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首页> 外文期刊>Cancer biology & therapy >MicroRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells
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MicroRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

机译：MicroRNA-17调节ATG7的表达并调节自噬过程，从而提高对胶质母细胞瘤细胞中替莫唑胺和小剂量电离辐射治疗的敏感性

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ATG7 is a key autophagy-promoting gene that plays a critical role in the regulation of cell death and survival of various cell types. We report here that microRNAs (miRNAs), a class of endogenous 22-24 nucleotide noncoding RNA molecules able to affect stability and translation of mRNA, may represent a novel mechanism for regulating ATG7 expression and therefore autophagy. We demonstrated that ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells. Treatment of these tumor cells with the miR-17 mimic decreased, and with the antagomir increased, the expression of ATG7 protein. Dual luciferase reporter assay confirmed that a specific miR-17 binding sequence in the 3'-UTR of ATG7 contributed to the modulation of the expression of the gene by miR-17. Interestingly, our results showed that anti-miR-17 administration activated autophagy through autophagosome formation, as resulted by LC3B and ATG7 protein expression increase, and by the analysis of GFP-LC3 positive autophagosome vesicles in living cells. Furthermore, the autophagy activation by antimiR- 17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells, while miR-17 modulation in U373-MG glioblastoma cells resulted in a sensitization to low ionizing radiation doses. Our study of the role of miR-17 in regulating ATG7 expression and autophagy reveals a novel function for this miRNA sequence in a critical cellular event with significant impacts in cancer development, progression and treatment.
机译：ATG7是一个关键的自噬促进基因，在各种细胞类型的细胞死亡和存活的调节中起着至关重要的作用。我们在这里报告，microRNA（miRNA），一类能够影响mRNA稳定性和翻译的内源性22-24核苷酸非编码RNA分子，可能代表调节ATG7表达并因此自噬的新机制。我们证明了ATG7是miR-17的潜在靶标，并且该miRNA可以负调控ATG7的表达，从而导致T98G胶质母细胞瘤细胞中自噬状态的调节。用miR-17模拟物处理这些肿瘤细胞会减少，而随着antagomir的处理，ATG7蛋白的表达会增加。双重荧光素酶报告基因测定证实，ATG7 3'-UTR中的特定miR-17结合序列有助于miR-17对基因表达的调节。有趣的是，我们的结果表明抗miR-17给药通过自噬小体形成激活了自噬，这是由于LC3B和ATG7蛋白表达增加以及对活细胞中GFP-LC3阳性自噬小泡的分析所致。此外，antimiR-17的自噬激活导致替莫唑胺剂量下的T98G细胞阈抗性降低，而U373-MG胶质母细胞瘤细胞中的miR-17调节导致对低电离辐射剂量的敏感性。我们对miR-17在调节ATG7表达和自噬中的作用的研究揭示了该miRNA序列在关键细胞事件中具有新功能，对癌症的发生，发展和治疗具有重大影响。

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