We use cookies on our website. Some are necessary for the operation of the website. You can also allow cookies for statistical purposes. You can adjust the data protection settings or agree to all cookies directly.
Data Protection Declaration
Imprint
Epigenetic regulation of cancer-relevant pathways in colon intestinal epithelial cells by microRNAs depending on the folate supply
Project
Project code: BfR-LMS-08-1322-592
Contract period: 01.03.2014
- 31.12.2015
Purpose of research: Applied research
An inverse association between folate status and the development of colorectal cancer in several epidemiological studies have found. Contrary, a tumor-promoting effect has as been shown in intervention studies using 800 micrograms of folic acid a day. These effect could also be confirmed in animal experiments. These findings are discussed in Germany in the context of the UL for folate of 1 mg per day as well as related to the increasing number of folic acid - fortified foods. The influence of folate - dependent C1 metabolism at the carcinogenic risk is clearly shown for folate deficiency. However, the methyl group donor folic acid also contributes to the methylation of the promoters of genes coding tumour suppressing proteins. Furthermore, there is evidence from a human intervention study that folic acid supplementation of 1 mg per day upregulates immune and inflammatory parameters in subjects.This may contribute to carcinogenetic processes. Cancer cells have to coordinate at least three basic needs. The maintenance of a high energy state, an increased synthesis of macromolecules as well as maintaining an appropriate redox status. Besides the cancer associated programmes cancer cells often display fundamental changes in pathway’s of energy metabolism and nutrient uptake. The coordination of growth with the corresponding metabolic needs is organized by a modified expression of regulatory micro-RNAs (Hatziapostolou et al. 2013). These modifications may be influenced by the availability of nutrients (Garcia- Segura et al. 2013). Especially, this should be true in the case of the C1 donor folic acid. Today, very few studies exist that examine the influence of nutrients on the micro - RNA expression of cancer cells. However, under folate deficiency micro RNA’s are deregulated. Half of them are deregulated in colon cancer cells too. Whether supraphysiological folate concentrations influence the expression of oncomiR 's and anti- oncomiR 's or not, remains to be elucidated. In this project, the mikro RNA expression in the following pathways should be analysed related to the folate state: WNT/ beta- catenin pathway, EMT and C1 metabolism.
Results:
The main result of the present study is the significant down-regulation of the micro-RNA hsa-miR-146a in HT29 colon carcinom cells by folic acid, which results in an up-regulation of the chemokine receptor CXCR4. This down-regulation occurs only in the HT29 cell line and not in the non-malignant HCEC-cell line. Usually, the activation of the CXCR4 signal cascade by the stromal derived factor 1 (SDF1 or CXCL12) triggers the migration ability of cells and the angiogenesis. The hsa-miR-146a regulates additional genes, which are relevant for tumor promotion (EGFR, KLF4 and UHRF1) and inflammation (FAS, TRAF6, IRAK 1 and 2) and it’s down-regulation should have tumorpromoting overall effects. The identified influence of folic acid of this key regulator of inflammation and carcinogenesis agree very well with data from human studies, which found a deregulation of inflammatory and immunological parameters by folic acid supplementation in colon tissues and blood plasma. However, the mode of action of folic acid on the regulation of the micro RNA is unknown. Additionally, it remains to elucidate, whether the down-regulation of hsa-miR-146a in HT29 colon carcinom cells by folic acid really results in an increasing migratory ability of the cells.
Section overview
Subjects
- Physiology of Nutrition
- Toxicology
