microRNA-218 increase the sensitivity of gastrointestinal stromal tumor to imatinib through PI3K/AKT pathway

Abstract

To detect the expressions of microRNA-218 (miR-218) in an imatinib mesylate-sensitive human gastrointestinal stromal tumor (GIST) cells (GIST882) and an imatinib mesylate-resistant cell line (GIST430) and explore the roles of miR-218 and GIST cells in the sensitivity of gastrointestinal stromal tumor to imatinib mesylate and its potential signaling pathways, with an attempt to provide new insights for the treatment of GIST. The GIST cell lines (GIST882 and GIST430) were cultured in vitro. Quantitative real-time PCR (qRT-PCR) was utilized to determine the expression profiles of miR-218 in both GIST cell lines. Forty-eight hours after the transfection of the miR-218 mimic or miR-218 inhibitor in the GIST cells, the changes in the expression of miR-218 in the GIST cells were detected with qRT-PCR. The effects of the ectopic expression of miR-218 in GIST882 or GIST430 cells on the imatinib mesylate-induced GIST cell viability were determined by MTT. The effects of miR-218 ectopic expression on the apoptosis of imatinib mesylate-induce GIST cells were determined by Annexin V/PI double staining method and flow cytometry. The effects of miR-218 ectopic expression on the AKT and phospho-AKT (p-AKT) expressions of imatinib mesylate-induce GIST cells were determined by Western blot and flow cytometry with the PI3K pathway inhibitor Wortmannin. As shown by qRT-PCR, compared with that in the imatinib mesylate-sensitive GIST882, the expression of miR-218 in imatinib mesylate-resistant GIST430 was significantly decreased (P < 0.01). Compared with the control group, the expression of miR-218 significantly increased in the GIST882 48 h after the transfection of miR-218 mimic (P < 0.01) and significantly declined after the transfection of miR-218 inhibitor (P < 0.01). As shown by MTT and flow cytometry, after the expression of miR-218 was inhibited in GIST882 under the effect of imatinib mesylate, the cell viability significantly increased (P < 0.01) and the number of apoptotic cells significantly decreased (P < 0.05); on the contrary, the over-expression of miR-218 in GIST430 under the effect of imatinib mesylate resulted in the significantly decreased cell viability (P < 0.01) and the significantly increased number of apoptotic cells (P < 0.05). Western blot and flow cytometry showed that, in comparison to the control group, Wortmannin could significantly inhibit the expression of p-AKT in GIST430 cells (P < 0.01) and stimulated apoptosis (P < 0.01). The expression of miR-218 is down-regulated in an imatinib mesylate-resistant GIST cell line (GIST430), whereas miR-218 over-expression can improve the sensitivity of GIST cells to imatinib mesylate, with PI3K/AKT signaling pathway possibly involved in the mechanism.

miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

“…These findings confirm that the PI3K/Akt pathway is essential for the development of colon cancer and is a promising target for the treatment of colon cancer. It has been previously reported that the upregulation of miR-218 inhibits the proliferation of oral squamous carcinoma cells by targeting Akt and mTOR (31), and increases the sensitivity of gastrointestinal stromal tumor cells to imatinib through the PI3K/Akt pathway (32). In the present study, we also revealed that the PI3K/Akt signaling pathway may be a potential target of miR-218 using gene target prediction programs.…”

MicroRNA-218 Increases the Sensitivity of Bladder Cancer to Cisplatin by Targeting Glut1

“…Explorations of the relationship between miRNAs and tumour chemo-sensitivity, in particular, have recently become a research hotspot. Previous studies have confirmed that miR-218 serves as a tumour suppressor in numerous human cancers and over-expressed miR-218 could inhibit the growth and regulate chemo-sensitivity in certain tumours, including gastric cancer and cervical cancer [25, 26]. It is well known that one miRNA may target many genes in different cell systems and miR-218 is no exception.…”

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

“…Reduced or absent expression of the phosphatase and tensin homolog (PTEN) was significantly associated with IM treatment in GIST patient samples, and PTEN deficiency in vitro results in hyperactivation of AKT (9). Two recent studies in IM-sensitive and resistant GIST cellular models established links between KIT activity (modified by specific KIT-targeting miRNAs), AKT expression and phosphorylation, and cell viability and apoptosis (42,43). Hence, AKT stands out as an attractive target for combination therapy with IM.…”