mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis.
mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis.
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DOI：
10.3390/ijms18010222
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发表时间：
2017-01-23
影响因子：
5.6
通讯作者：
Fortunato O
中科院分区：
文献类型：
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作者：
Borzi C;Calzolari L;Centonze G;Milione M;Sozzi G;Fortunato O
肺癌是全世界癌症相关死亡的最常见原因，治疗选择有限，耐药性发展迅速。microrna是一类控制不同生理过程的小非编码rna，作为促癌rna或肿瘤抑制mirna与癌症的发展有关。在本研究中，我们研究了mir-486-5p和mir-660-5p这两种独立的肿瘤抑制mirna之间的相互作用，以评估它们在肺癌治疗中的可能作用和协同作用。我们的数据显示，在A549肺癌细胞中，mir-660-5p过表达诱导了mir-486-5p表达水平和活性的显著增加，检测为其靶基因p85的降低。microRNA原位杂交证实mir-486-5p表达。mir-660-5p通过沉默其直接靶点之一的小鼠双分钟2 (Mouse Double Minute 2, MDM2)，然后通过刺激p53来调节mir-486-5p。该调控途径对A549有效，但对H1299无效；因此，只有在p53蛋白具有功能的情况下。我们的研究结果支持mir-486-5p在肺癌细胞系中通过mir-660-MDM2-p53途径受到mir-660-5p的正调控的结论，这使得mir-660-5p在肺癌治疗中的潜在成功应用更加有趣。
Lung cancer is the most frequent cause of cancer-related death worldwide, with limited therapeutic options and rapid development of drug resistance. MicroRNAs, a class of small non-coding RNAs that control different physiological processes, have been associated with cancer development, as either oncomiRNAs or tumor-suppressor miRNAs. In the present study we investigated the interaction between mir-486-5p and mir-660-5p, two independent tumor-suppressor miRNAs, to assess their possible role and synergistic effect in lung cancer treatment. Our data show that mir-660-5p over-expression in A549 lung cancer cells induced a remarkable increase in mir-486-5p expression level and activity, detected as a reduction of its target gene, p85. mir-486-5p expression was confirmed by microRNA in situ hybridization. mir-660-5p modulated mir-486-5p through the silencing of Mouse Double Minute 2 (MDM2), one of its direct target, and then through p53 stimulation. This regulatory pathway was effective in A549, but not in H1299; therefore, only in the context of a functional p53 protein. Our findings support the conclusion that mir-486-5p is positively regulated by mir-660-5p in lung cancer cell lines, through the mir-660-MDM2-p53 pathway, making mir-660-5p even more interesting for its potential successful use in lung cancer therapy.