MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma.
MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma.
复制标题
MicroRNA-451通过PI3K/Akt/mTOR信号通路调节多发性骨髓瘤侧群细胞的干性
DOI：
10.18632/oncotarget.3802
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Hou J
中科院分区：
文献类型：
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作者：
Du J;Liu S;He J;Liu X;Qu Y;Yan W;Fan J;Li R;Xi H;Fu W;Zhang C;Yang J;Hou J
侧群（SP）细胞是具有干细胞特征的癌症起始细胞的富集来源，由增加的ABC转运蛋白活性产生，这已成为多发性骨髓瘤（MM）干细胞研究的独特标志。在这里，我们通过Hoechst 33342染色分离和鉴定MM SP细胞。此外，我们证明，SP细胞具有异常的细胞周期，克隆形成，和高药物外排特性，所有这些都是常见的干细胞的功能。有趣的是，我们发现硼替佐米，三氧化二砷，和美法仑都影响SP细胞的凋亡和克隆形成。我们随后表征了MM SP细胞的miRNA特征，并验证了特异性miR-451靶向结节性硬化症1（TSC 1）基因，以揭示其激活MM SP细胞中的PI 3 K/Akt/mTOR信号传导。抑制miR-451可通过增加细胞凋亡、降低克隆形成和降低MDR 1 mRNA表达来增强抗骨髓瘤新药的有效性。此外，新型特异性PI 3 K/Akt/mTOR信号传导抑制剂S14161通过靶向MM SP细胞显示其作为潜在治疗剂的威力。我们的研究结果提供了对MM SP细胞调节机制的见解，并提供了一种新的策略来克服对现有骨髓瘤治疗的耐药性。
Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics-all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents' effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma.