Demethylation by low-dose 5-aza-2-deoxycytidine impairs 3D melanoma invasion partially through miR-199a-3p expression revealing the role of this miR in melanoma
Demethylation by low-dose 5-aza-2-deoxycytidine impairs 3D melanoma invasion partially through miR-199a-3p expression revealing the role of this miR in melanoma
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DOI：
10.1186/s13148-018-0600-2
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发表时间：
2019-01-16
影响因子：
5.7
通讯作者：
Arimondo, Paola B.
中科院分区：
文献类型：
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作者：
Desjobert, Cecile;Carrier, Arnaud;Arimondo, Paola B.
背景仍然缺乏针对转移性黑色素瘤播散的有效治疗方法。在这里，我们报告低细胞毒性浓度的 5-aza-2-deoxycytidine（一种 DNA 去甲基化剂）可防止转移性黑色素瘤细胞的体外 3D 侵袭，并减少体内肺转移的形成。结果我们发现，这种有益效果部分归因于启动子去甲基化重新表达 MIR-199A2。单独而言，这种 miR 显示出抗侵袭和抗转移作用。在 5-aza-2-deoxycytidine 处理后，通过将 micro-RNA 靶点预测数据库与转录组分析进行整合，我们发现 miR-199a-3p 下调了一组与侵袭/迁移过程显着相关的基因。此外，对黑色素瘤患者数据的分析显示，DNA 甲基化对 MIR-199A2 表达存在阶段性和组织类型依赖性调节。结论因此，我们的数据表明，基于表观遗传和/或 miR 的治疗策略可能与限制黑色素瘤的转移性传播有关。
BackgroundEfficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo.ResultsWe unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect. Throughout integration of micro-RNA target prediction databases with transcriptomic analysis after 5-aza-2-deoxycytidine treatments, we found that miR-199a-3p downregulates set of genes significantly involved in invasion/migration processes. In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation.ConclusionsThus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma.