Network-based analysis of microRNAs targeting the RAS/MAPK signaling pathway in colorectal cancer

Introduction: Colorectal cancer remains one of the leading causes of cancer-related morbidity and mortality worldwide. The rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) signaling pathway plays a pivotal role in the regulation of cellular proliferation, differentiation, and survival, and its dysregulation is strongly associated with colorectal tumorigenesis. Recent studies suggest that microRNAs (miRNAs) critically influence cancer progression by targeting key components of this pathway. Objectives: This study aimed to systematically investigate dysregulated miRNAs that target the RAS/MAPK signaling pathway in colorectal cancer and identify core regulatory genes, enriched biological functions, and potential therapeutic targets using a systems biology approach. Materials and Methods: In this in silico study, differentially expressed miRNAs in colorectal cancer were identified from comprehensive literature and validated via the miRDB database (score >90). High-confidence target genes were analyzed using STRING to construct protein-protein interaction (PPI) networks. Hub genes were detected using CytoHubba in Cytoscape through multiple centrality algorithms (MNC, MCC, DMNC, Degree). Gene ontology (GO), KEGG, and transcription factor enrichment were performed using Enrichr. Promoter motif analysis was conducted via Tomtom and GOMO, and DrugBank was used to evaluate druggability of hub proteins. Results: Several hub proteins, including STAT3, JUN, PTEN, ESR1, KRAS, and HIF1A, were identified as central components of the miRNA-target network. Gene ontology and KEGG enrichment highlighted their roles in transcriptional regulation, MAPK cascade, and cell proliferation. Promoter analysis revealed key regulatory motifs, while DrugBank analysis identified several approved and investigational compounds targeting these hub proteins. Conclusion: The integration of miRNA –gene interaction analysis with network biology and drug discovery tools provided novel insights into the regulatory mechanisms underlying colorectal cancer. Hub proteins identified in this study show potential for targeted therapy and biomarker development. This study highlights critical miRNAs regulating the RAS/MAPK pathway in colorectal cancer and provides a framework for therapeutic target prioritization through integrative network analysis.