OncomiR Structure and Network Prediction on Adenomatosis Polyposis Coli (APC) Gene Silencing Regulation in Colorectal Cancer

Abstract

The emergence of colorectal cancer cells is associated with the inactivation of the adenomatosis polyposis coli (APC) gene which increases the activity of ß-catenin, one of which is due to oncomiRNA (cancer-inducing microRNA). miR-135a/b-5p and miR-494-3p were thought to be involved in silencing the APC gene and increasing cell proliferation and could potentially be used as anti-miR targets. However, there is a need for an in-depth evaluation of the involvement of the oncomiR as a therapeutic target in preventing the formation of CRC. Therefore, this study aimed to predict the mechanism of inhibition of oncomiR hsa-miR-135a/b, and has-miR-494-3p against APC in the Wnt/ß-catenin signaling pathway. This research was conducted through in silico analysis using a web-based application to describe the stability of the secondary structure, binding position on mRNA, and conserved nucleotides that support biological activity. The data obtained were then used to develop miRNA interaction networks with APCs on the CRC-associated Wnt/ß-catenin signaling pathway. This study suggests that miR-135a-5p, and miR-135b-5p probably evolved earlier in the evolutionary evolution of the conserved oncomiR CRC in various vertebrate species, whereas miR-494-3p is more conserved and commonly found in mammals. The biological activity of miR-494-3p is likely to be more stable and patent to bind to APC gene mRNA and trigger CRC cell proliferation. Furthermore, miR-135a/b-5p and miR-494-3p have the potential to be developed as targets for anti-miR-based transcriptomic therapy as well as for early diagnosis of CRC development. Anti-miR therapy will likely need to involve more than 1 miRNA, as each gene has more than 1 miRNA binding site. HIGHLIGHTS Important findings in this study include: Adenomatosis polyposis coli (APC) gene silencing in CRC cases correlates to oncomiR activity of miR-135a/b-3p and miR-494-3p miR-494 tends to inhibit the translation of APC mRNA more strongly than miR-135a/b-5p represented by lower context++ score in mRNA binding simulation In some cases, CRC formation was also caused by silencing activity by oncomiRs, such as miR-135a-5p, miR-135b-5p and miR-494-3p which inhibited APC gene mRNA translation This study suggests that miR-135a-5p, and miR-135b-5p likely evolved earlier in the evolution of conserved CRC development in various vertebrate species, whereas miR-494-3p is more conserved and common in mammals Based on the biological activity miR-494-3p is likely to be more stable and potent to bind to the mRNA of the APC miR-135a/b-5p and miR-494-3p is potentially developed as targets for transcriptomic anti-miR-based therapy as well as for early diagnosis of CRC development GRAPHICAL ABSTRACT