文章：

寡单链DNA模拟hsa-miR-15a-5p对多发性骨髓瘤的治疗作用

Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma 

原文发布日期：2020-01-28 

英文摘要：

Despite the fact that a few novel agents improve the outcome of patients, MM remains incurable. Hence, developing a novel treatment strategy may prove to be promising for the clinical management of MM. Noncoding small RNAs, a cluster of RNAs that do not encode functional proteins, have been underlined that play a pivotal role in the pathogenesis of MM. Our previous study indicated that miR-15a acted as a tumor suppressor, which inhibited the cell proliferation and promoted the apoptosis of MM cells. The level of miR-15a was downregulated in MM cells and correlated with inferior outcome of MM patients. In the present study, we first developed an oligo-single-stranded DNA mimicking the sequence of hsa-miR-15a-5p (OMM-15a) and modified with locked nucleic acid (LNA-15a) to evaluate its anti-MM effects. Our results indicated that the LNA-15a presented an exciting anti-MM effect that showed notable cell growth suppression and apoptosis promotion in MM and other cancer cell lines through downregulating the expression level of target genes BCL-2, VEGF-A, and PHF19. Moreover, LNA-15a treatment significantly improved the anti-MM activity of bortezomib with the synergism effect in OCI-My5 MM cells. In our in vivo study, LNA-15a treatment significantly suppressed the tumor growth, and prolonged the survival of mice compared with the control group. However, our results indicated that the native form of oligo-single-stranded DNA mimic of hsa-miR-15a-5p (OMM-15a) without any modification had no effective inhibition on cell growth, even after increasing the dosage of OMM-15a in the treatment. Altogether, our finding provides the preclinical rationale to support the oligo-single-stranded DNA mimic of hsa-miR-15a with LNA modification, which is a promising tool for the therapy of both MM and other tumors with miR-15a downregulation. 

摘要翻译： 

尽管一些新型药物改善了患者的预后，多发性骨髓瘤（MM）仍无法治愈。因此，开发新型治疗策略可能为MM的临床管理带来希望。非编码小RNA（一类不编码功能蛋白的RNA群）已被强调在MM发病机制中起关键作用。我们先前的研究表明，miR-15a作为肿瘤抑制因子，可抑制MM细胞增殖并促进其凋亡。MM细胞中miR-15a水平下调且与患者不良预后相关。本研究首次开发了模拟hsa-miR-15a-5p序列的寡聚单链DNA（OMM-15a），并通过锁核酸修饰（LNA-15a）评估其抗MM效果。结果表明，LNA-15a通过下调靶基因BCL-2、VEGF-A和PHF19的表达水平，在MM及其他癌细胞系中展现出显著的细胞生长抑制和凋亡促进作用。此外，LNA-15a处理能显著增强硼替佐米在OCI-My5 MM细胞中的抗MM活性，并产生协同效应。在体内实验中，与对照组相比，LNA-15a处理显著抑制肿瘤生长并延长小鼠生存期。但研究同时发现，未经修饰的天然hsa-miR-15a-5p模拟寡聚单链DNA（OMM-15a）即使增加给药剂量也无法有效抑制细胞生长。综上所述，我们的发现为锁核酸修饰的hsa-miR-15a模拟寡聚单链DNA提供了临床前理论依据，表明该技术是治疗MM及其他miR-15a下调肿瘤的有效工具。

原文链接：

Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma