Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis
Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis
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DOI：
10.1111/j.1349-7006.2010.01489.x
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发表时间：
2010-04-01
期刊：
影响因子：
5.7
通讯作者：
Fei, Jia
中科院分区：
文献类型：
--
作者：
Li, Yumin;Zhu, Xuejiao;Fei, Jia
三氧化二砷（ATO）是一种古老的传统中药，已被成功地用于治疗白血病。耐药性和毒性是治疗的主要问题。微小RNA（microRNAs，miRNAs）是一种内源性非编码小RNA分子，可调节细胞对抗癌药物的敏感性。miRNA-21（miR-21）是参与人类癌症各个方面的最突出的miRNA之一。然而，miR-21在慢性髓细胞性白血病（CML）中很少被表征。在此，我们使用特异性抗miR-21寡核苷酸（AMO-miR-21）通过降解miR-21来使K562细胞对ATO敏感。结果表明，AMO-miR-21和ATO均能抑制K562细胞生长，诱导细胞凋亡，并使细胞G1期阻滞。同时，AMO-miR-21显著促进ATO介导的生长抑制和凋亡，而不影响G1期。姬姆萨染色法观察凋亡细胞的形态学变化。此外，双荧光素酶报告载体，含有两个串联的miR-21结合位点从PDCD 4的3 'UTR，验证PDCD 4的直接调控的miR-21。因此，AMO-miR-21通过诱导凋亡而对ATO致敏，部分原因是其上调PDCD 4蛋白水平。ATO和AMO-miR-21的组合呈现出对CML的治疗潜力。（Cancer Sci 2010; 101：948-954）
Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO-mediated growth inhibition and apotosis without affecting the G1 phase. Apoptotic cells were confirmed morphologically with Giemsa's staining. Furthermore, dual-luciferase reporter vector, containing two tandem miR-21 binding sites from PDCD4 3'UTR, validated that PDCD4 was directly regulated by miR-21. Therefore, AMO-miR-21 sensitized leukemic K562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level. The combination of ATO and AMO-miR-21 present therapeutic potential for CML. (Cancer Sci 2010; 101: 948-954)