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Abstract
BackgroundGastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Compared to typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance.MethodsDifferences in gene expression profiles between advanced and nonadvanced GISTs were comprehensively analyzed based on the Gene Expression Omnibus (GEO) dataset GSE136755. A protein–protein interaction (PPI) network was constructed to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events related to the target gene based on the GSE47911 dataset. Subsequently, immunohistochemistry and Kaplan–Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its function in the proliferation, apoptosis, and imatinib resistance of GIST/T1 cells.ResultsIn the current study, a total of 606 differentially expressed genes (DEGs) were screened based on the GSE136755 dataset, and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersecting hub gene, Aurora kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Analysis of the Oncomine and GEPIA databases revealed a pattern of elevated AURKA expression in most human malignances. Clinical assays demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation, inhibit cell apoptosis, and enhance imatinib resistance in GIST/T1 cells.ConclusionsThese findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs.
Highlights
Gastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme
Identification of differentially expressed genes (DEGs) A total of 65 human GIST samples without preoperative imatinib treatment were included in the GSE13675 dataset
Functional annotation of DEGs To evaluate the biological clustering of DEGs, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the up- and downregulated DEGs were performed using DAVID
Summary
Gastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary system and originates from the interstitial cells of Cajal (ICC) [1]. Cheng et al Cancer Cell Int (2021) 21:407 of GISTs is stratified based on tumor size, mitotic index, and location according to the modified NIH criteria [4]. Due to acquired resistance to imatinib, approximately 85–90% of patients with GIST experience disease progression within 20–24 months [2, 3, 7]. Further research is urgently needed to reveal the mechanism of GIST progression and explore novel therapeutic targets to combat imatinib resistance
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