Five hub genes contributing to the oncogenesis and trastuzumab-resistance in gastric cancer

Background: Monoclonal antibodies, as the targeted therapeutic strategies, provide huge clinical benefits for tumor patients. However, after undergoing several times treatment, patients developed drug resistance which is a major bottleneck in clinical cancer therapy. In this study, we aimed to explore the potential molecular mecha-nism of trastuzumab-resistant and cancer progression, and identify valuable diagnosis biomarkers for gastric cancer.Materials and methods: Gene expression profiles and RNA-sequencing dataset of gastric cancer were acquired from Gene Expression Omnibus (GEO) dataset and The Cancer Genome Atlas (TCGA) dataset, respectively. The Differently expressed genes (DEGs) were screened by R programing language, and Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were adopted separately to analyze the function and pathway of DEGs. Subsequently, Search Tool for the Retrieval of Interacting (STRING) and Cytoscape was performed to establish the protein-protein interaction (PPI) network and to screen hub genes. The Receiver Operating Characteristic (ROC) curves were used to evaluate the diagnostic values of the hub genes. Results: Integrated analysis of TCGA-STAD (Stomach adenocarcinoma) and GEO databases identified 310 com-mon DEGs. GSEA, GO and KEGG enrichment analysis revealed several crucial enriched oncological signatures and trastuzumab-resistant signaling pathways, which may help to explain the potential modulating mechanisms of trastuzumab-resistant. Based on the PPI network, 10 hub genes were screened and five genes (GNGT1, KRT7, KRT16, SOX9, TIMP1) were identified with good performance in the diagnosis of gastric cancer by ROC analysis. Furthermore, Kaplan-Meier analysis and log-rank test suggested that upregulation of KRT16 was correlated with overall survival in gastric cancer.Conclusion: Overall, our study identified five hub genes that may play a critical role in promoting trastuzumab-resistant in gastric cancer, and would be a promising diagnostic and therapeutic biomarker for trastuzumab-resistant gastric cancer.