Abstract:
Colorectal cancer (CRC) is the third leading cause of cancer-related mortality. The aetiology of CRC is complex and involves the interaction of genetic and environmental factors. Recently, obesity has emerged as a major environmental risk factor for CRC. However, the mechanisms underlying this relationship have not yet been fully explained. Peroxisome proliferator-activated receptor gamma (PPARγ) has a well-established central role in differentiation and function of mature adipocytes. It plays a pivotal role in adipogenesis, inflammatory response and differentiation. Furthermore, PPARγ exerts antineoplastic effects. Its activation induces apoptosis and reduces tumour development by halting cancer cell proliferation. Various changes in the activity and expression of PPARγ have been reported in obesity. Epigenetic mechanisms such as DNA methylation, and microRNAs (miRNAs) might be involved in the deregulated expression of PPARγ. In an attempt to unravel one of the mechanisms responsible for the pathogenesis of obesity and its role in CRC susceptibility, the differential expression of miRNAs 27b, 130b and 138 in case of health, obesity and CRC were analysed, the role of the deregulation of the aforementioned miRNAs in obesity and CRC on PPARγ expression were investigated, and the methylation pattern of PPARγ gene promoter and how it affected PPARγ production in obesity and CRC was studied. 70 CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included in the study. MiRNA levels were measured in serum. PPARγ promoter methylation was evaluated in blood. PPARγ level was evaluated by measuring mRNA level in blood and protein level in serum. The three tested miRNAs were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low gene expression and protein levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. No significant association was found between obesity and PPARγ promoter hypermethylation. In conclusion, the study results suggest that upregulation of microRNAs 27b, 130b and 138, as well as, promoter hypermethylation are responsible for suppressed PPARγ production in CRC patients. In addition, the study introduces obesity as the risk factor that triggers this miRNA overexpression.
