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Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma.
Cancer Gene Therapy ( IF 4.8 ) Pub Date : 2020-01-28 , DOI: 10.1038/s41417-020-0161-3
Zhongqing Li 1, 2 , Lanting Liu 2 , Chenxing Du 2 , Zhen Yu 2 , Yuanyuan Yang 2 , Jie Xu 2 , Xiaojing Wei 2 , Fenghuang Zhan 3 , Yongrong Lai 1 , Lugui Qiu 2 , Mu Hao 2
Affiliation  

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.

中文翻译:

模拟 hsa-miR-15a-5p 的寡单链 DNA 对多发性骨髓瘤的治疗作用。

尽管一些新型药物可以改善患者的预后,但 MM 仍然无法治愈。因此,开发一种新的治疗策略可能被证明有利于 MM 的临床管理。非编码小 RNA 是一组不编码功能性蛋白质的 RNA,已被强调在 MM 的发病机制中起关键作用。我们之前的研究表明,miR-15a 作为肿瘤抑制因子,抑制细胞增殖并促进 MM 细胞的凋亡。miR-15a 水平在 MM 细胞中下调,并与 MM 患者的不良预后相关。在本研究中,我们首先开发了一种模拟 hsa-miR-15a-5p (OMM-15a) 序列并用锁核酸 (LNA-15a) 修饰的寡单链 DNA,以评估其抗 MM 效果。我们的结果表明,LNA-15a 表现出令人兴奋的抗 MM 作用,通过下调靶基因 BCL-2、VEGF-A 和 PHF19 的表达水平,在 MM 和其他癌细胞系中显示出显着的细胞生长抑制和细胞凋亡促进。此外,LNA-15a 处理显着提高了硼替佐米的抗 MM 活性,并在 OCI-My5 MM 细胞中具有协同作用。在我们的体内研究中,与对照组相比,LNA-15a 治疗显着抑制了肿瘤生长,并延长了小鼠的存活期。然而,我们的结果表明,未经任何修饰的 hsa-miR-15a-5p (OMM-15a) 寡聚单链 DNA 模拟物的天然形式对细胞生长没有有效抑制,即使在增加 OMM-15a 的剂量后在治疗中。共,
更新日期:2020-01-28
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