Abstract
Gastric cancer, a highly invasive and aggressive malignancy, is the third leading cause of death from cancer worldwide. Genetic association studies have successfully revealed several important genes consistently associated with gastric cancer to date. However, these robust gastric cancer-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. In the present study, we performed an alternative approach, a gene expression-based genome-wide association study (eGWAS) across 13 independent microarray experiments (including 251 gastric cancer cases and 428 controls), to identify top candidates (p<0.00001). Additionally, we conducted gene ontology analysis, pathway analysis and network analysis and identified aurora kinase A (AURKA) as our candidate. We observed that MLN8237, which is a specific inhibitor of AURKA, decreased the β-catenin and the phosphorylation of Akt1 and GSK-3β, as well as blocked the Akt and Wnt signaling pathways. Furthermore, MLN8237 arrested the cells in the G2/M phase. The activity of Wnt and Akt signaling pathways affected the level of histone methylation significantly, and we supposed that MLN8237 affected the level of histone methylation through these two signaling pathways. Additionally, the treatment of MLN8237 influenced the level of H3K4 me1/2/3 and H3K27 me1/2/3. Chip data on cell lines suggested that MLN8237 increases the level of H3K27 me3 on the promoter of Twist and inhibits EMT (epithelial-mesenchymal transition). In summary, AURKA is a potential therapeutic target in gastric cancer and induces EMT through histone methylation.
Highlights
Gastric cancer is a highly invasive and aggressive malignancy and one of the leading causes of death from cancer worldwide; investigations into its initiation and development are of great importance [1,2,3]
EGWASs identify aurora kinase A (AURKA) as a functional candidate gene for gastric cancer We performed expressionbased genome-wide association study (eGWAS) for gastric cancer using 13 independent microarray experiments, and 679 samples were collected from public repositories
Several groups have published genome-wide association studies (GWASs) of gastric cancer focusing on singlenucleotide polymorphisms (SNPs), such as in a locus on chromosome 10q23 in the PLCE1 gene or in PRKAA1 at
Summary
Gastric cancer is a highly invasive and aggressive malignancy and one of the leading causes of death from cancer worldwide; investigations into its initiation and development are of great importance [1,2,3]. Recent studies have established that aberrant EMT activation in the human stomach is closely associated with gastric carcinogenesis and tumor progression [4, 5]. The prognosis of gastric cancer patients usually depends on the early detection and treatment of malignant tumor characteristics such as invasion and metastasis, which are the primary causes of treatment failure. There have been few fully identified, functionally important genes in the pathogenesis of gastric cancer because many genes are often detected as significant in each microarray experiment, and it is difficult to subselect optimal candidates from individual studies for further verification
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