Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low 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. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.
Highlights
Triglyceride levels were significantly higher in obese subjects and obese colorectal cancer (CRC) patients as compared to lean CRC patients and healthy controls (P < 0.0001 each)
PPARγ is a transcription factor that belongs to the nuclear receptor superfamily
It is abundant in adipose tissue, gastrointestinal tract, and macrophages
Summary
Among obesity-related disorders, a direct and independent relationship has been ascertained for CRC11, 12 The mechanisms underlying this relationship have not yet been fully explained[13]. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor abundant in adipose tissue. It has a central role in differentiation and function of mature adipocytes[14]. Epigenetic events, including microRNA (miRNA) expression and DNA methylation, might be involved in the deregulated expression of PPARγ19. This could be explained on the basis that miRNAs are involved in post-transcriptional gene silencing through imperfect hybridization to 3′ untranslated region (3′-UTR) in target mRNAs20. Blood-derived DNA methylation alterations may be useful in understanding how this epigenetic alteration may contribute fundamentally to carcinogenesis[30]
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