Integrated omics and virtual screening predict Tabularin as a dual inhibitor of the prognostic microRNAs mir-19a and mir-32 in colorectal cancer.

Colorectal cancer (CRC) progression is driven by alterations in gene expression and post-transcriptional regulation. We conducted an integrative omics study using differential gene and miRNA expression analysis, survival profiling, miRNA-target interactions, pathway enrichment, and network topology analysis. We observed that some miRNAs and genes are uniquely dysregulated in different CRC stages, while others are expressed across all stages. We found 8, 3, 5, and 6 miRNAs and 342, 137, 102, and 350 genes are exclusively expressed in stages I-IV, respectively, indicating their roles as molecular drivers in CRC progression. We also identified 16 prognostic miRNAs and 287 gene signatures along with the enriched pathways that influence CRC prognosis across its stages. Among the 16 survival-associated miRNAs, hsa-mir-19a and hsa-mir-32 emerged as critical prognostic miRNAs, targeting several hub genes involved in apoptosis, epithelial-mesenchymal transition, immunological signaling, and cellular stress responses. These predicted miRNAs are likely associated with the crucial tumor-suppressive pathways, thereby reducing patient survival in CRC. Subsequently, our structure-based RNA-ligand docking, TD-DFT, and molecular dynamics (MD) simulation study predicted Tabularin, a phytocompound, as a dual inhibitor of these miRNAs, showing efficient binding affinity at their Dicer binding sites. This indicates that Tabularin may inhibit Dicer-mediated processing and suppress the maturation of these two prognostic miRNAs, thereby improving patient survival. In summary, this study identified stage-specific miRNAs and genes that could serve as potential biomarkers for stage-dependent diagnosis, and predicted mir-19a and mir-32 as key regulators of CRC prognosis through modulation of hub genes, which Tabularin can target to improve survival outcome in CRC.