Imatinib mesylate resistance occurs in some patients with gastrointestinal stromal tumors (GISTs) during the course of treatment. In this study, we investigated the relationship between microRNAs (miRNAs) and imatinib-resistant GISTs, and the effect of miR-518a-5p on PIK3C2A in imatinib-resistant GISTs. A total of 20 matched-pair GIST samples from imatinibresistant patients were included in the study. Each of the paired tumor specimens were from the same patient who had surgical removal of GISTs preimatinib and postimatinib treatment. Seven pairs of tissues were resected for microarray analysis, and the remaining 13 pairs were utilized for miRNAs analysis. Target genes were selected based on bioinformatics from multiple biological databases. Luciferase reporter assays were used to confirm the binding of miR-518a-5p to PIK3C2A 3′UTR. GIST882R-NC, 882R-miR-518a-5p-OE, and 882R-miR-518a-5p-KD cell lines were constructed using lentiviral vectors. miR-518a-5p and PIK3C2A expression in 882R-NC, 882R-OE, and 882R-KD cells was assessed by real-time PCR and western blotting. A cell counting kit was used to detect the influence of miR-518a-5p to cell proliferation. TUNEL staining was applied to detect the influence of miR-518a-5p to cell apoptosis. Microarray analysis showed that miR-518a-5p was downregulated in imatinib-resistant GISTs, and the expression of miR-518a-5p was confirmed with good concordance between real-time PCR and miRNA microarray results. Luciferase reporter assays indicated that miR-518a-5p bound to the PIK3C2A 3′UTR. Compared with 882R-OE, PIK3C2A expression was significantly increased in 882R-KD cells. MiR-518a-5p reduced 882R proliferation and promoted 882R apoptosis. In conclusion, PIK3C2A is a gene-specific target of miR-518a-5p in imatinib mesylate-resistant GISTs. Low expression of miR-518a-5p is likely to upregulate PIK3C2A and affect the cellular response to the drug, causing resistance to imatinib in GISTs.

Gastric cancer is an important health problem, being the fifth most common cancer and the third leading cause of cancer-related death worldwide. Aberrant protein translation contributes to the oncogenesis and development of cancers, and upregulation of translation initiation factor eIF4A1 has been observed in several kinds of malignancies. However, the role of eIF4A1 in gastric cancer progression remains unclear. In this study, we found that the expression of eIF4A1, a component of translation initiation complex, was increased in gastric cancer. High expression of eIF4A1 was positively associated with poor tumor differentiation, late T stage, lymph node metastasis, advanced TNM stage, and poor prognosis in patients with gastric cancer. Overexpression of eIF4A1 promoted the migration and invasion of gastric cancer cells in vitro and enhanced tumor metastasis in nude mice model. Mechanism studies revealed that eIF4A1 induced epithelial-to-mesenchymal transition (EMT) of gastric cancer cells through driving the translation of SNAI1 mRNA. Together, these findings indicate that eIF4A1 promotes EMT and metastasis of gastric cancer and suggest that eIF4A1 is a potential target for the adjuvant therapy for gastric cancer patients.