Department of Hematology, Lymphoma and Myeloma Center, HMC Cancer Institute, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China.
Department of Hematological Oncology, Sun Yat‑sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Int J Mol Med. 2020 Oct;46(4):1289-1300. doi: 10.3892/ijmm.2020.4675. Epub 2020 Jul 15.
Leukemia is a type of cancer which originates in blood‑forming tissues. MicroRNAs (miRNAs or miRs) have been shown to be involved leukemogenesis. In the present study, following the gain‑ and loss‑function of miR‑145 and ATP‑binding cassette sub‑family E member 1 (ABCE1) in K562 cells and K562 adriamycin‑resistant cells (K562/ADM cells), the levels of multidrug resistance protein 1 (MRP1) and P‑glycoprotein (P‑gp) were measured. The viability of the K562 cells and K562/ADM cells treated with various concentrations of ADM, and cell sensitivity to ADM were measured. The apoptosis of stem cells was detected. K562/ADM cells were transfected with miR‑145 mimic or with miR‑145 mimic together with ABCE1 overexpression plasmid to examine the effects of ABCE1 on the sensitivity of K562/ADM cells to ADM. The association between miR‑145 and ABCE1/MRP1 was then verified. The dose‑ and time‑dependent effects of ADM on the K562 cells and K562/ADM cells were examined. The K562/ADM cells exhibited a greater resistance to ADM, higher levels of MRP1 and P‑gp, and a lower miR‑145 expression. The K562/ADM cells and stem cells in which miR‑145 was overexpressed exhibited a suppressed cell proliferation, decreased MRP1 and P‑gp levels, and an increased apoptotic rate. However, K562 cells with a low expression of miR‑145 exhibited an increased cell proliferation, increased levels of MRP1 and P‑gp, and a suppressed apoptotic rate. Compared with the overexpression of miR‑145, the combination of miR‑145 and ABCE1 decreased the sensitivity of drug‑resistant K562/ADM cells to ADM. The above‑mentioned effects of miR‑145 were achieved by targeting ABCE1. Taken together, the findings of the present study demonstrate that the overexpression of miR‑145 promotes leukemic stem cell apoptosis and enhances the sensitivity of K562/ADM cells to ADM by inhibiting ABCE1.
白血病是一种起源于造血组织的癌症。已经证明 microRNAs（miRNAs 或 miRs）参与了白血病的发生。在本研究中，通过在 K562 细胞和 K562 阿霉素耐药细胞（K562/ADM 细胞）中过表达和敲低 miR-145 和 ATP 结合盒亚家族 E 成员 1（ABCE1），测量了多药耐药蛋白 1（MRP1）和 P-糖蛋白（P-gp）的水平。测量了用不同浓度阿霉素处理的 K562 细胞和 K562/ADM 细胞的活力以及细胞对阿霉素的敏感性。检测了干细胞的凋亡。用 miR-145 模拟物或 miR-145 模拟物与 ABCE1 过表达质粒转染 K562/ADM 细胞，以研究 ABCE1 对 K562/ADM 细胞对阿霉素敏感性的影响。然后验证了 miR-145 与 ABCE1/MRP1 的关联。然后检查了 ADM 对 K562 细胞和 K562/ADM 细胞的剂量和时间依赖性影响。K562/ADM 细胞对 ADM 的抗性更强，MRP1 和 P-gp 的水平更高，miR-145 的表达水平更低。过表达 miR-145 的 K562/ADM 细胞和干细胞表现出抑制的细胞增殖，降低的 MRP1 和 P-gp 水平以及增加的凋亡率。然而，miR-145 低表达的 K562 细胞表现出增加的细胞增殖，增加的 MRP1 和 P-gp 水平以及抑制的凋亡率。与过表达 miR-145 相比，miR-145 与 ABCE1 的组合降低了耐药 K562/ADM 细胞对 ADM 的敏感性。miR-145 的上述作用是通过靶向 ABCE1 实现的。总之，本研究的结果表明，过表达 miR-145 通过抑制 ABCE1 促进白血病干细胞凋亡并增强 K562/ADM 细胞对 ADM 的敏感性。
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