Aurora kinase A (AURKA) promotes the progression and imatinib resistance of advanced gastrointestinal stromal tumors

Abstract

Background Gastrointestinal 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. Methods Differences 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. Results In 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. Conclusions These findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs.

Chromosomal instability and a deregulated cell cycle are intrinsic features of high‐risk gastrointestinal stromal tumours with a metastatic potential

“…Of these, the aurora kinases AURKA and AURKB have been shown to enhance the generation of aneuploid cells, facilitating genomic instability and malignant transformation (reviewed in [ 66 ]). Overexpression of AURKA has been suggested to be an independent unfavourable prognostic factor in both treatment‐naïve [ 21 , 67 ] and imatinib‐treated advanced GIST patients [ 68 ]. AURKA overexpression has been shown to enhance the resistance of GIST cells to imatinib [ 21 ], thus an AURKA inhibitor may have potential as a therapeutic agent for both imatinib‐sensitive and imatinib‐resistant GIST [ 68 ].…”

“…Overexpression of AURKA has been suggested to be an independent unfavourable prognostic factor in both treatment‐naïve [ 21 , 67 ] and imatinib‐treated advanced GIST patients [ 68 ]. AURKA overexpression has been shown to enhance the resistance of GIST cells to imatinib [ 21 ], thus an AURKA inhibitor may have potential as a therapeutic agent for both imatinib‐sensitive and imatinib‐resistant GIST [ 68 ].…”

“…Several studies have revealed the enrichment of deregulated cell cycle processes in GIST [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Using a cohort comparable to ours, including only primary, treatment‐naïve, high‐risk GIST, samples with higher mitotic counts were shown to have a significantly increased protein expression of cyclin D1, p53 and E2F1 [ 17 ].…”

“…Mutation of the KIT and PDGF receptors leads to a constitutional activation and ligand‐independent downstream signalling through the RAS/RAF/MAPK, PI3K/AKT/mTOR and STAT3 pathways [ 12 , 13 ]. These pathways further upregulate important transcriptional activators, stimulating the cell cycle and having anti‐apoptotic effects [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. The cell cycle pathways are part of complex interacting networks with miRNAs as central regulatory functions [ 22 ].…”

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors

“…A clinical analysis has demonstrated that AURKA can be an independent prognostic factor for GISTs. In addition, experiments have shown that overexpression of AURKA can promote the proliferation of GIST-T1 cells, inhibit cell apoptosis, and enhance the resistance of cells to IM ( 89 ).…”