Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells
Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells
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DOI：
10.4161/auto.9064
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发表时间：
2009-08-16
期刊：
影响因子：
13.3
通讯作者：
Yang, Jin-Ming
中科院分区：
文献类型：
--
作者：
Zhu, Hua;Wu, Hao;Yang, Jin-Ming
beclin 1 是酵母 Atg6 的哺乳动物同源物，是一种关键的自噬促进基因，在调节细胞死亡和各类细胞的存活中发挥着关键作用。然而，最近的研究发现，beclin 1 的表达在某些疾病（包括癌症）中发生了改变。 beclin 1 异常表达的原因仍然很大程度上未知。我们在此报道，microRNA (miRNA) 是一类内源性 22-24 核苷酸非编码 RNA 分子，能够影响 mRNA 的稳定性和翻译，可能代表了一种以前未被认识的调节 beclin 1 表达和自噬的机制。我们证明beclin 1是miRNA miR-30a的潜在靶标，并且该miRNA可以负向调节beclin 1表达，导致自噬活性降低。用 miR-30a 模拟物处理肿瘤细胞后，beclin 1 mRNA 和蛋白的表达量减少，而 antagomir 则增加。双荧光素酶报告基因测定证实，beclin 1 3'-UTR 中的 miR-30a 结合序列有助于 miR-30a 对 beclin 1 表达的调节。此外，miR-30a 模拟物对 beclin 1 表达的抑制会减弱雷帕霉素诱导的自噬激活。我们对 miR-30a 在调节 beclin 1 表达和自噬中的作用的研究揭示了 miRNA 在关键细胞事件中的新功能，对癌症的发生、进展和治疗以及其他疾病具有重大影响。
beclin 1, the mammalian homologue of the yeast Atg6, is a key autophagy-promoting gene that plays a critical role in the regulation of cell death and survival of various types of cells. However, recent studies have observed that the expression of beclin 1 is altered in certain diseases including cancers. The causes underlying the aberrant expression of beclin 1 remain largely unknown. 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 previously unrecognized mechanism for regulating beclin 1 expression and autophagy. We demonstrated that beclin 1 is a potential target for miRNA miR-30a, and this miRNA could negatively regulate beclin 1 expression resulting in decreased autophagic activity. Treatment of tumor cells with the miR-30a mimic decreased, and with the antagomir increased, the expression of beclin 1 mRNA and protein. Dual luciferase reporter assay confirmed that the miR-30a binding sequences in the 3'-UTR of beclin 1 contribute to the modulation of beclin 1 expression by miR-30a. Furthermore, inhibition of beclin 1 expression by the miR-30a mimic blunted activation of autophagy induced by rapamycin. Our study of the role of miR-30a in regulating beclin 1 expression and autophagy reveals a novel function for miRNA in a critical cellular event with significant impacts in cancer development, progression and treatment, and in other diseases.