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Introduction: Esophageal Cancer (EC) ranks among the most common malignancies worldwide. Most EC patients acquire drug resistance to chemotherapy either intrinsically or acquired after T-DM1 treatment, which shows that increasing or decreasing the expression of particular genes might influence chemotherapeutic sensitivity or resistance. Therefore, gaining a deeper understanding of the altered expression of genes involved in EC drug resistance and developing new therapeutic methods are essential targets for continued advancement in EC therapy. Methods: The present study aimed to find critical regulatory genes/pathways in the progression of T-DM1 resistance in OE-19 EC cells. Expression datasets were extracted from GEO omnibus. Gene interactions were analyzed, and the protein-protein interaction network was drawn. Then, enrichment analysis of the hub genes and network cluster analysis of the hub genes was performed. Finally, the genes were screened in the DrugBank database as therapeutic targets and molecular docking analysis was done on the selected targets. Results: In the current study, nine hub genes were identified in TDM-1-resistant EC cells (CTGF, CDH17, THBS1, CXCL8, NRP1, ITGB5, EDN1, FAT1, and PTGS2). The KEGG analysis highlighted the IL-17 signaling pathway and ECM-receptor interaction pathway as the most critical pathways; cluster analysis also showed the significance of these pathways. Therefore, the genes involved in these two pathways, including CXCL8, FSCN1, PTGS2, SERPINE2, LEF1, THBS1, CCN2, TAGLN, CDH11, and ITGA6, were searched in DrugBank as therapeutic targets. The DrugBank analysis suggests a potential role for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in reducing T-DM1 drug resistance in EC. The docking results revealed that NSAIDs, including Diclofenac, Mefenamic acid, Celecoxib, Naproxen, and Etoricoxib, significantly suppress resistant cancer cells. Conclusion: This comprehensive bioinformatics analysis deeply explains the molecular mechanisms governing TDM-1 resistance in EC. The identified hub genes and their associated pathways offer potential targets for therapeutic interventions. Moreover, the possible role of NSAIDs in mitigating T-DM1 resistance presents an intriguing avenue for further investigation. This research contributes significantly to the field and establishes a basis for further research to enhance treatment efficacy for EC patients.
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OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies worldwide and it is considered the fourth most common cause of cancer death. This study aimed to find critical genes/pathways in GC pathogenesis to be used as biomarkers or therapeutic targets. METHODS: Differentially expressed genes were explored between human gastric cancerous and noncancerous tissues, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment analyses were done. Hub genes were identified based on the protein-protein interaction network constructed in the STRING database with Cytoscape software. The hub genes were selected for further investigation using GEPIA2 and DrugBank databases. RESULTS: Ten overexpressed hub genes in GC were identified in the current study, including FN1, TP53, IL-6, CXCL5, ELN, ADAMTS2, WISP1, MMP2, CTGF, and THBS1. The study demonstrated the PI3K-Akt pathway's central involvement in GC, with pronounced alterations in essential components. Survival analysis revealed significant correlations between CTGF, FN1, IL-6, THBS1, and WISP1 overexpression and reduced overall survival times in GC patients. CONCLUSION: A mutual interplay emerged, where PI3K-Akt signaling could upregulate certain genes, forming feedback loops and intensifying cancer phenotypes. The interconnected overexpression of genes and the PI3K-Akt pathway fosters gastric tumorigenesis, suggesting therapeutic potential. DrugBank analysis identified limited FDA-approved drugs, advocating for further exploration while targeting these hub genes could reshape GC treatment. The identified genes could be novel diagnostic/prognostic biomarkers or potential therapeutic targets for GC, but further clinical validation is required.