miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1
miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1
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miR-181b 通过靶向 HMGB1 和 Mcl-1 提高急性髓系白血病的药物敏感性
DOI：
10.3892/ijo.2014.2390
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发表时间：
2014-07-01
影响因子：
5.2
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Lu, Fei;Zhang, Jingru;Ji, Chunyan
多药耐药（MDR）仍然是成人急性髓系白血病（AML）复发和预后不良的主要原因。越来越多的证据表明，耐药性不仅存在于传统的化疗药物，而且还限制了新的生物制剂的疗效。因此，阐明AML患者产生耐药性的机制非常重要。MicroRNA在调节AML化疗耐药性中发挥重要作用。详细了解AML中临床相关的microRNA机制可能会提高我们预测和克服耐药性的能力。在这里，我们首次证明了miR-181 b在人类多药耐药白血病细胞和复发/难治性AML患者样本中显著降低。过表达miR-181 b可增加白血病细胞对化疗药物的敏感性，促进药物诱导的细胞凋亡。此外，miR-181 b通过直接结合HMGB 1和Mcl-1的3 '非翻译区来抑制HMGB 1和Mcl-1表达。此外，HMGB 1在复发/难治性AML患者中以高水平表达，并且通过RNA干扰抑制HMGB 1使多药耐药白血病细胞对化疗敏感并诱导凋亡。总之，这些结果为开发基于miR-181 b的治疗策略以增强AML治疗功效提供了强有力的依据。
Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.