Development of Shortened miR-506-3p Mimics Exhibiting Strong Differentiation-Inducing Activity in Neuroblastoma Cells.
Development of Shortened miR-506-3p Mimics Exhibiting Strong Differentiation-Inducing Activity in Neuroblastoma Cells.
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DOI：
10.3390/molecules28176295
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发表时间：
2023-08-28
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microRNA mimics是一种合成的RNA分子，模仿成熟的miRNA双链及其功能。这些模拟物在治疗癌症方面显示出了希望。已经研究了microRNA模拟物的核苷酸化学修饰，并改善了microRNA模拟物的稳定性。然而，基于序列修饰的模拟类似物的潜在治疗益处尚未被探索。miR-506-3p在神经母细胞瘤细胞中被鉴定为诱导分化的microRNA，提示miR-506-3p模拟物在神经母细胞瘤分化治疗中的应用潜力。在这项研究中，我们探索了开发缩短的miR-506-3p类似物的可能性，该类似物可以保持与野生型miR-506-3p类似物相当的诱导分化活性。我们发现，与野生型模拟物相比，在miR-506-3p序列的3 '端或中间区域删除多达两个核苷酸完全保持了诱导分化的活性。从3 '端删除最多4个核苷酸或在中间位置删除3个核苷酸会降低诱导分化的活性，但类似物仍保持显著高于阴性对照寡核苷酸的诱导分化活性。缩短的类似物设计可能从两个方面对患者有益：(1)降低了制造缩短类似物的成本；(2)由于其分子尺寸较小，降低了非特异性毒性。
microRNA mimics are synthetic RNA molecules that imitate the mature miRNA duplexes and their functions. These mimics have shown promise in treating cancers. Nucleotide chemical modifications of microRNA mimics have been investigated and have improved the stability of miRNA mimics. However, the potential therapeutic benefit of mimic analogs based on sequence modifications has not been explored. miR-506-3p was identified as a differentiation-inducing microRNA in neuroblastoma cells, suggesting the potential of applying the miR-506-3p mimic in neuroblastoma differentiation therapy. In this study, we explored the possibility of developing shortened miR-506-3p analogs that can maintain differentiation-inducing activities comparable to the wild-type miR-506-3p mimic. We found that deleting up to two nucleotides at either the 3′ end or within the middle region of the miR-506-3p sequence fully maintained the differentiation-inducing activity when compared to the wild-type mimic. Deleting up to four nucleotides from the 3′ end or deleting three nucleotides in the middle positions diminished the differentiation-inducing activity, but the analogs still maintained differentiation-inducing activities that were significantly higher than the negative control oligo. The shortened analog designs potentially benefit patients from two perspectives: (1) the reduced cost of manufacturing shortened analogs, and (2) the reduced non-specific toxicity due to their smaller molecular sizes.
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