Deciphering the structural dynamics of Argonaute (AGO)-mediated gene silencing of miR-21-5p, miR-221-3p, miR-126-3p, miR-34a-5p and their role as potential biomarkers in lung cancer.

Abstract

Lung Cancer is the leading cause of cancer-related deaths worldwide, with over 85% of the cases being of non-small cell lung cancer. Despite the recent advances, lung cancer remains undiagnosed until after the disease has advanced. The role of miRNAs in gene silencing is driven by RNA-induced silencing complex (RISC) consisting of Argonaute (AGO) protein. Understanding the miRNA-assisted gene regulation in lung cancer poses a prospect for an improved diagnostic and preventive measure towards the disease. This study explores miRNA interactions and their target genes in lung cancer, identifying four key miRNAs: miR-21-5p, miR-221-3p, miR-126-3p, and miR-34a-5p. These were shortlisted through their minimum free energy score, pattern conservation, functional, and network analysis. The AGO protein was retrieved, prepared for docking analysis with miRNA-mRNA duplexes, and docked using the HDOCK webserver. The docking results pointed towards the strong binding affinity of the miRNAs towards their targets and the AGO protein playing a crucial role as a driving force for gene expression. Furthermore, the miRNAs were established for their clinical relevance, particularly noting the association of high miR-21-5p expression with poor overall survival, suggesting potential avenues for further molecular investigation in lung cancer development.