Dietary Methyl Deficiency, microRNA Expression and Susceptibility to Liver Carcinogenesis

Abstract

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 μParaflo 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.

Maternal folate depletion and high‐fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring

“…In addition, it may be informative to investigate gene‐specific 5hmC and 5mC levels and to broaden the enquiry to include other epigenetic marks and post‐translational modifications. For example, folate deficiency and high‐fat diets have been shown to affect histone modification (53, 54) and microRNA (55, 56), but, to our knowledge, this has not been investigated in relation DNA repair.…”

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

“…The cells were cultured for 21 days in RPMI-1640 medium with modified FA concentrations as follows: FA-free (0 nM), FA-deficient (22.6 nM), or control (2,260 nM). The human HL-7702 and QGY-7703 cell lines were selected because folate deficiency has been identified as an important risk factor for HCC, and alterations in the expression of miRNAs have been shown to be prominent events during the early stages of liver carcinogenesis [32]. Su YH et al [33] showed that a folate-deficient tumor microenvironment promoted epithelial-to-mesenchymal transition in hepatocytes.…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…According to the results of this study, the expression of 164 genes was significantly altered in the liver of treated animals, and an inverse relationship was found between the level of gene expression and the pattern of CpG island methylation. Most importantly, differential methylation was observed for the genes involved with DNA damage repair processes, the lipid and glucose metabolism and liver remodelling (Starlard-Davenport et al, 2011). These findings therefore imply that the negative effects of a low dietary folate deprivation may be mostly pronounced in the liver, possibly affecting the genome stability of this tissue.…”

“…The authors compared the genome-wide pattern of DNA methylation of CpG islands and gene expression in liver samples taken from patients suffering from the non-alcoholic steatohepatitis (fatty liver) disease to those caused by a methyl deficient diet in mice (Starlard-Davenport et al, 2011). According to the results of this study, the expression of 164 genes was significantly altered in the liver of treated animals, and an inverse relationship was found between the level of gene expression and the pattern of CpG island methylation.…”

“…It is worth mentioning that the expression of the Ahcy gene in the liver of treated mice was found to be severely down-regulated (Starlard-Davenport et al, 2011). This gene encodes for the SAHH enzyme involved in the hydrolysis of SAH to homocysteine and adenosine (Bailey & Gregory, 1999).…”