Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Sci Rep. 2012;2:808. doi: 10.1038/srep00808. Epub 2012 Nov 13.
We compared the expression levels of 307 miRNAs in six different B16F1 melanoma cell lines of differing malignant properties and found that the miR-290-295 cluster showed a strong upregulation in the more malignant B16F1 daughter cell lines. Its overexpression in B16F1 cells had no major effects on cell proliferation, migration or anchorage-independent growth, but conferred resistance to glucose starvation. This was mediated by miR-290-295-induced downregulation of several essential autophagy genes, including Atg7 and ULK1, which resulted in inhibition of autophagic cell death induced by glucose starvation. Similar effects were observed after knockdown of Atg7 or ULK1 in B16F1 melanoma cells, and after treatment with two chemical inhibitors of autophagy. Together, these results indicate that autophagy mediates cell death of melanoma cells under chronic nutrient deprivation, and they reveal an unanticipated role of the miR-290-295 cluster in conferring a survival advantage to melanoma cells by inhibiting autophagic cell death.
我们比较了 6 种不同恶性特性的 B16F1 黑色素瘤细胞系中 307 种 miRNA 的表达水平，发现 miR-290-295 簇在恶性程度更高的 B16F1 子细胞系中强烈上调。在 B16F1 细胞中过表达 miR-290-295 对细胞增殖、迁移或非锚定依赖性生长没有重大影响，但赋予了细胞对葡萄糖饥饿的抗性。这是通过 miR-290-295 诱导的几个必需自噬基因（包括 Atg7 和 ULK1）的下调介导的，导致葡萄糖饥饿诱导的自噬性细胞死亡受到抑制。在 B16F1 黑色素瘤细胞中敲低 Atg7 或 ULK1 以及用两种自噬化学抑制剂处理后，也观察到类似的效果。这些结果表明自噬介导了黑色素瘤细胞在慢性营养剥夺下的细胞死亡，并揭示了 miR-290-295 簇出人意料的作用，通过抑制自噬性细胞死亡，赋予黑色素瘤细胞生存优势。
