miR-137 Suppresses the Phosphorylation of AKT and Improves the Dexamethasone Sensitivity in Multiple Myeloma Cells Via Targeting MITF
miR-137 Suppresses the Phosphorylation of AKT and Improves the Dexamethasone Sensitivity in Multiple Myeloma Cells Via Targeting MITF
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miR-137 通过靶向 MITF 抑制 AKT 磷酸化并提高多发性骨髓瘤细胞对地塞米松的敏感性
DOI：
10.2174/1568009616666160203114140
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发表时间：
2016-01-01
影响因子：
3
通讯作者：
Zhao, Fei
中科院分区：
文献类型：
--
作者：
Zhang, Benping;Ma, Ling;Zhao, Fei
背景资料：多发性骨髓瘤（MM）是一种以骨髓浆细胞增殖为特征的克隆性B细胞恶性肿瘤，目前仍是一种无法治愈的疾病，因此，迫切需要寻找新的治疗靶点。虽然microRNA-137（miR-137）参与多种细胞过程，但已报道其在多种类型的实体瘤中低表达，但其在MM中的作用尚不清楚。方法：本研究探讨了miR-137在MM中的靶基因和潜在作用。结果显示，MM细胞系和MM患者的CD 138+骨髓单个核细胞中miR-137的表达显著下调。双荧光素酶报告基因分析显示，MITF是miR-137的直接靶点。过表达miR-137或转染MITF-shRNA对丝氨酸/苏氨酸蛋白激酶（AKT）的表达无明显影响，但MITF、c-MET、p-AKT及其磷酸化底物蛋白的表达明显下降，并伴随p53表达的增加。此外，过表达miR-137或MITF-shRNA可显著提高地塞米松处理的多发性骨髓瘤细胞的36 h抑制率和凋亡率。结论：MITF是miR-137的直接作用靶点。miR-137可通过靶向MITF降低c-MET表达，进而降低AKT磷酸化水平，从而提高多发性骨髓瘤细胞对地塞米松的敏感性。
Background: Multiple myeloma (MM), a clonal B cell malignancy characterized by the proliferation of plasma cells within the bone marrow, is still an incurable disease, and therefore, finding new therapeutic targets is urgently required. Although microRNA-137 (miR-137), which is involved in a variety of cellular processes, has been reported to be under-expressed in many types of solid tumors, its role in MM is less known.Methods: In this study, the target gene and the potential effect of miR-137 in MM were investigated.Results: The results showed significantly down regulated expression of miR-137 in MM cell lines and in the CD138+ bone marrow mononuclear cells of MM patients. A dual luciferase reporter gene analysis revealed that MITF is a direct target of miR-137. The overexpression of miR-137 or transfection of MITF-shRNA had no significant effect on the expression of serine/threonine protein kinase (AKT), but the expression of MITF, c-MET, p-AKT, and its phosphorylated substrate protein decreased significantly, which was accompanied by an increase in p53 expression. In addition, the overexpression of miR-137 or MITF-shRNA significantly improved the 36-hour inhibition rate and apoptosis rate in multiple myeloma cells treated with dexamethasone. The overexpression of MITF could counteract the biological effect of miR-137 in multiple myeloma cells.Conclusion: We conclude that MITF is a direct target of miR-137. The miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AKT phosphorylation via targeting MITF.