Integrated Network Analysis Suggests an
miR
‐21/
MMP
/
VEGF
‐Associated Regulatory Axis in Gastri
Fatemeh Babajani, Hadi Mozafari ABSTRACT
Background, Aims
Gastric cancer (GC) pathogenesis involves complex molecular interactions that remain incompletely understood at a biological systems level. While microRNA‐21 (miR‐21), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) have been individually implicated in GC, their integrated role as a coordinated regulatory network remains uncharacterized. And we aim to reveal novel biology systems level insights into the miR‐21/MMP/VEGF regulatory axis.
Methods
In this study, 27 tumor and matched adjacent noncancerous tissues in GC patients were analyzed. Expression of miR‐21, MMP‐2/9, and VEGF was analyzed using qRT‐PCR, Western blotting, and zymography (for MMP‐2/9 activity). Computational analyses integrated KEGG pathway enrichment (clusterProfiler), random forest machine learning, structural equation modeling (lavaan), and protein–protein interaction network analysis (igraph) to decipher system‐level organization. All statistical analyses and computational modeling were performed using RStudio version 4.4.2.
Results
Pathway analysis revealed significant enrichment in cancer‐related pathways, including MicroRNAs in cancer ( p = 8.66 × 10 −10 , FDR = 2.09 × 10 −7 ). Random forest classification achieved a mean cross‐validated accuracy of 85.0% (±14.8%) in discriminating tumor from normal tissues, identifying miR‐21 as the most potent predictor. Structural equation modeling demonstrated a significant direct effect of miR‐21 on tumor size (β = 0.576, p = 0.001) and an indirect effect mediated through MMP‐9 (β = 0.194, p = 0.047). Network topology analysis confirmed miR‐21 as the central hub (degree = 5).
Conclusion
Our integrated biology systems analysis suggests that the miR‐21/MMP‐9/VEGF axis may represent a candidate regulatory network in GC, with miR‐21 appearing to play a central role in tumor progression. These findings offer preliminary insights and highlight molecules of interest for further studies for intervention in GC pathogenesis.