Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92
Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92
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DOI：
10.1038/sj.onc.1210425
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发表时间：
2007-09-01
期刊：
影响因子：
8
通讯作者：
Takahashi, T.
中科院分区：
文献类型：
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作者：
Matsubara, H.;Takeuchi, T.;Takahashi, T.
最近报道了13 q31.3处miR- 17- 92 microRNA（miRNA）簇的扩增和过表达，其功能涉及B细胞淋巴瘤和肺癌的发展。在本研究中，我们发现用反义寡核苷酸（ON）抑制miR- 17- 5 p和miR-20 a可以选择性地诱导过表达miR- 17- 92的肺癌细胞凋亡，这表明在肺癌的一个子集中，Oncomi R对这些miRNA表达成瘾的可能性。与此形成鲜明对比的是，针对miR-18 a和miR-19 a的反义ON没有表现出这样的抑制作用，而miR-92-1的抑制仅导致细胞生长的适度减少，这表明miR- 17- 92簇的miRNA在它们在癌细胞生长中的作用方面存在显著差异。在该研究过程中，我们还发现，位于C13 orf 25的内含子3中miR- 17- 92的30位的基因组区域（称为C2）的强制表达导致与双链RNA依赖性蛋白激酶活化相关的显著生长抑制。最后，本研究还揭示了绝大多数C13 orf 25转录物在北方印迹分析中被检测为Drosha加工的切割产物，并且在miR- 17- 92簇的30处和C2区的50处存在新的聚腺苷酸化位点。总之，目前的研究结果有助于更好地理解miR- 17- 92的致癌作用，这可能最终导致未来转化为临床应用。
Amplification and overexpression of the miR- 17- 92 microRNAs ( miRNA) cluster at 13q31.3 has recently reported, with pointers to functional involvement in the development of B- cell lymphomas and lung cancers. In the present study, we show that inhibition of miR- 17- 5p and miR- 20a with antisense oligonucleotides ( ONs) can induce apoptosis selectively in lung cancer cells overexpressing miR- 17- 92, suggesting the possibility of 'Oncomi R addiction to expression of these miRNAs in a subset of lung cancers. In marked contrast, antisense ONs against miR-18a and miR- 19a did not exhibit such inhibitory effects, whereas inhibition of miR-92-1 resulted in only modest reduction of cell growth, showing significant distinctions among miRNAs of the miR- 17- 92 cluster in terms of their roles in cancer cell growth. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 30 to miR- 17- 92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA- dependent protein kinase activation. Finally, this study also revealed that the vast majority of C13orf25 transcripts are detected as Drosha- processed cleavage products on Northern blot analysis and that a novel polyadenylation site is present 30 to the miR- 17- 92 cluster and 50 to the C2 region. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR- 17- 92, which might ultimately lead to the future translation into clinical applications.