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

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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.

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Acknowledgments

This study was supported by Key Project of Science and Technology Commission of Shanghai Municipality (No. 13411950900).

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Correspondence to Jie Zhong.

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Fan, R., Zhong, J., Zheng, S. et al. microRNA-218 increase the sensitivity of gastrointestinal stromal tumor to imatinib through PI3K/AKT pathway. Clin Exp Med 15, 137–144 (2015). https://doi.org/10.1007/s10238-014-0280-y

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  • DOI: https://doi.org/10.1007/s10238-014-0280-y

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