Zhang Yuan, Liu Yufeng, Xu Xueju
Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
Transl Oncol. 2017 Jun;10(3):410-418. doi: 10.1016/j.tranon.2017.03.003. Epub 2017 Apr 23.
miR-142-3p was reported to be downregulated in acute myelogenous leukemia (AML) and acted as a novel diagnostic marker. However, the regulatory effect of miR-142-3p on drug resistance of AML cells and its underlying mechanism have not been elucidated. Here, we found that miR-142-3p was significantly downregulated and high mobility group box 1 (HMGB1) was dramatically upregulated in AML samples and cells, as well as drug-resistant AML cells. P-gp level and autophagy were markedly enhanced in HL-60/ADR and HL-60/ATRA cells. miR-142-3p overexpression improved drug sensitivity of AML cells by inhibiting cell viability and promoting apoptosis, and inhibited P-gp level and autophagy in drug-resistant AML cells, whereas HMGB1 overexpression obviously reversed these effect. HMGB1 was demonstrated to be a target of miR-142-3p, and miR-142-3p negatively regulated HMGB1 expression. In conclusion, our study elucidated that upregulation of miR-142-3p improves drug sensitivity of AML through reducing P-glycoprotein and repressing autophagy by targeting HMGB1, contributing to better understanding the molecular mechanism of drug resistance in AML.
据报道，miR-142-3p在急性髓系白血病（AML）中表达下调，并作为一种新型诊断标志物。然而，miR-142-3p对AML细胞耐药性的调节作用及其潜在机制尚未阐明。在此，我们发现miR-142-3p在AML样本、细胞以及耐药AML细胞中显著下调，而高迁移率族蛋白B1（HMGB1）则显著上调。HL-60/ADR和HL-60/ATRA细胞中的P-糖蛋白水平和自噬明显增强。miR-142-3p过表达通过抑制细胞活力和促进凋亡提高AML细胞的药物敏感性，并抑制耐药AML细胞中的P-糖蛋白水平和自噬，而HMGB1过表达明显逆转了这些作用。HMGB1被证明是miR-142-3p的靶标，且miR-142-3p负向调节HMGB1的表达。总之，我们的研究阐明了miR-142-3p的上调通过降低P-糖蛋白并靶向HMGB1抑制自噬来提高AML的药物敏感性，有助于更好地理解AML耐药的分子机制。
