MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells
MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells
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DOI：
10.18632/oncotarget.5871
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Li, Gang
中科院分区：
文献类型：
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作者：
Guo, Xing;Xue, Hao;Li, Gang
人多形性胶质母细胞瘤（GBM）是一种以严重缺氧为特征的恶性实体瘤。自噬在缺氧条件下对癌细胞起保护作用。然而，在GBM中，低氧减少自噬的microRNA （miRNA）相关分子机制仍然知之甚少。在这项研究中，我们对GBM细胞进行了miRNA微阵列分析，发现在缺氧条件下，许多miRNA存在差异表达。进一步研究发现，miR224-3p作为显著下调的miRNAs之一，参与了缺氧诱导的GBM细胞自噬的调节。过表达miR224-3p可消除低氧诱导的自噬，而敲低内源性miR224-3p可增加常氧条件下的自噬活性。此外，我们发现miR224-3p通过直接抑制两个自噬相关基因（ATGs），即200 kDa的ATG5和FAK家族相互作用蛋白（FIP200）的表达来抑制自噬。此外，在体外实验中，miR224-3p可抑制细胞增殖，促进缺氧诱导的细胞凋亡；在体内实验中，miR224-3p过表达可抑制GBM细胞的肿瘤发生。总的来说，我们的研究发现了一种新的低氧下调miRNA miR224-3p，通过抑制GBM细胞中的ATGs，作为自噬的关键调节剂。
Human glioblastoma multiforme (GBM) is a malignant solid tumor characterized by severe hypoxia. Autophagy plays a protective role in cancer cells under hypoxia. However, the microRNA (miRNA)-related molecular mechanisms underlying hypoxia-reduced autophagy remain poorly understood in GBM. In this study, we performed a miRNA microarray analysis on GBM cells and found that numerous miRNAs were differentially expressed under hypoxic conditions. Further research showed that miR224-3p, one of the significantly down-regulated miRNAs, was involved in regulating hypoxia-induced autophagy in GBM cells. Overexpression of miR224-3p abolished hypoxia-induced autophagy, whereas knocking down endogenous miR224-3p increased autophagic activity under normoxia. In addition, we demonstrated that miR224-3p inhibited autophagy by directly suppressing the expression of two autophagy-related genes (ATGs), ATG5 and FAK family-interacting protein of 200 kDa (FIP200). Furthermore, in vitro, miR224-3p attenuated cell proliferation and promoted hypoxia-induced apoptosis, and in vivo, overexpression of miR224-3p inhibited tumorigenesis of GBM cells. Collectively, our study identified a novel hypoxia-down-regulated miRNA, miR224-3p, as a key modulator of autophagy by inhibiting ATGs in GBM cells.