Unravelling colorectal cancer mechanisms: Insights from a regulatory network of ncRNAs, TFs, and mutated genes

Abstract

Colorectal cancer (CRC) presents a significant challenge due to its complexity and high mortality rates, yet the precise molecular drivers remain elusive. Non-coding RNAs (ncRNAs), known for their roles in various cancers including CRC, are implicated in these intricate mechanisms. This study aimed to elucidate key regulators by constructing a regulatory network integrating CRC patient-mutated genes with transcription factors (TFs) and ncRNAs. Utilizing Onco-DB and COSMIC, we detected overexpressed genes and analyzed their mutational profiles, constructing a curated interactome network. Topological analysis identified the top ten hub genes, with five (CDK1, MYC, TOP2A, CCNA2, BRCA1) implicated in the gene regulatory network (GRN). These genes, characterized by high mutation rates, play pivotal roles in CRC tumour formation via mechanisms like gene amplification, cancer progression, proliferation, and migration. Additionally, potential TFs (SP1, E2F1, ESR1, MYC, E2F3) and miRNAs (hsa-miR-16-5p, hsa-miR-186-5p, hsa-miR-29b-3p) were identified, as a regulatory element. Additionally, the construction of the ceRNA network revealed that the 7 circRNA and 3 lncRNA collectively sponged the same miRNA “hsa-miR-16-5p”, ultimately affecting the expression of targeted mRNA BRCA1 and CDK1. This comprehensive approach sheds light on the molecular mechanisms of regulatory elements underlying CRC development, offering insights for clinical diagnosis and innovative treatment strategies.