New MicroRNAs Candidates to Treat Human Colorectal Cancer; Molecular Dynamic Simulations Found a Major Down-Regulator of CLCA4 Tumor Suppressor Gene

Abstract IntroductionColorectal cancer (CRC) is one of the most common malignancies worldwide. The expression of CLCA4, a tumor suppressor gene, decreases significantly in cancer cells of CRC. In this study, we identified miRNAs target the mRNA of the CLCA4 gene. ObjectiveThe aim of this study was the identification of miRNAs involved in CRC.Material and methodsWe predicted miRNA(s) that target CLCA4 mRNA applying TargetScan v.7. Then through analysis of Gene Expression Omnibus (GEO) datasets, among them, miRNA(s) over-expressed in CRC cells were determined. To identify miRNAs with the highest potential to down-regulate CLCA4 through binding, we calculated the binding free energies of the candidate miRNA- mRNA complexes using the molecular mechanics energies combined with several solvation models: The Poisson–Boltzmann (MM/PBSA), the generalized Born (MM/GBSA), and the three-dimensional reference interaction site model with Kovalenko–Hirata closure relation (3D-RISM-KH). ResultsOur TargetScan analysis predicted that 106 miRNAs could bind to CLCA4 3' UTR mRNA. Hsa-miR-934, hsa-miR-574-5p, hsa-miR-377-3p, hsa-miR-5580-3p, hsa-miR-4775, hsa-miR-590-3p and hsa-miR-501-5p showed increased expression in CRC samples compared to normal cells. MD results found the lowest free energy changes in three hsa-miR-377-3p, hsa-miR-574-5p and hsa-miR-501-5p miRNAs. ConclusionThis research beside introducing a new fast and low cost plan to find best candidate of miRNAs to bind their targets, suggested miR-501-5p as a biomarker for early diagnosis of CRC. As well, preventing of down regulation of the CLCA4 expression through interrupting in the expression of miR-574-5p and miR-377-3p and more effectively miR-501-5p probably treat or slow down the development of colorectal cancer.