Network toxicology-based analysis and multi-dimensional validation of TP53 as a critical biomarker in nitrosamine-induced gastric cancer

Abstract

This study applied network toxicology to dissect molecular regulatory networks of nitrosamine-induced gastric cancer, providing theoretical support for exploring its pathogenesis and targeted therapies. Nitrosamine SMILES were retrieved from PubChem for ProTox-3.0 toxicity prediction. Compound targets from STITCH and gastric-cancer targets from GeneCards, OMIM and TTD were intersected for GO/KEGG enrichment. PPI and compound-target-disease networks were built; hub genes were screened by CytoHubba. Multi-dimensional bioinformatic validations including expression, clinical correlation, diagnosis, survival, subcellular localization, immune infiltration and mutation landscape were conducted for key targets. Twenty-one intersecting targets were obtained. Network analysis revealed TP53, GSTM1 and KRAS as core nodes, and TP53 was identified as the primary hub gene in this network. Experiments demonstrated significantly elevated TP53 expression in gastric cancer tissues. High TP53 expression existed across diverse clinical subgroups. Its diagnostic AUC reached 0.819, and high-expression patients showed better survival. TP53 localized in nucleus and cytoplasm. Its expression positively correlated with Th2 cell infiltration, and immune cell proportions differed greatly between high- and low-expression groups. ARID1A exhibited the highest co-mutation frequency with TP53 among top 15 mutated genes. Nitrosamines facilitate gastric tumorigenesis mainly through core target TP53 by regulating DNA adduct formation, platinum drug resistance, Ras signaling and oxidoreductase activity. TP53 serves as a promising therapeutic biomarker for gastric cancer. Limitations of this work should be noted: all findings are derived from bioinformatic mining of public datasets; further cellular and animal experiments are essential to validate the causal link between nitrosamine exposure and TP53 dysregulation.