Single nucleotide polymorphism rs4648298 in miRNAs hsa-miR21 and hsa-miR590 binding site of COX gene is a strong colorectal cancer determinant

Colorectal cancer (CRC) rated as the third diagnosed malignancy and fourth most common cause of cancer mortality worldwide. In developed regions, the occurrence of CRC for men and women increases to 37.7 and 24.3 per 100,000 persons per year (1,2). However the incidence of CRC is lower in Asian than in western countries, recent studies have shown, increasing rates of CRC in Asia and especially in Iran as a developing country (3,4). Although previous reports revealed that many environmental and lifestyle factors such as high body mass index (BMI), smoking, low activity and alcohol drinking increase the risk of CRC (5,6). Albeit, from all people who are exposed to same risk factors just some of them developed CRC. It could interpret that CRC is a complex disease, influenced by genetics and environmental factors. MicroRNAs constitute a novel discovered class of small non-coding RNAs (about 22 nucleotides) that play important roles in the regulation of gene expression by binding to the 3'-untranslated regions (3'-UTR) of specific mRNAs, and leading to mRNA cleavage or translational repression. Accumulated evidences demonstrated that miRNAs are one of the key players in cell differentiation, growth, apoptosis and insulin secretion (7,8). The most frequent type of variations in the human genome is single nucleotide polymorphism (SNP) that they exist once almost in every 300 nucleotides. Several studies demonstrated that SNPs in 3'UTR of mRNA may impact microRNAs functions by influence in secondary structure of 3'UTR and thermodynamic features of hybridization site (7,9,10). These SNPs can deregulate expression of target gene by change in binding capacity of miRNAs. The association between in？ammation and tumorigenesis especially in CRC is well-established. COXs are rate-limiting enzymes that mediate the formation of prostaglandins from arachidonic acid (11,12). Two major cyclooxygenase isoforms are Cyclooxygenase-1 (COX-1) and COX-2 with 60% homology, most tissues express COX-1 at relatively low levels (13). Cyclooxygenase-2 (COX-2) is the inducible isoform that is not found in most normal tissues but can be induced by cytokines (inflammatory reactions), growth factors or tumor promoters (14-17). In overall COX-2 could be known as an acute response protein that is expressed as part of respond to inflammation (18). Overexpression of COX-2 is sufficient for carcinogenesis in animal models and blockage of the COX-2 pathway results in decrease in tumor occurrence and progression (19). COX-2 overexpression is observed in multiple cancers especially sporadic CRC