miR-106b∼25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300
miR-106b∼25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300
复制标题
MiR-106b~25 簇通过下调 EP300 以不依赖 ABC 转运蛋白的方式调节多药耐药性。
DOI：
10.3892/or.2015.4412
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发表时间：
2016-02-01
期刊：
影响因子：
4.2
通讯作者：
Yaguee, Ernesto
中科院分区：
文献类型：
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作者：
Hu, Yunhui;Li, Kaiyong;Yaguee, Ernesto
类似于25簇的MicroRNA (miR)-106b通过下调E-cadherin转录激活因子EP300调控阿霉素旁路和γ辐射诱导的衰老。我们询问类似于25簇的miR-106的上调是否会产生具有真正多药耐药（MDR）表型的细胞，以及这是否由于atp结合盒（ABC）转运体p糖蛋白的上调。我们使用了最低限度转化的乳腺上皮性乳腺癌细胞（MTMECs），其中类似于25簇的miR-106b通过慢病毒转染实验上调，或者用慢病毒表达靶向EP300或E-cadherin mrna的发夹。我们发现类似于25簇的miR-106b过表达导致MDR mtmes的产生（对依托泊苷、秋水仙碱和紫杉醇耐药）。实验下调EP300或E-cadherin后，还研究了紫杉醇抗性。然而，这些细胞都没有过度表达p糖蛋白或能够排出紫杉醇的荧光衍生物，使这种表型与药物转运蛋白无关。紫杉醇治疗mtmes导致早期凋亡细胞（Annexin v阳性）增加，caspase-9活化，细胞周期G2/M期细胞比例增加。然而，过表达miR-106b类似于25簇的MTMEC，或EP300或E-cadherin下调，显示出较少的凋亡激活，caspase-9和caspase-3/-7活性。因此，类似于25簇的miR-106b通过下调EP300逃避细胞凋亡来控制转运蛋白非依赖性MDR。
MicroRNA (miR)-106b similar to 25 cluster regulates bypass of doxorubicin and gamma-radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106 similar to 25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b similar to 25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b similar to 25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b similar to 25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b similar to 25 cluster controls transporter-independent MDR by apoptosis evasion via downregulation of EP300.