, including miR-29c, miR-34a, miR-122, miR-155, miR-200b, miR-200c, and miR-221, in the livers of mice fed a methyl-deficient diet for 12 weeks as compared to their age-matched control mice. The targets for these microRNAs are known to affect cell proliferation, apoptosis, lipid metabolism, oxidative stress, DNA methylation, and inflammation. Interestingly, DBA/2J mice, which develop more extensive hepatic steatosis-specific pathomorphological changes, had a greater extent of miR-29c, miR-34a, miR-155, and miR-200b expression. CONCLUSIONS: These results demonstrate that alterations in expression of microRNAs are a prominent event during early stages of liver carcinogenesis induced by methyl deficiency. More importantly, our data link alterations in microRNA expression to the pathogenesis of liver cancer and strongly suggest that differences in the susceptibility to liver carcinogenesis may be determined by the differences in the microRNA expression response.
